AbstractThe Apolipoprotein E (APOE) e4 allele is associated with reduced longevity and increased Coronary Artery Disease (CAD) and Alzheimer’s disease, with e4e4 having markedly larger effect sizes than e3e4. The e2 longevity promoting variant is less studied. We conducted a phenome-wide association study of ApoE e2e3 and e2e2 with aging phenotypes, to assess their potential as targets for anti-aging interventions. Data were from 379,000 UK Biobank participants, aged 40 to 70 years. e2e3 (n=46,535) had mostly lower lipid-related biomarker levels including reduced total and LDL-cholesterol, and lower risks of CAD (Odds Ratio=0.87, 95% CI: 0.83 to 0.90, p=4.92×10−14) and hypertension(OR=0.94, 95% CI: 0.92 to 0.97, p=7.28×10−7) versus e3e3. However, lipid changes in e2e2 (n=2,398) were more extreme, including a marked increase in triglyceride levels (0.41 Standard Deviations, 95% CI: 0.37 to 0.45, p=5.42×10−92), with no associated changes in CAD risks. There were no associations with biomarkers of kidney function. The effects of both e2e2 and e2e3 were minimal on falls, muscle mass, grip strength or frailty. In conclusion, e2e3 has protective effects on some health outcomes, but the effects of e2e2 are not similar, complicating the potential usefulness of e2 as a target for anti-aging intervention.

AbstractWith no known treatments or vaccine, COVID-19 presents a major threat, particularly to older adults, who account for the majority of severe illness and deaths. The age-related susceptibility is partly explained by increased comorbidities including dementia and type II diabetes [1]. While it is unclear why these diseases predispose risk, we hypothesize that increased biological age, rather than chronological age, may be driving disease-related trends in COVID-19 severity with age. To test this hypothesis, we applied our previously validated biological age measure (PhenoAge) [2] composed of chronological age and nine clinical chemistry biomarkers to data of 347,751 participants from a large community cohort in the United Kingdom (UK Biobank), recruited between 2006 and 2010. Other data included disease diagnoses (to 2017), mortality data (to 2020), and the UK national COVID-19 test results (to May 31, 2020) [3]. Accelerated aging 10-14 years prior to the start of the COVID-19 pandemic was associated with test positivity (OR=1.15 per 5-year acceleration, 95% CI: 1.08 to 1.21, p=3.2×10−6) and all-cause mortality with test-confirmed COVID-19 (OR=1.25, per 5-year acceleration, 95% CI: 1.09 to 1.44, p=0.002) after adjustment for demographics including current chronological age and pre-existing diseases or conditions. The corresponding areas under the curves were 0.669 and 0.803, respectively. Biological aging, as captured by PhenoAge, is a better predictor of COVID-19 severity than chronological age, and may inform risk stratification initiatives, while also elucidating possible underlying mechanisms, particularly those related to inflammaging.

BACKGROUND: Higher continuity of GP care (CGPC), that is, consulting the same doctor consistently, can improve doctor-patient relationships and increase quality of care; however, its effects on patients with dementia are mostly unknown. AIM: to estimate the associations between CGPC and potentially inappropriate prescribing (PIP), and with the incidence of adverse health outcomes (AHOs) in patients with dementia. DESIGN AND SETTING: a retrospective cohort study with 1 year of follow-up anonymised medical records from 9324 patients with dementia, aged ≥65 years living in England in 2016. METHOD: CGPC measures include the Usual Provider of Care (UPC), Bice-Boxerman Continuity of Care (BB), and Sequential Continuity (SECON) indices. Regression models estimated associations with PIPs and survival analysis with incidence of AHOs during the follow-up adjusted for age, sex, deprivation level, 14 comorbidities, and frailty. RESULTS: the highest quartile (HQ) of UPC (highest continuity) had 34.8% less risk of delirium (odds ratio [OR] 0.65, 95% confidence interval [CI] = 0.51 to 0.84), 57.9% less risk of incontinence (OR 0.42, 95% CI = 0.31 to 0.58), and 9.7% less risk of emergency admissions to hospital (OR 0.90, 95% CI = 0.82 to 0.99) compared with the lowest quartile. Polypharmacy and PIP were identified in 81.6% (n = 7612) and 75.4% (n = 7027) of patients, respectively. The HQ had fewer prescribed medications (HQ: mean 8.5, lowest quartile (LQ): mean 9.7, P

BACKGROUND: the iron overload condition hereditary hemochromatosis (HH) can cause liver cirrhosis and cancer, diabetes, and arthritis. Males homozygous for the p.C282Y missense mutation in the Homeostatin Iron Regulator (HFE) gene have greatest risk; yet, only a minority develop these conditions. We aimed to determine whether common genetic variants influencing iron levels or liver disease risk in the general population also modify clinical penetrance in HFE p.C282Y and p.H63D carriers. METHODS: We studied 1294 male and 1596 female UK Biobank HFE p.C282Y homozygous participants of European ancestry with medical records up to 14 years after baseline assessment. Polygenic scores quantified genetic effects of blood iron biomarkers and relevant diseases (identified in the general population). Analyses were also performed in other HFE p.C282Y/p.H63D genotype groups. RESULTS: in male p.C282Y homozygotes, a higher iron polygenic score increased the risk of liver fibrosis or cirrhosis diagnoses (odds ratio for the top 20% of iron polygenic score vs. the bottom 20% = 4.90: 95% confidence intervals, 1.63-14.73; p = 0.005), liver cancer, and osteoarthritis but not diabetes. A liver cirrhosis polygenic score was associated with liver cancer diagnoses. In female p.C282Y homozygotes, the osteoarthritis polygenic score was associated with increased osteoarthritis diagnoses and type-2 diabetes polygenic score with diabetes. However, the iron polygenic score was not robustly associated with diagnoses in p.C282Y female homozygotes or in other p.C282Y/p.H63D genotypes. CONCLUSIONS: HFE p.C282Y homozygote penetrance to clinical disease in a large community cohort was partly explained by common genetic variants that influence iron and risks of related diagnoses in the general population, including polygenic scores in HH screening and diagnosis, may help in estimating prognosis and treatment planning.

Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) meta-analysis of a frailty index in European descent UK Biobank participants (n = 164,610, 60-70 years) and Swedish TwinGene participants (n = 10,616, 41-87 years). FI calculation was based on 49 or 44 self-reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene, respectively. 14 loci were associated with the FI (p 

Abstract
.
. Background
. Age and disease prevalence are the 2 biggest risk factors for Coronavirus disease 2019 (COVID-19) symptom severity and death. We therefore hypothesized that increased biological age, beyond chronological age, may be driving disease-related trends in COVID-19 severity.
.
.
. Methods
. Using the UK Biobank England data, we tested whether a biological age estimate (PhenoAge) measured more than a decade prior to the COVID-19 pandemic was predictive of 2 COVID-19 severity outcomes (inpatient test positivity and COVID-19-related mortality with inpatient test-confirmed COVID-19). Logistic regression models were used with adjustment for age at the pandemic, sex, ethnicity, baseline assessment centers, and preexisting diseases/conditions.
.
.
. Results
. Six hundred and thirteen participants tested positive at inpatient settings between March 16 and April 27, 2020, 154 of whom succumbed to COVID-19. PhenoAge was associated with increased risks of inpatient test positivity and COVID-19-related mortality (ORMortality = 1.63 per 5 years, 95% CI: 1.43–1.86, p = 4.7 × 10−13) adjusting for demographics including age at the pandemic. Further adjustment for preexisting diseases/conditions at baseline (ORM = 1.50, 95% CI: 1.30–1.73 per 5 years, p = 3.1 × 10−8) and at the early pandemic (ORM = 1.21, 95% CI: 1.04–1.40 per 5 years, p =. 011) decreased the association.
.
.
. Conclusions
. PhenoAge measured in 2006–2010 was associated with COVID-19 severity outcomes more than 10 years later. These associations were partly accounted for by prevalent chronic diseases proximate to COVID-19 infection. Overall, our results suggest that aging biomarkers, like PhenoAge may capture long-term vulnerability to diseases like COVID-19, even before the accumulation of age-related comorbid conditions.
.

AbstractLow muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1p = 4 × 10−17), arthritis (GDF5p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.

Background: Brain iron deposition occurs in dementia. In European ancestry populations, the HFE p.C282Y variant can cause iron overload and hemochromatosis, mostly in homozygous males. Objective: to estimate p.C282Y associations with brain MRI features plus incident dementia diagnoses during follow-up in a large community cohort. Methods: UK Biobank participants with follow-up hospitalization records (mean 10.5 years). MRI in 206 p.C282Y homozygotes versus 23,349 without variants, including T2. measures (lower values indicating more iron). Results: European ancestry participants included 2,890 p.C282Y homozygotes. Male p.C282Y homozygotes had lower T2. measures in areas including the putamen, thalamus, and hippocampus, compared to no HFE mutations. Incident dementia was more common in p.C282Y homozygous men (Hazard Ratio HR = 1.83; 95% CI 1.23 to 2.72, p = 0.003), as was delirium. There were no associations in homozygote women or in heterozygotes. Conclusion: Studies are needed of whether early iron reduction prevents or slows related brain pathologies in male HFE p.C282Y homozygotes.

IMPORTANCE: treatment of dementia in individuals with comorbidities is complex, leading to potentially inappropriate prescribing (PIP). The impact of PIP in this population is unknown. OBJECTIVE: to estimate the rate of PIP and its effect on adverse health outcomes (AHO). DESIGN: retrospective cohort. SETTING: primary care electronic health records linked to hospital discharge data from England. SUBJECTS: 11,175 individuals with dementia aged over 65 years in 2016 and 43,463 age- and sex-matched controls. METHODS: Screening Tool of Older Persons' Prescriptions V2 defined PIP. Logistic regression tested associations with comorbidities at baseline, and survival analyses risk of incident AHO, adjusted for age, gender, deprivation and 14 comorbidities. RESULTS: the dementia group had increased risk of PIP (73% prevalence; odds ratio [OR]: 1.92; confidence interval [CI]: 83-103%; P 

In this paper we review the methodological underpinnings of the general pharmacogenetic approach for uncovering genetically-driven treatment effect heterogeneity. This typically utilises only individuals who are treated and relies on fairly strong baseline assumptions to estimate what we term the ‘genetically moderated treatment effect’ (GMTE). When these assumptions are seriously violated, we show that a robust but less efficient estimate of the GMTE that incorporates information on the population of untreated individuals can instead be used. In cases of partial violation, we clarify when Mendelian randomization and a modified confounder adjustment method can also yield consistent estimates for the GMTE. A decision framework is then described to decide when a particular estimation strategy is most appropriate and how specific estimators can be combined to further improve efficiency. Triangulation of evidence from different data sources, each with their inherent biases and limitations, is becoming a well established principle for strengthening causal analysis. We call our framework ‘Triangulation WIthin a STudy’ (TWIST)’ in order to emphasise that an analysis in this spirit is also possible within a single data set, using causal estimates that are approximately uncorrelated, but reliant on different sets of assumptions. We illustrate these approaches by re-analysing primary-care-linked UK Biobank data relating to CYP2C19 genetic variants, Clopidogrel use and stroke risk, and data relating to APOE genetic variants, statin use and Coronary Artery Disease.

BACKGROUND: Extensive work in basic and clinical science suggests that biological mechanisms of aging are causally related to the development of disease and disability in late life. Modulation of the biological mechanisms of aging can extend both life span and health span in animal models, but translation to humans has been slow. METHODS: Summary of workshop proceedings from the 2018-2019 Epidemiology of Aging Workshop hosted by the Intramural Research Program at the National Institute on Aging. RESULTS: Epidemiologic studies play a vital role to progress in this field, particularly in evaluating new risk factors and measures of biologic aging that may influence health span, as well as developing relevant outcome measures that are robust and relevant for older individuals. CONCLUSIONS: Appropriately designed epidemiological studies are needed to identify targets for intervention and to inform study design and sample size estimates for future clinical trials designed to promote health span.

BACKGROUND: Blood pressure (BP) management in frail older people is challenging. An randomised controlled trial of largely non-frail older people found cardiovascular and mortality benefit with systolic (S) BP target 150 mmHg. Associations with mortality varied between non-frail

Background: Fatigability is a construct that measures whole-body tiredness anchored to activities of a fixed intensity and duration; little is known about its epidemiology and heritability. Methods: Two generations of family members enriched for exceptional longevity and their spouses were enrolled (2006-2009) in the Long Life Family Study (LLFS). At Visit 2 (2014-2017, N = 2,355) perceived physical fatigability was measured using the 10-item self-administered Pittsburgh Fatigability Scale (PFS), along with demographic, medical, behavioral, physical, and cognitive risk factors. Results: Residual genetic heritability of fatigability was 0.263 (p = 6.6 × 10-9) after adjustment for age, sex, and field center. PFS physical scores (mean ± SD) and higher physical fatigability prevalence (% PFS = 15) were greater with each age strata: 60-69 (n = 1,009, 11.0 ± 7.6, 28%), 70-79 (n = 847, 12.5 ± 8.1, 37%), 80-89 (n = 253, 19.3 ± 9.9, 65.2%), and 90-108 (n = 266, 28.6 ± 9.8, 89.5%), p

In the article, the Longevity-Associated SH2B3 (LNK) Genetic Variant: Selected Aging Phenotypes in 379,758 Subjects, the first two sentences of the Funding section have been updated to the following: This study was partly funded by an award to D.M. by the UK Medical Research Council (MR/M023095/1) and an Intergovernmental Personnel Act agreement (20170526) by the Intramural research Program of the NIH, National institute on Aging.

BACKGROUND: Whereas the independent effects of biomarkers, including 25-hydroxy vitamin D (25(OH)D), insulin-like growth factor 1, C-reactive protein, and interleukin 6 (IL-6), on gait speed in older adults have been evaluated, their joint effects on gait speed are not well understood. METHODS: Study subjects aged at least 65 at baseline (N = 970) were enrolled in the population-based Invecchiare in Chianti (InCHIANTI) study from 1998 to 2000 and were followed up at 3 and 6 years. All above biomarkers and gait speed data were measured at each of the three time points. Using a generalized estimating equation approach, we determined if slow gait speed (

IMPORTANCE: risk factors for delirium in hospital inpatients are well established, but less is known about whether delirium occurring in the community or during an emergency admission to hospital care might be predicted from routine primary-care records. OBJECTIVES: identify risk factors in primary-care electronic health records (PC-EHR) predictive of delirium occurring in the community or recorded in the initial episode in emergency hospitalisation. Test predictive performance against the cumulative frailty index. DESIGN: Stage 1: case-control; Stages 2 and 3: retrospective cohort. SETTING: clinical practice research datalink: PC-EHR linked to hospital discharge data from England. SUBJECTS: Stage 1: 17,286 patients with delirium aged ≥60 years plus 85,607 controls. Stages 2 and 3: patients ≥ 60 years (n = 429,548 in 2015), split into calibration and validation groups. METHODS: Stage 1: logistic regression to identify associations of 110 candidate risk measures with delirium. Stage 2: calibrating risk factor weights. Stage 3: validation in independent sample using area under the curve (AUC) receiver operating characteristic. RESULTS: fifty-five risk factors were predictive, in domains including: cognitive impairment or mental illness, psychoactive drugs, frailty, infection, hyponatraemia and anticholinergic drugs. The derived model predicted 1-year incident delirium (AUC = 0.867, 0.852:0.881) and mortality (AUC = 0.846, 0.842:0.853), outperforming the frailty index (AUC = 0.761, 0.740:0.782). Individuals with the highest 10% of predicted delirium risk accounted for 55% of incident delirium over 1 year. CONCLUSIONS: a risk factor model for delirium using data in PC-EHR performed well, identifying individuals at risk of new onsets of delirium. This model has potential for supporting preventive interventions.

BACKGROUND: Aging is characterized by chronic inflammation plus loss of muscle mass and strength, termed sarcopenia. Human leukocyte antigen (HLA) types are drivers of autoimmune disease, although with limited penetrance. We tested whether autoimmune diagnoses are associated with sarcopenia, and whether HLA types and related genetic variants are associated with sarcopenia in autoimmune disease-free older people. METHODS: Data were collected from 181,301 UK Biobank European descent volunteers aged 60-70 with measured hand grip strength and impedance. Logistic regression analysis estimated HLA type and sarcopenia associations, adjusted for confounders and multiple testing. RESULTS: Having any autoimmune diagnosis was associated with sarcopenia (odds ratio [OR] 1.83, 95% confidence interval (CI) 1.74-1.92, p = 4.0*10-125). After excluding autoimmune diagnoses, 6 of 100 HLA types (allele frequency >1%) were associated with sarcopenia (low grip strength and muscle mass). Having two HLA-DQA1*03:01 alleles increased odds of sarcopenia by 19.3% (OR 1.19, CI 1.09-1.29, p = 2.84*10-5), compared to no alleles. Having ≥6 of the 12 HLA alleles increased sarcopenia odds by 23% (OR 1.23, CI 1.12-1.35, p = 7.28*10-6). of 658 HLA region non-coding genetic variants previously implicated in disease, 4 were associated with sarcopenia, including rs41268896 and rs29268645 (OR 1.08, CI 1.05-1.11, p = 1.06*10-8 and 1.07, CI 1.04-1.09, p = 1.5*10-6, respectively). Some HLA associations with sarcopenia were greater in female participants. CONCLUSION: Autoimmune diagnoses are strongly associated with sarcopenia in 60- to 70-year olds. Variation in specific HLA types and non-coding single nucleotide polymorphisms is also associated with sarcopenia in older carriers free of diagnosed autoimmune diseases. Patients with sarcopenia might benefit from targeted treatment of autoimmune processes.

Human SH2B3 is involved in growth factor and inflammation signaling. A SH2B3 missense variant (rs3184504) is associated with cardiovascular diseases plus breast, colorectal, and lung cancers, with highly correlated variants across the ATXN2/SH2B3/BRAP locus linked to parental age at death, suggesting a geroscience common mechanism of aging and disease. To better understand the SH2B3-related aging pathway and its potential as an intervention target, we undertook a phenotype-wide association study (PheWAS) of 52 aging traits. Data were obtained from 379,758 European-descent UK Biobank participants, aged 40-70 at baseline: 27% of participants were CC homozygotes and 23% TT at rs3184504. Parental extreme longevity (mothers aged ≥98 years, fathers aged ≥96 years) was more common in CC versus TT (odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.07 to 1.29) with an additive per allele effect. The C allele associated with better cognitive function and white blood cell counts were more likely to be normal. The C allele reduced risks of coronary heart disease (OR = 0.95, 95% CI: 0.93 to 0.96) but was also associated with a modestly higher cancer rate (OR = 1.03, 95% CI: 1.02 to 1.04), suggesting a trade-off across aging outcomes and limiting its potential as an anti-aging target.

A few studies report that parental longevity is associated with preserved cognition and physical function and lower risk of Alzheimer’s disease. However, data on structural neuroimaging correlates of parental longevity and its spatial distribution are limited. This study aims to examine relationships of parental longevity with regional brain structure and to explore sex differences. We identified 12,970 UK Biobank participants (mean age = 64.4, 51.5%women) with data on parental longevity, regional gray matter volumes, and white matter microstructure. Participants were categorized based on whether at least one parent lived to age 85 or older or neither parent survived to age 85. Associations of parental longevity, maternal, and paternal longevity with each neuroimaging marker of interest were examined using linear regression, adjusted for demographics, APOE e4 status, lifestyle, and cardiometabolic conditions. Compared to participants whose both parents died before 85 (43%), those with at least one parent surviving to 85 (57%) had greater volumes in hippocampus, parahippocampal gyrus, middle temporal lobe, and primary sensorimotor cortex and had lower mean diffusivity in posterior thalamic radiation and uncinate fasciculus. Associations were prominent with maternal longevity. Adjustment for cardiometabolic conditions did not affect observed associations except mean diffusivity in posterior thalamic radiation. There were no structural differences in other areas. Parental longevity is associated with preserved brain structure localized in primary sensorimotor cortex and temporal areas including hippocampus. These relationships are prominent with maternal longevity. Longitudinal studies are needed to determine whether changes in these brain structures account for the association between parental longevity and dementia.

Background: Incidence rates of dementia appear to be declining in high-income countries according to several large epidemiological studies. We aimed to describe declining incident dementia rates across successive birth cohorts in a U.S. population-based sample and to explore the influences of sex and education on these trends. Methods: We pooled data from two community-sampled prospective cohort studies with similar study aims and contiguous sampling regions: the Monongahela Valley Independent Elders Survey (1987-2001) and the Monongahela-Youghiogheny Healthy Aging Team (2006-Ongoing). We identified four decade-long birth cohorts spanning birth years 1902-1941. In an analysis sample of 3,010 participants (61% women, mean baseline age = 75.7 years, mean follow-up = 7.1 years), we identified 257 cases of incident dementia indicated by a Clinical Dementia Rating of 1.0 or higher. We used Poisson regression to model incident dementia rates by birth cohort, age, sex, education, and interactions of Sex × Cohort and Sex × Education. We further examined whether cohort effects varied by education, testing a Cohort × Education interaction and stratifying the models by education. Results: Compared to the earliest birth cohort (1902-1911), each subsequent cohort had a significantly lower incident dementia rate (1912-1921: Incidence rate ratio [IRR] = 0.655, 95% confidence interval [95% CI] = 0.477-0.899; 1922-1931: IRR = 0.387, 95% CI = 0.265-0.564; 1932-1941: IRR = 0.233, 95% CI = 0.121-0.449). We observed no significant interactions of either sex or education with birth cohort. Conclusions: a decline in incident dementia rates was observed across successive birth cohorts independent of sex, education, and age.

Inherited genetic variation influencing leukocyte telomere length provides a natural experiment for testing associations with health outcomes, more robust to confounding and reverse causation than observational studies. We tested associations between genetically determined telomere length and aging-related health outcomes in a large European ancestry older cohort. Data were from n = 379,758 UK Biobank participants aged 40-70, followed up for mean of 7.5 years (n = 261,837 participants aged 60 and older by end of follow-up). Thirteen variants strongly associated with longer telomere length in peripheral white blood cells were analyzed using Mendelian randomization methods with Egger plots to assess pleiotropy. Variants in TERC, TERT, NAF1, OBFC1, and RTEL1 were included, and estimates were per 250 base pairs increase in telomere length, approximately equivalent to the average change over a decade in the general white population. We highlighted associations with false discovery rate-adjusted p-values smaller than .05. Genetically determined longer telomere length was associated with lowered risk of coronary heart disease (CHD; OR = 0.95, 95% CI: 0.92-0.98) but raised risk of cancer (OR = 1.11, 95% CI: 1.06-1.16). Little evidence for associations were found with parental lifespan, centenarian status of parents, cognitive function, grip strength, sarcopenia, or falls. The results for those aged 60 and older were similar in younger or all participants. Genetically determined telomere length was associated with increased risk of cancer and reduced risk of CHD but little change in other age-related health outcomes. Telomere lengthening may offer little gain in later-life health status and face increasing cancer risks.

Dysregulation of splicing factor expression is emerging as a driver of human ageing; levels of transcripts encoding splicing regulators have previously been implicated in ageing and cellular senescence both in vitro and in vivo. We measured the expression levels of an a priori panel of 20 age- or senescence-associated splicing factors by qRT-PCR in peripheral blood samples from the InCHIANTI Study of Aging, and assessed longitudinal relationships with human ageing phenotypes (cognitive decline and physical ability) using multivariate linear regression. AKAP17A, HNRNPA0 and HNRNPM transcript levels were all predictively associated with severe decline in MMSE score (p = 0.007, 0.001 and 0.008 respectively). Further analyses also found expression of these genes was associated with a performance decline in two other cognitive measures; the Trail Making Test and the Purdue Pegboard Test. AKAP17A was nominally associated with a decline in mean hand-grip strength (p = 0.023), and further analyses found nominal associations with two other physical ability measures; the Epidemiologic Studies of the Elderly-Short Physical Performance Battery and calculated speed (m/s) during a timed 400 m fast walking test. These data add weight to the hypothesis that splicing dyregulation may contribute to the development of some ageing phenotypes in the human population.

IMPORTANCE There is mixed evidence that blood pressure (BP) stabilizes or decreases in later life. It is also unclear whether BP trajectories reflect advancing age, proximity to end of life, or selective survival of persons free from hypertension. OBJECTIVE to estimate individual patient BP for each of the 20 years before death and identify potential mechanisms that may explain trajectories. DESIGN, STUDY, AND PARTICIPANTS We analyzed population-based Clinical Practice Research Datalink primary care and linked hospitalization electronic medical records from the United Kingdom, using retrospective cohort approaches with generalized linear mixed-effects modeling. Participants were all available individuals with BP measures over 20 years, yielding 46 634 participants dying aged at least 60 years, from 2010 to 2014. We also compared BP slopes from 10 to 3 years before death for 20 207 participants who died, plus 20 207 birth-year and sex-matched participants surviving longer than 9 years. MAIN OUTCOMES AND MEASURES Clinically recorded individual patient repeated systolic BP (SBP) and diastolic BP (DBP). RESULTS in 46 634 participants (51.7% female; mean [SD] age at death, 82.4 [9.0] years), SBPs and DBPs peaked 18 to 14 years before death and then decreased progressively. Mean changes in SBP from peak values ranged from -8.5 mm Hg (95% CI, -9.4 to -7.7) for those dying aged 60 to 69 years to -22.0 mm Hg (95% CI, -22.6 to -21.4) for those dying at 90 years or older; overall, 64.0% of individuals had SBP changes of greater than -10 mm Hg. Decreases in BP appeared linear from 10 to 3 years before death, with steeper decreases in the last 2 years of life. Decreases in SBP from 10 to 3 years before death were present in individuals not treated with antihypertensive medications, but mean yearly changes were steepest in patients with hypertension (-1.58; 95% CI, -1.56 to -1.60 mm Hg vs -0.70; 95% CI, -0.65 to -0.76 mm Hg), dementia (-1.81; 95% CI, -1.77 to -1.87 mm Hg vs -1.41; 95% CI, -1.38 to -1.43 mm Hg), heart failure (-1.66; 95% CI, -1.62 to -1.69 mm Hg vs -1.37; 95% CI, -1.34 to -1.39 mm Hg), and late-life weight loss. CONCLUSIONS AND RELEVANCE Mean SBP and DBP decreased for more than a decade before death in patients dying at 60 years and older. These BP decreases are not simply attributable to age, treatment of hypertension, or better survival without hypertension. Late-life BP decreases may have implications for risk estimation, treatment monitoring, and trial design.

OBJECTIVES: to estimate associations between long-term use of proton pump inhibitors (PPIs) and pneumonia incidence in older adults in primary care. DESIGN: Longitudinal analyses of electronic medical records. SETTING: England PARTICIPANTS: Individuals aged 60 and older in primary care receiving PPIs for 1 year or longer (N=75,050) and age- and sex-matched controls (N=75,050). MEASUREMENTS: Net hazard ratios for pneumonia incidence in Year 2 of treatment were estimated using the prior event rate ratio (PERR), which adjusts for pneumonia incidence differences before initiation of treatment. Inverse probability weighted models adjusted for 78 demographic, disease, medication, and healthcare usage measures. RESULTS: During the second year after initiating treatment, PPIs were associated with greater hazard of incident pneumonia (PERR-adjusted hazard ratio=1.82, 95% confidence interval=1.27-2.54), accounting for pretreatment pneumonia rates. Estimates were similar across age and comorbidity subgroups. Similar results were also obtained from propensity score- and inverse probability-weighted models. CONCLUSION: in a large cohort of older adults in primary care, PPI prescription was associated with greater risk of pneumonia in the second year of treatment. Results were robust across alternative analysis approaches. Controversies about the validity of reported short-term harms of PPIs should not divert attention from potential long-term effects of PPI prescriptions on older adults.

Higher Red Blood Cell Distribution Width (RDW or anisocytosis) predicts incident coronary artery disease (CAD) plus all-cause and cardiovascular mortality, but its predictive value for other common diseases in healthy volunteers is less clear. We aimed to determine the shorter and longer term associations between RDW and incident common conditions in participants free of baseline disease, followed for 9 years. We undertook a prospective analysis of RDW% using 240,477 healthy UK Biobank study volunteers aged 40–70 years at baseline, with outcomes ascertained during follow-up (9 years). Participants were free of anemia, CAD, type-2 diabetes, stroke, hypertension, COPD, and any cancer (except non-melanoma skin cancer) at baseline. Survival models (with competing Hazards) tested associations with outcomes from hospital admission records and death certificates. High RDW (15% variation, n = 6,050) compared to low (

Coronary heart disease (CHD) is a leading cause of morbidity in people over 65 years of age; >40% of all deaths are due to this condition. The association between increasing age and CHD is well documented; the accumulation of senescent cells in cardiac and vascular tissues may represent one factor underpinning this observation. We aimed to identify senescence-related expression changes in primary human senescent cardiomyocytes and endothelial cells and to relate transcript expression in peripheral blood leucocytes to prevalent and incident CHD in the InCHIANTI study of aging. We quantified splicing factor expression and splicing patterns of candidate transcripts in proliferative and senescent later passage endothelial cells and cardiomyocytes using qRTPCR. Senescence-associated isoforms also expressed in peripheral blood leucocytes were then examined for associations with CHD status in 134 pairs of age, sex and BMI-matched CHD cases and controls. Splicing factor expression was dysregulated in senescent cardiomyocytes, as previously reported for endothelial cells, as was the expression of alternatively expressed cardiac and vascular candidate genes in both cell types. We found nominal associations between the expression of VEGFA156b and FNI-EIIIIA isoforms in peripheral blood mRNA and CHD status. Dysregulated splicing factor expression is a key feature of senescent cardiomyocytes and endothelial cells. Altered splicing of key cardiac or endothelial genes may contribute to the risk of CHD in the human population.

Importance: Delirium is associated with accelerated cognitive decline. The pathologic substrates of this association are not yet known, that is, whether they are the same as those associated with dementia, are independent, or are interrelated. Objective: to examine whether the accelerated cognitive decline observed after delirium is independent of the pathologic processes of classic dementia. Design, setting, and participants: Harmonized data from 987 individual brain donors from 3 observational cohort studies with population-based sampling (Vantaa 85+, Cambridge City Over-75s Cohort, Cognitive Function and Ageing Study) performed from January 1, 1985, through December 31, 2011, with a median follow-up of 5.2 years until death, were used in this study. Neuropathologic assessments were performed with investigators masked to clinical data. Data analysis was performed from January 1, 2012, through December 31, 2013. Clinical characteristics of brain donors were not different from the rest of the cohort. Outcome ascertainment was complete given that the participants were brain donors. Exposures: Delirium (never vs ever) and pathologic burden of neurofibrillary tangles, amyloid plaques, vascular lesions, and Lewy bodies. Effects modeled using random-effects linear regression and interactions between delirium and pathologic burden were assessed. Outcomes: Change in Mini-Mental State Examination (MMSE) scores during the 6 years before death. Results: There were 987 participants (290 from Vantaa 85+, 241 from the Cambridge City Over-75s Cohort, and 456 from the Cognitive Function and Ageing Study) with neuropathologic data; mean (SD) age at death was 90 (6.4) years, including 682 women (69%). The mean MMSE score 6 years before death was 24.7 points. The 279 individuals with delirium (75%women) had worse initial scores (-2.8 points; 95%CI, -4.5 to -1.0; P <. 001). Cognitive decline attributable to delirium was -0.37 MMSE points per year (95%CI, -0.60 to -0.13; P <. 001). Decline attributable to the pathologic processes of dementia was -0.39 MMSE points per year (95%CI, -0.57 to -0.22; P <. 001). However, the combination of delirium and the pathologic processes of dementia resulted in the greatest decline, in which the interaction contributed an additional -0.16 MMSE points per year (95%CI, -0.29 to -0.03; P =. 01). The multiplicative nature of these variables resulted in individuals with delirium and the pathologic processes of dementia declining 0.72 MMSE points per year faster than age-, sex-, and educational level-matched controls. Conclusions and relevance: Delirium in the presence of the pathologic processes of dementia is associated with accelerated cognitive decline beyond that expected for delirium or the pathologic process itself. These findings suggest that additional unmeasured pathologic processes specifically relate to delirium. Age-related cognitive decline has many contributors, and these findings at the population level support a role for delirium acting independently and multiplicatively to the pathologic processes of classic dementia.

Background: for older groups, being overweight [body mass index (BMI; in kg/m2): 25 to

BACKGROUND: Having longer lived parents has been shown to be an important predictor of health trajectories and life span. As such, parental life span is an important phenotype that may uncover genes that affect longevity. METHODS: a genome-wide association study of parental life span in participants of European and African ancestry from the Health and Retirement Study was conducted. RESULTS: a genome-wide significant association was observed for rs35715456 (log10BF = 6.3) on chromosome 18 for the dichotomous trait of having at least one long-lived parent versus not having any long-lived parent. This association was not replicated in an independent sample from the InCHIANTI and Framingham Heart Study. The most significant association among single nucleotide polymorphisms in longevity candidate genes (APOE, MINIPP1, FOXO3, EBF1, CAMKIV, and OTOL1) was observed in the EBF1 gene region (rs17056207, p =. 0002). CONCLUSIONS: a promising genetic signal for parental life span was identified but was not replicated in independent samples.

We undertook a genome-wide association study (GWAS) of parental longevity in European descent UK Biobank participants. For combined mothers' and fathers' attained age, 10 loci were associated (p

MicroRNAs (miRNAs) are small non-coding RNA species that have been shown to have roles in multiple processes that occur in higher eukaryotes. They act by binding to specific sequences in the 3' untranslated region of their target genes and causing the transcripts to be degraded by the RNA-induced silencing complex (RISC). MicroRNAs have previously been reported to demonstrate altered expression in several aging phenotypes such as cellular senescence and age itself. Here, we have measured the expression levels of 521 small regulatory microRNAs (miRNAs) in spleen tissue from young and old animals of 6 mouse strains with different median strain lifespans by quantitative real-time PCR. Expression levels of 3 microRNAs were robustly associated with strain lifespan, after correction for multiple statistical testing (miR-203-3p [β-coefficient = -0.6447, p = 4.8 × 10-11], miR-664-3p [β-coefficient = 0.5552, p = 5.1 × 10-8] and miR-708-5p [β-coefficient = 0.4986, p = 1.6 × 10-6]). Pathway analysis of binding sites for these three microRNAs revealed enrichment of target genes involved in key aging and longevity pathways including mTOR, FOXO and MAPK, most of which also demonstrated associations with longevity. Our results suggests that miR-203-3p, miR-664-3p and miR-708-5p may be implicated in pathways determining lifespan in mammals.

INTRODUCTION: Variability in red blood cell volumes (distribution width, RDW) increases with age and is strongly predictive of mortality, incident coronary heart disease and cancer. We investigated inherited genetic variation associated with RDW in 116,666 UK Biobank human volunteers. RESULTS: a large proportion RDW is explained by genetic variants (29%), especially in the older group (60+ year olds, 33.8%,

BACKGROUND: Inorganic nitrate from the oxidation of endogenously synthesized nitric oxide (NO) or consumed in the diet can be reduced to NO via a complex enterosalivary circulation pathway. The relationship between total nitrate exposure by measured urinary nitrate excretion and blood pressure in a large population sample has not been assessed previously. METHODS: for this cross-sectional study, 24-hour urinary nitrate excretion was measured by spectrophotometry in the 919 participants from the InChianti cohort at baseline and blood pressure measured with a mercury sphygmomanometer. RESULTS: After adjusting for age and sex only, diastolic blood pressure was 1.9 mm Hg lower in subjects with ≥2 mmol urinary nitrate excretion compared with those excreting

BACKGROUND: There is limited evidence on statin risk and effectiveness for patients aged 80+. We estimated risk of recurrent myocardial infarction, muscle-related and other adverse events, and statin-related incremental costs in "real-world" older patients treated with statins versus no statins. METHODS: We used primary care electronic medical records from the UK Clinical Practice Research Datalink. Subhazard ratios (competing risk of death) for myocardial infarction recurrence (primary end point), falls, fractures, ischemic stroke, and dementia, and hazard ratios (Cox) for all-cause mortality were used to compare older (60+) statin users and 1:1 propensity-score-matched controls (n = 12,156). Participants were followed-up for 10 years. RESULTS: Mean age was 76.5±9.2 years; 45.5% were women. Statins were associated with near significant reduction in myocardial infarction recurrence (subhazard ratio = 0.84, 0.69-1.02, p =. 073), with protective effect in the 60-79 age group (0.73, 0.57-0.94) but a nonsignificant result in the 80+ group (1.06, 0.78-1.44; age interaction p =. 094). No significant associations were found for stroke or dementia. Data suggest an increased risk of falls (1.36, 1.17-1.60) and fractures (1.33, 1.04-1.69) in the first 2 years of treatment, particularly in the 80+ group. Treatment was associated with lower all-cause mortality. Statin use was associated with health care cost savings in the 60-79 group but higher costs in the 80+ group. CONCLUSIONS: Estimates of statin effectiveness for the prevention of recurrent myocardial infarction in patients aged 60-79 years were similar to trial results, but more evidence is needed in the older group. There may be an excess of falls and fractures in very old patients, which deserves further investigation.

BACKGROUND: Altered expression of mRNA splicing factors occurs with ageing in vivo and is thought to be an ageing mechanism. The accumulation of senescent cells also occurs in vivo with advancing age and causes much degenerative age-related pathology. However, the relationship between these two processes is opaque. Accordingly we developed a novel panel of small molecules based on resveratrol, previously suggested to alter mRNA splicing, to determine whether altered splicing factor expression had potential to influence features of replicative senescence. RESULTS: Treatment with resveralogues was associated with altered splicing factor expression and rescue of multiple features of senescence. This rescue was independent of cell cycle traverse and also independent of SIRT1, SASP modulation or senolysis. Under growth permissive conditions, cells demonstrating restored splicing factor expression also demonstrated increased telomere length, re-entered cell cycle and resumed proliferation. These phenomena were also influenced by ERK antagonists and agonists. CONCLUSIONS: This is the first demonstration that moderation of splicing factor levels is associated with reversal of cellular senescence in human primary fibroblasts. Small molecule modulators of such targets may therefore represent promising novel anti-degenerative therapies.

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.

Cigarette smoking is a leading modifiable cause of death worldwide. We hypothesized that cigarette smoking induces extensive transcriptomic changes that lead to target-organ damage and smoking-related diseases. We performed a meta-analysis of transcriptome-wide gene expression using whole blood-derived RNA from 10,233 participants of European ancestry in six cohorts (including 1421 current and 3955 former smokers) to identify associations between smoking and altered gene expression levels. At a false discovery rate (FDR) 

Dysregulation of splicing factor expression and altered alternative splicing are associated with aging in humans and other species, and also with replicative senescence in cultured cells. Here, we assess whether expression changes of key splicing regulator genes and consequent effects on alternative splicing are also associated with strain longevity in old and young mice, across 6 different mouse strains with varying lifespan (A/J, NOD.B10Sn-H2(b) /J, PWD.Phj, 129S1/SvlmJ, C57BL/6J and WSB/EiJ). Splicing factor expression and changes to alternative splicing were associated with strain lifespan in spleen and to a lesser extent in muscle. These changes mainly involved hnRNP splicing inhibitor transcripts with most changes more marked in spleens of young animals from long-lived strains. Changes in spleen isoform expression were suggestive of reduced cellular senescence and retained cellular proliferative capacity in long-lived strains. Changes in muscle isoform expression were consistent with reduced pro-inflammatory signalling in longer-lived strains. Two splicing regulators, HNRNPA1 and HNRNPA2B1, were also associated with parental longevity in humans, in the InCHIANTI aging study. Splicing factors may represent a driver, mediator or early marker of lifespan in mouse, as expression differences were present in the young animals of long-lived strains. Changes to alternative splicing patterns of key senescence genes in spleen and key remodelling genes in muscle suggest that correct regulation of alternative splicing may enhance lifespan in mice. Expression of some splicing factors in humans was also associated with parental longevity, suggesting that splicing regulation may also influence lifespan in humans.

BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P 

Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10-9), independent of chronological age, even after adjusting for additional risk factors (p

BACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. METHODS AND RESULTS: to comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P

The available oocyte pool is determined before birth, with the majority of oocytes lost before puberty. We hypothesised that events occurring before birth, in childhood or in adolescence ('early-life risk factors') could influence the size of the oocyte pool and thus the timing of menopause. We included cross-sectional data from 273,474 women from the UK Biobank, recruited in 2006-2010 from across the UK. We analysed the association of early menopause with events occurring before adulthood in 11,781 cases (menopause aged under 45) and 173,641 controls (menopause/pre-menopausal at ≥ 45 years), in models controlling for potential confounding variables. Being part of a multiple birth was strongly associated with early menopause (odds ratio = 1.42, confidence interval: 1.11, 1.82, P = 8.0 × 10(-9), fully-adjusted model). Earlier age at menarche (odds ratio = 1.03, confidence interval: 1.01, 1.06, P = 2.5 × 10(-6)) and earlier year of birth were also associated with EM (odds ratio = 1.02, confidence interval: 1.00, 1.04, P = 8.0 × 10(-6)). We also confirmed previously reported associations with smoking, drinking alcohol, educational level and number of births. We identified an association between multiple births and early menopause, which connects events pre-birth, when the oocyte pool is formed, with reproductive ageing in later life.

Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20-104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate-limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R, and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (

Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus(CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7x10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.

Genome-wide association studies (GWAS) have successfully identified genetic loci associated with glycemic traits. However, characterizing the functional significance of these loci has proven challenging. We sought to gain insights into the regulation of fasting insulin and fasting glucose through the use of gene expression microarray data from peripheral blood samples of participants without diabetes in the Framingham Heart Study (FHS) (n = 5,056), the Rotterdam Study (RS) (n = 723), and the InCHIANTI Study (Invecchiare in Chianti) (n = 595). Using a false discovery rate q

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p

BACKGROUND: High risk medications are commonly prescribed to older US patients. Currently, less is known about high risk medication prescribing in other Western Countries, including the UK. We measured trends and correlates of high risk medication prescribing in a subset of the older UK population (community/institutionalized) to inform harm minimization efforts. METHODS: Three cross-sectional samples from primary care electronic clinical records (UK Clinical Practice Research Datalink, CPRD) in fiscal years 2003/04, 2007/08 and 2011/12 were taken. This yielded a sample of 13,900 people aged 65 years or over from 504 UK general practices. High risk medications were defined by 2012 Beers Criteria adapted for the UK. Using descriptive statistical methods and regression modelling, prevalence of 'any' (drugs prescribed at least once per year) and 'long-term' (drugs prescribed all quarters of year) high risk medication prescribing and correlates were determined. RESULTS: While polypharmacy rates have risen sharply, high risk medication prevalence has remained stable across a decade. A third of older (65+) people are exposed to high risk medications, but only half of the total prevalence was long-term (any = 38.4 % [95 % CI: 36.3, 40.5]; long-term = 17.4 % [15.9, 19.9] in 2011/12). Long-term but not any high risk medication exposure was associated with older ages (85 years or over). Women and people with higher polypharmacy burden were at greater risk of exposure; lower socio-economic status was not associated. Ten drugs/drug classes accounted for most of high risk medication prescribing in 2011/12. CONCLUSIONS: High risk medication prescribing has not increased over time against a background of increasing polypharmacy in the UK. Half of patients receiving high risk medications do so for less than a year. Reducing or optimising the use of a limited number of drugs could dramatically reduce high risk medications in older people. Further research is needed to investigate why the oldest old and women are at greater risk. Interventions to reduce high risk medications may need to target shorter and long-term use separately.

The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn's disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus.

In mouse models, CCAAT enhancer-binding protein beta (CEBPB) is necessary for M2 macrophage-mediated regeneration after muscle injury. In humans, CEBPB expression in blood was strongly associated with muscle strength. In this study we aimed to test whether CEBPB expression in blood in people is increased 2 days after exercise designed to induce muscle damage and subsequent repair. Sixteen healthy male volunteers undertook elbow flexor exercises designed to induce acute muscle micro-damage. Peripheral blood samples were collected at baseline and days 1, 2, 4 and 7 following exercise. Expression of CEBPB and related genes were analysed by qRT-PCR. Extent of muscle damage was determined by decline in maximal voluntary isometric torque and by plasma creatine kinase activity. Nine subjects had peak (day 4) creatine kinase activity exceeding 10,000 U/l. In this subgroup, CEBPB expression was elevated from baseline to 2 days post exercise (paired-samples t(1,8) = 3.72, p = 0.006). Related expression and selected cytokine changes after exercise did not reach significance. Muscle-damaging exercise in humans can be followed by induction of CEBPB transcript expression in peripheral blood. Associations between CEBPB expression in blood and muscle strength may be consistent with the CEBPB-dependent muscle repair process.

In mouse models, CCAAT enhancer-binding protein beta (CEBPB) is necessary for M2 macrophage-mediated regeneration after muscle injury. In humans, CEBPB expression in blood was strongly associated with muscle strength. In this study we aimed to test whether CEBPB expression in blood in people is increased 2 days after exercise designed to induce muscle damage and subsequent repair. Sixteen healthy male volunteers undertook elbow flexor exercises designed to induce acute muscle micro-damage. Peripheral blood samples were collected at baseline and days 1, 2, 4 and 7 following exercise. Expression of CEBPB and related genes were analysed by qRT-PCR. Extent of muscle damage was determined by decline in maximal voluntary isometric torque and by plasma creatine kinase activity. Nine subjects had peak (day 4) creatine kinase activity exceeding 10,000 U/l. In this subgroup, CEBPB expression was elevated from baseline to 2 days post exercise (paired-samples t (1,8) = 3.72, p = 0.006). Related expression and selected cytokine changes after exercise did not reach significance. Muscle-damaging exercise in humans can be followed by induction of CEBPB transcript expression in peripheral blood. Associations between CEBPB expression in blood and muscle strength may be consistent with the CEBPB-dependent muscle repair process.

MicroRNAs are non-coding RNAs with roles in many cellular processes. Tissue-specific miRNA profiles associated with senescence have been described for several cell and tissue types. We aimed to characterise miRNAs involved in core, rather than tissue-specific, senescence pathways by assessment of common miRNA expression differences in two different cell types, with follow-up of predicted targets in human peripheral blood. MicroRNAs were profiled in early and late passage primary lung and skin fibroblasts to identify commonly-deregulated miRNAs. Expression changes of their bioinformatically-predicted mRNA targets were then assessed in both cell types and in human peripheral blood from elderly participants in the InCHIANTI study. 57/178 and 26/492 microRNAs were altered in late passage skin and lung cells respectively. Three miRNAs (miR-92a, miR-15b and miR-125a-3p) were altered in both tissues. 14 mRNA targets of the common miRNAs were expressed in lung and skin fibroblasts, of which two demonstrated up-regulation in late passage skin and lung cells (LYST; p = 0.02 [skin] and 0.02 [lung] INMT; p = 0.03 [skin] and 0.04 [lung]). ZMPSTE24 and LHFPL2 demonstrated altered expression in late passage skin cells only (p = 0.01 and 0.05 respectively). LHFPL2 was also positively correlated with age in peripheral blood (p value = 6.6 × 10(-5)). We find that the majority of senescence-associated miRNAs demonstrate tissue-specific effects. However, miRNAs showing common effects across tissue types may represent those associated with core, rather than tissue-specific senescence processes.

BACKGROUND: Epigenetic mechanisms might be involved in the regulation of interindividual lipid level variability and thus may contribute to the cardiovascular risk profile. The aim of this study was to investigate the association between genome-wide DNA methylation and blood lipid levels high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol. Observed DNA methylation changes were also further analyzed to examine their relationship with previous hospitalized myocardial infarction. METHODS AND RESULTS: Genome-wide DNA methylation patterns were determined in whole blood samples of 1776 subjects of the Cooperative Health Research in the Region of Augsburg F4 cohort using the Infinium HumanMethylation450 BeadChip (Illumina). Ten novel lipid-related CpG sites annotated to various genes including ABCG1, MIR33B/SREBF1, and TNIP1 were identified. CpG cg06500161, located in ABCG1, was associated in opposite directions with both high-density lipoprotein cholesterol (β coefficient=-0.049; P=8.26E-17) and triglyceride levels (β=0.070; P=1.21E-27). Eight associations were confirmed by replication in the Cooperative Health Research in the Region of Augsburg F3 study (n=499) and in the Invecchiare in Chianti, Aging in the Chianti Area study (n=472). Associations between triglyceride levels and SREBF1 and ABCG1 were also found in adipose tissue of the Multiple Tissue Human Expression Resource cohort (n=634). Expression analysis revealed an association between ABCG1 methylation and lipid levels that might be partly mediated by ABCG1 expression. DNA methylation of ABCG1 might also play a role in previous hospitalized myocardial infarction (odds ratio, 1.15; 95% confidence interval=1.06-1.25). CONCLUSIONS: Epigenetic modifications of the newly identified loci might regulate disturbed blood lipid levels and thus contribute to the development of complex lipid-related diseases.

Objective We compared the distribution by wealth of self-reported illness burden (estimated from validated scales, biomarker and reported symptoms) for angina, cataract, depression, diabetes and osteoarthritis, with the distribution of self-reported medical diagnosis and treatment. We aimed to determine if the greater illness burden borne by poorer participants was matched by appropriately higher levels of diagnosis and treatment.Design the English Longitudinal Study of Ageing, a panel study of 12�
765 participants aged 50�
years and older in four waves from 2004 to 2011, selected using a stratified random sample of households in England. Distribution of illness burden, diagnosis and treatment by wealth was estimated using regression analysis.Outcome measures the main outcome measures were ORs for the illness burden, diagnosis and treatment, respectively, adjusted for age, sex and wealth. We estimated the illness burden for angina with the Rose Angina scale, diabetes with fasting glycosylated haemoglobin, depression with the Centre for Epidemiologic Studies Depression Scale, osteoarthritis with self-reported pain and disability and cataract with self-reported poor vision. Medical diagnoses were self-reported for all conditions. Treatment was defined as β-blocker prescription for angina, surgery for osteoarthritis and cataract, and receipt of predefined effective interventions for diabetes and depression.Results Compared with the wealthiest, the least wealthy participant had substantially higher odds for illness burden from any of the five conditions at all four time points, with ORs ranging from 4.2 (95% CI 2.6 to 6.8) for diabetes to 15.1 (11.4 to 20.0) for osteoarthritis. The ORs for diagnosis and treatment were smaller in all five conditions, and ranged from 0.9 (0.5 to 1.4) for diabetes treatment to 4.5 (3.3 to 6.0) for angina diagnosis.Conclusions the substantially higher illness burden in less wealthy participants was not matched by appropriately higher levels of diagnosis and treatment.

INTRODUCTION: Chronically elevated circulating inflammatory markers are common in older persons but mechanisms are unclear. Many blood transcripts (>800 genes) are associated with interleukin-6 protein levels (IL6) independent of age. We aimed to identify gene transcripts statistically mediating, as drivers or responders, the increasing levels of IL6 protein in blood at older ages. METHODS: Blood derived in-vivo RNA from the Framingham Heart Study (FHS, n=2422, ages 40-92 yrs) and InCHIANTI study (n=694, ages 30-104 yrs), with Affymetrix and Illumina expression arrays respectively (>17,000 genes tested), were tested for statistical mediation of the age-IL6 association using resampling techniques, adjusted for confounders and multiple testing. RESULTS: in FHS, IL6 expression was not associated with IL6 protein levels in blood. 102 genes (0.6% of 17,324 expressed) statistically mediated the age-IL6 association of which 25 replicated in InCHIANTI (including 5 of the 10 largest effect genes). The largest effect gene (SLC4A10, coding for NCBE, a sodium bicarbonate transporter) mediated 19% (adjusted CI 8.9 to 34.1%) and replicated by PCR in InCHIANTI (n=194, 35.6% mediated, p=0.01). Other replicated mediators included PRF1 (perforin, a cytolytic protein in cytotoxic T lymphocytes and NK cells) and IL1B (Interleukin 1 beta): few other cytokines were significant mediators. CONCLUSIONS: This transcriptome-wide study on human blood identified a small distinct set of genes that statistically mediate the age-IL6 association. Findings are robust across two cohorts and different expression technologies. Raised IL6 levels may not derive from circulating white cells in age related inflammation.

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P 20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

BACKGROUND: the oldest old (85+) pose complex medical challenges. Both underdiagnosis and overdiagnosis are claimed in this group. OBJECTIVE: to estimate diagnosis, prescribing and hospital admission prevalence from 2003/4 to 2011/12, to monitor trends in medicalisation. DESIGN AND SETTING: observational study of Clinical Practice Research Datalink (CPRD) electronic medical records from general practice populations (eligible; n = 27,109) with oversampling of the oldest old. METHODS: we identified 18 common diseases and five geriatric syndromes (dizziness, incontinence, skin ulcers, falls and fractures) from Read codes. We counted medications prescribed ≥1 time in all quarters of studied years. RESULTS: there were major increases in recorded prevalence of most conditions in the 85+ group, especially chronic kidney disease (stages 3-5: prevalence

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P 

Aims
Diabetes complications are potentially avoidable, yet incomplete care is common. Little is known about patient characteristics that predict incomplete care.
Methods
English Longitudinal Study of Ageing participants aged 50 years or older with diabetes reported on four diabetes quality indicators (QIs) in 2008-9 and 2010-11. Annual checks for glycated haemoglobin (HbA1c), proteinuria and foot examination were assessed as a care bundle (n=907). A further QI
assessed whether participants with cardiac risk factors were offered ACE inhibitors/receptor blockers
(n=759). Individual's baseline (2008-9) socio-demographic, lifestyle and health characteristics,
diabetes self-management knowledge and health literacy, and previous QI achievement were assessed
with logistic regressions on outcomes in 2010-11.
Results
A third of participants (2008-9=32.8%; 2010-11=32.2%) did not receive all annual checks in the care
bundle. Nearly half of those eligible were not offered ACE inhibitors/receptor blockers (2008-
9=44.6%; 2010-11=44.5%). Odds of not receiving a complete care bundle were increased for
participants lacking diabetes self-management knowledge (OR=2.05), having poorer cognitive
performance (OR=1.78) or having previously received incomplete care (OR=3.32). Participants who
were single (OR=2.16), had with low health literacy (OR=1.50) and who had received incomplete care
previously (OR=6.94) were less likely to subsequently be offered ACE inhibitors/receptor blockers,
whereas trend test showed that being older (OR=0.76) and increased BMI categorisation (OR=0.70)
improved odds of receiving this aspect of care.
Conclusions
Quality improvement initiatives for diabetes might usefully target patients with characteristics shown
here to predict non-receipt of indicated care, such as poor knowledge of annual diabetes care
processes or previous receipt of incomplete care.

BACKGROUND: US studies suggest that leptin, a fat-derived hormone, may be protective against the development of dementia. OBJECTIVE: to investigate the complex relationship between leptin levels and cognitive decline in elderly Italians. METHODS: We studied circulating fasting leptin levels in 809 elderly adults free from dementia who participated in the prospective Italian population-based InCHIANTI study between 1998 and 2009 (mean follow-up of 8.0 years). Global cognitive decline was defined as a reduction of ≥5 points on the Mini-Mental State Examination (MMSE). Trail-Making Tests a and B were also incorporated, with cognitive decline defined as discontinued testing or the worst 10% of change from baseline. We also investigated whether any association could be explained by midlife weight and whether cognitive decline was associated with changing leptin levels. RESULTS: the multivariate adjusted relative risk ([RR]; 95% confidence interval [CI]) of cognitive decline on the MMSE was 0.84 (95% CI 0.73-0.97) in relation to baseline sex-standardized log-leptin levels. High leptin levels showed a non-significant trend toward a reduced risk of decline on the Trail-Making Tests a (RR = 0.85, 95% CI 0.71-1.02) and B (RR = 0.90, 0.79-1.02). Adjusting for midlife weight or change in weight did not alter the pattern of results, and cognitive decline was not associated with changing leptin levels. CONCLUSIONS: High leptin levels were independently associated with a reduced risk of cognitive decline in elderly Italians.

BackgroundShortfalls in the receipt of recommended health care have been previously reported in England, leading to preventable poor health.ObjectivesTo assess changes over 6 years in the receipt of effective health-care interventions for people aged 50 years or over in England with cardiovascular disease, depression, diabetes or osteoarthritis; to identify how quality varied with participant characteristics; and to compare the distribution of illness burden in the population with the distributions of diagnosis and treatment.Setting and participantsInformation on health-care quality indicators and participant characteristics was collected using face-to-face structured interviews and nurse visits in participants’ homes by the English Longitudinal Study of Ageing in 2004–5, 2006–7, 2008–9 and 2010–11. A total of 16,773 participants aged 50 years or older were interviewed at least once and 5114 were interviewed in all four waves; 5404 reported diagnosis of one or more of four conditions in 2010–11.Main outcome measuresPercentage of indicated health care received by eligible participants for 19 quality indicators: seven for cardiovascular disease, three for depression, five for diabetes and four for osteoarthritis, and condition-level quality indicator achievement, including achievement of a bundle of three diabetes indicators.AnalysisChanges in quality indicator achievement over time and variations in quality with participant characteristics were tested with Pearson’s chi-squared test and logistic regression models. The size of inequality between the hypothetically wealthiest and poorest participants, for illness burden, diagnosis and treatment, was estimated using slope indices of wealth inequality.ResultsAchievement of indicators for cardiovascular disease was 82.7% [95% confidence interval (CI) 79.9% to 85.5%] in 2004–5 and 84.2% (95% CI 82.1% to 86.2%) in 2010–11, for depression 63.3% (95% CI 57.6% to 69.0%) and 59.8% (95% CI 52.4% to 64.3%), for diabetes 76.0% (95% CI 74.1% to 77.8%) and 76.5% (95% CI 74.8% to 78.1%), and for osteoarthritis 31.2% (95% CI 28.5% to 33.8%) and 35.6% (95% CI 34.2% to 37.1%). Achievement of the diabetes care bundle was 67.8% (95% CI 64.5% to 70.9%) in 2010–11. Variations in quality by participant characteristics were generally small. Diabetes indicator achievement was worse in participants with cognitive impairment [odds ratio (OR) 0.5, 95% CI 0.4 to 0.7] and better in those living alone (OR 1.7, 95% CI 1.3 to 2.0). Hypertension care was better for those aged over 74 years (vs. 50–64 years) (OR 3.2, 95% CI 2.0 to 5.3). Osteoarthritis care was better for those with severe (vs. mild) pain (OR 1.8, 95% CI 1.4 to 2.2), limiting illness (OR 1.8, 95% CI 1.5 to 2.1), and obesity (OR 1.6, 95% CI 1.2 to 2.0). Previous non-achievement of the diabetes care bundle was the biggest predictor of non-achievement 2 years later (OR 3.3, 95% CI 2.2 to 4.7). Poorer participants were always more likely than wealthier participants to have illness burden (statistically significant OR 3.9 to 16.0), but not always more likely to be diagnosed or receive treatment (0.2 to 5.3).ConclusionsShortfalls in quality of care for these four conditions have persisted over 6 years, with only half of the level of indicated health care achieved for osteoarthritis, compared with the other three conditions. Quality for osteoarthritis improved slightly over time but remains poor. The relatively high prevalence of specific illness burden in poorer participants was not matched by an equally high prevalence of diagnosis or treatment, suggesting that barriers to equity may exist at the stage at diagnosis. Further research is needed into the association between quality and health system characteristics at the level of clinicians, general practices or hospitals, and regions. Linkage to routinely collected data could provide information on health service characteristics at the individual patient level.FundingThe National Institute for Health Research Health Services and Delivery Research programme.

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Initial results from sequencing studies suggest that there are relatively few low-frequency (

Background Parental longevity confers lower risks for some age-related diseases in offspring. We tested the association between parental longevity and late-life cognitive decline or dementia.

Bisphenol a (BPA) is a widely used plastics constituent that has been associated with endocrine, immune and metabolic effects. Evidence for how BPA exerts significant biological effects at chronic low levels of exposure has remained elusive. In adult men, exposure to BPA has been associated with higher expression of two nuclear receptors, oestrogen receptor-β (ERβ) and oestrogen-related-receptor-α (ERRα), in peripheral white blood cells in vivo. In this study, we explore the expression of ESR2 (ERβ) and ESRRA (ERRα) in human leukaemic T-cell lymphoblasts (Jurkat cells) exposed to BPA in vitro. We show that exposure to BPA led to enhanced expression of ESRRA within 6 h of exposure (mean±s.e.m.: 1.43±0.08-fold increase compared with the control, P

BACKGROUND: little is known about changes in the quality of medical care for older adults over time. OBJECTIVE: to assess changes in technical quality of care over 6 years, and associations with participants' characteristics. DESIGN: a national cohort survey covering RAND Corporation-derived quality indicators (QIs) in face-to-face structured interviews in participants' households. PARTICIPANTS: a total of 5,114 people aged 50 or more in four waves of the English Longitudinal Study of Ageing. METHODS: the percentage achievement of 24 QIs in 10 general medical and geriatric clinical conditions was calculated for each time point, and associations with participants' characteristics were estimated using logistic regression. RESULTS: participants were eligible for 21,220 QIs. QI achievement for geriatric conditions (cataract, falls, osteoarthritis and osteoporosis) was 41% [95% confidence interval (CI): 38-44] in 2004-05 and 38% (36-39) in 2010-11. Achievement for general medical conditions (depression, diabetes mellitus, hypertension, ischaemic heart disease, pain and cerebrovascular disease) improved from 75% (73-77) in 2004-05 to 80% (79-82) in 2010-11. Achievement ranged from 89% for cerebrovascular disease to 34% for osteoarthritis. Overall achievement was lower for participants who were men, wealthier, infrequent alcohol drinkers, not obese and living alone. CONCLUSION: substantial system-level shortfalls in quality of care for geriatric conditions persisted over 6 years, with relatively small and inconsistent variations in quality by participants' characteristics. The relative lack of variation by participants' characteristics suggests that quality improvement interventions may be more effective when directed at healthcare delivery systems rather than individuals.

Ageing in man is associated with changes to the splicing factor pool. A proportion of splicing factors are regulated during ageing by mechanisms involving the Ataxia Telangiectasia Mutated (ATM) gene, but the factors that determine the remaining proportion have yet to be identified. DNA methylation is known to be an important regulatory mechanism of gene expression. We assessed age-associated methylation and expression levels for 27 splicing factor genes, in peripheral blood samples from the InCHIANTI study. Examination of splicing patterns at specific loci was examined in a second cohort, the Exeter 10000 study. 27/502 methylation probes in 17 different genes were associated with age. Most changes were not associated with transcript expression levels or splicing patterns, but hypomethylation of the SF3B1 promoter region was found to mediate 53% of the relationship between age and transcript expression at this locus (p=0.02). DNA methylation does not appear to play a major role in regulation of the splicing factors, but changes in SF3B1 expression may be attributable to promoter hypomethylation at this locus. SF3B1 encodes a critical component of the U2 snRNP; altered expression of this gene may therefore contribute to the loss of regulated mRNA splicing that occurs with age.

BACKGROUND: Circulating interleukin-6 levels increase with advancing age and are a risk factor for various diseases and mortality. The characterization of gene expression profiles associated with interleukin-6 levels might suggest important molecular events underlying its regulation. METHODS AND RESULTS: We studied the association of transcriptional profiles with interleukin-6 levels in 2422 participants from the Framingham Heart Study Offspring Cohort using Affymetrix Human Exon 1.0 ST Array. We identified 4139 genes that were significantly associated with interleukin-6 levels (FDR

BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. METHODS: in this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p

Perfluorooctanoic acid (PFOA, 'C8') and perfluoroctane sulphonate (PFOS) are environmentally stable compounds with industrial and consumer uses and long half-lives in humans. Concern has been raised over chronic exposure effects to human health, especially in relation to cholesterol metabolism. Here, we explore the association between exposure to PFOA and PFOS and the in vivo expression of genes involved in cholesterol metabolism. We studied 290 individuals exposed to background levels of PFOS and elevated concentrations of PFOA through drinking water. Using adjusted linear regression models, we found inverse associations between serum PFOA levels and the whole blood expression level of genes involved in cholesterol transport (NR1H2, NPC1 and ABCG1; p=0.002, 0.026 and 0.014 respectively). A positive association was seen between PFOS and a transcript involved in cholesterol mobilisation (NCEH1; p=0.018), and a negative relationship with a transcript involved in cholesterol transport (NR1H3; p=0.044). When sexes were analysed separately, reductions in the levels of mRNAs involved in cholesterol transport were seen with PFOA in men (NPC1, ABCG1, and PPARA; p=0.025, 0.024 and 0.012 respectively) and in women (NR1H2 expression; p=0.019), whereas an increase in the levels of a cholesterol mobilisation transcript (NCEH1; p=0.036) was noted in women alone. PFOS was positively associated with expression of genes involved in both cholesterol mobilisation and transport in women (NCEH1 and PPARA; p=0.003 and 0.039 respectively), but no effects were evident in men. This is the first report of associations between the in vivo expression of genes involved in cholesterol metabolism and exposure to PFOA or PFOS, suggested that exposure to these compounds may promote a hypercholesterolaemic environment, with wider implications for human disease.

Low level chronic exposure to toxicants is associated with a range of adverse health effects. Understanding the various factors that influence the chemical burden of an individual is of critical importance to public health strategies. We investigated the relationships between socioeconomic status (SES) and bio-monitored chemical concentration in five cross-sectional waves of the U.S. National Health and Nutrition Examination Survey (NHANES). We utilised adjusted linear regression models to investigate the association between 179 toxicants and the poverty income ratio (PIR) for five NHANES waves. We then selected a subset of chemicals associated with PIR in 3 or more NHANES waves and investigated potential mediating factors using structural equation modelling. PIR was associated with 18 chemicals in 3 or more NHANES waves. Higher SES individuals had higher burdens of serum and urinary mercury, arsenic, caesium, thallium, perfluorooctanoic acid, perfluorononanoic acid, mono(carboxyoctyl) phthalate and benzophenone-3. Inverse associations were noted between PIR and serum and urinary lead and cadmium, antimony, bisphenol a and three phthalates (mono-benzyl, mono-isobutyl, mono-n-butyl). Key mediators included fish and shellfish consumption for the PIR, mercury, arsenic, thallium and perfluorononanoic acid associations. Sunscreen use was an important mediator in the benzophenone-3/PIR relationship. The association between PIR and cadmium or lead was partially mediated by smoking, occupation and diet. These results provide a comprehensive analysis of exposure patterns as a function of socioeconomic status in US adults, providing important information to guide future public health remediation measures to decrease toxicant and disease burdens within society.

Human ageing is associated with decreased cellular plasticity and adaptability. Changes in alternative splicing with advancing age have been reported in man, which may arise from age-related alterations in splicing factor expression. We determined whether the mRNA expression of key splicing factors differed with age, by microarray analysis in blood from two human populations and by qRT-PCR in senescent primary fibroblasts and endothelial cells. Potential regulators of splicing factor expression were investigated by siRNA analysis. Approximately one third of splicing factors demonstrated age-related transcript expression changes in two human populations. Ataxia Telangiectasia Mutated (ATM) transcript expression correlated with splicing factor expression in human microarray data. Senescent primary fibroblasts and endothelial cells also demonstrated alterations in splicing factor expression, and changes in alternative splicing. Targeted knockdown of the ATM gene in primary fibroblasts resulted in up-regulation of some age-responsive splicing factor transcripts. We conclude that isoform ratios and splicing factor expression alters with age in vivo and in vitro, and that ATM may have an inhibitory role on the expression of some splicing factors. These findings suggest for the first time that ATM, a core element in the DNA damage response, is a key regulator of the splicing machinery in man.

With white blood cell count emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genomewide association analyses to identify variants specifically associated with monocyte count in 11 014 subjects in the electronic Medical Records and Genomics Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (P-value =2.7x10(-16), β=-0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value =1.88x10(-7), β=0.30) and a region of replication found in ribophorin I (RPN1) (P-value=2.63x10(-16), β=-0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA binding protein2 gene that has been previously shown to be associated with coronary heart disease. On chromosome 9, we found a novel association in the prostaglandin reductase 1 gene (P-value =2.29x10(-7), β=0.16), which is downstream from lysophosphatidic acid receptor 1. This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (P-value =5.68x10(-17), β=-0.23) at the integrin, alpha 4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count. © the Author 2013. Published by Oxford University Press. All rights reserved.

BACKGROUND: in recent years there has been an exponential increase in tungsten demand, potentially increasing human exposure to the metal. Currently, the toxicology of tungsten is poorly understood, but mounting evidence suggests that both the elemental metal and its alloys have cytotoxic effects. Here, we investigate the association between tungsten and cardiovascular disease (CVD) or stroke using six waves of the National Health and Nutrition Examination Survey (NHANES). METHODS: We investigated associations using crude and adjusted logistic regression models in a cohort of 8614 adults (18-74 years) with 193 reported stroke diagnoses and 428 reported diagnoses of CVD. We also stratified our data to characterize associations in a subset of younger individuals (18-50 years). RESULTS: Elevated tungsten concentrations were strongly associated with an increase in the prevalence of stroke, independent of typical risk factors (Odds Ratio (OR): 1.66, 95% Confidence Interval (95% CI): 1.17, 2.34). The association between tungsten and stroke in the young age category was still evident (OR: 2.17, 95% CI: 1.33, 3.53). CONCLUSION: This study represents the most comprehensive analysis of the human health effects of tungsten to date. Individuals with higher urinary tungsten concentrations have double the odds of reported stroke. We hypothesize that the pathological pathway resulting from tungsten exposure may involve oxidative stress.

Genome-wide association (GWA) studies have been limited by the reliance on common variants present on microarrays or imputable from the HapMap Project data. More recently, the completion of the 1000 Genomes Project has provided variant and haplotype information for several million variants derived from sequencing over 1,000 individuals. To help understand the extent to which more variants (including low frequency (1% ≤ MAF

BACKGROUND: Children of centenarians have lower cardiovascular disease prevalence and live longer. We aimed to estimate associations between the full range of parental attained ages and health status in a middle-aged U.S. representative sample. METHODS: Using Health and Retirement Study data, models estimated disease incidence and mortality hazards for respondents aged 51-61 years at baseline, followed up for 18 years. Full adjustment included sex, race, smoking, wealth, education, body mass index, and childhood socioeconomic status. Mother's and father's attained age distributions were used to define short-, intermediate-, and long-lived groups, yielding a ranked parental longevity score (n = 6,055, excluding short-long discordance). Linear models (n = 8,340) tested mother's or father's attained ages, adjusted for each other. RESULTS: with increasing mother's or father's survival (>65 years), all-cause mortality declined 19% (hazard ratio [HR] = 0.81, 95% CI: 0.76-0.86, p <. 001) and 14% per decade (HR = 0.87, 95% CI: 0.81-0.92, p <. 001). Estimates changed only modestly when fully adjusted. Parent-in-law survival was not associated with mortality (n = 1,809, HR = 1.00, 95% CI: 0.90-1.12, p =. 98). Offspring with one or two long-lived parents had lower cancer incidence (938 cases, HR per parental longevity score = 0.76, 95% CI: 0.61-0.94, p =. 01) versus two intermediate parents. Similar HRs for diabetes (HR = 0.89, 95% CI: 0.84-0.96, p =. 001), heart disease (HR = 0.88, 95% CI: 0.82-0.93, p <. 001), and stroke (HR = 0.86, 95% CI: 0.78-0.95, p =. 002) were significant, but there was no trend for arthritis. CONCLUSIONS: the results provide the first robust evidence that increasing parental attained age is associated with lower cancer incidence in offspring. Health advantages of having centenarian parents extend to a wider range of parental longevity and may provide a quantitative trait of slower aging.

The human transcriptome is exceptionally complex. Over 95% of human DNA is transcribed into RNA; the transcriptome containing not only the messenger RNAs (mRNAs) but also a range of large and small non-coding regulatory RNAs and components of the translational machinery. The transcriptome is therefore at the heart of the gene-environment interaction, and this complexity, together with the diversity brought about by alternative mRNA processing gives the human transcriptome unprecedented plasticity and adaptability. Many human diseases are associated with effects at the level of the mRNA transcript, either as part of the causal pathway, or as a response to disease. Analysis of the transcriptome thus has enormous potential for the development of potential biomarkers of disease, and to increase our understanding of the disease processes themselves. In the last few decades, technological advances have made profiling of the entire transcriptome an affordable and manageable prospect. These advances have made high-throughput analysis of the output of the human genome accessible, allowing transcriptional alterations with disease phenotypes to be determined in large human populations. In this review, we will describe some of the recent advances in our understanding of fundamental human processes such as human ageing, and common chronic disorders that have been achieved by whole genome transcriptional profiling. We will outline some of the methodologies that have been employed to answer these important questions, as well as present some examples from our own laboratory where we have used these approaches to investigate mechanisms ofageing and in specific age-related disorders such as frailty and cognitive decline. Gene expression profiling has an important role to play in inferring mechanisms underlying certain diseases, and technological advances will render it an increasingly powerful tool in the future. © 2013 by Nova Science Publishers, Inc. All rights reserved.

OBJECTIVES: Past research has shown that parental longevity is related to offspring physical health and longevity. Preliminary studies suggest that parental longevity may be linked to the offspring's personality traits. A comprehensive 5-factor personality model has been related to physical health, but the association with parental longevity has not yet been investigated. We used a 5-factor personality model to investigate the relationship between parental longevity and offspring personality. METHOD: Data from the longitudinal Health and Retirement Study (HRS) was used in the analyses. Using the Midlife Development Inventory and the Life Orientation test, the relationship between parental attained age and offspring personality was assessed using regression models for both men and women. RESULTS: Male offspring of long-lived fathers and mothers were more likely to be open to new experiences (p <. 01) and be more extroverted (p =. 03) compared with male offspring of short-lived fathers or mothers. Maternal or paternal attained age had no effect on the female offspring personality traits. DISCUSSION: Personality is an important phenotype to consider when investigating genetic and environmental determinants of longevity. Further research is needed to investigate the potential of gender-specific mechanisms.

Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3′ UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants. © 2013 Nature America, Inc. All rights reserved.

We have previously described a statistical model capable of distinguishing young (age

OBJECTIVES: to estimate the association between uric acid and cardiovascular mortality in older adults, independent of traditional risk factors, and to estimate the risk prediction gain by adding uric acid measurements to the Framingham Cardiovascular Risk Score (FCRS). DESIGN: Longitudinal observational study of two population-based cohorts. SETTING: the Established Populations for Epidemiologic Studies of the Elderly, Iowa (Iowa-EPESE) and the Third National Health and Nutritional Examination Survey (NHANES III). PARTICIPANTS: One thousand twenty-eight Iowa-EPESE participants and 1,316 NHANES III participants. Selected participants were aged 70 and older without overt cardiovascular disease, renal dysfunction, or diuretic use who lived for 3 years or longer after baseline. MEASUREMENTS: Outcome was age at cardiovascular death during follow-up (12–20 years). Uric acid and cardiovascular risk factors such as smoking, systolic blood pressure, diabetes mellitus, obesity, serum cholesterol, and high-density lipoprotein cholesterol were measured at baseline. RESULTS: High serum uric acid (>7.0 mg/dL) was associated with male sex, obesity, lipid levels, and estimated glomerular filtration rate at baseline. Fully adjusted hazard ratios (HRs) for cardiovascular death with high uric acid versus normal were 1.36 (95% confidence interval (CI) = 1.10–1.69) in Iowa-EPESE and 1.43 (95% CI = 1.04–1.99) in NHANES III; pooled HR was 1.38 (95% CI = 1.16–1.61). The net reclassification improvement achieved by adding uric acid measurement to the FCRS was 9% to 20%. CONCLUSION: in individuals aged 70 and older without overt CVD, renal dysfunction, or diuretic use, serum uric acid greater than 7.0 mg/dL was associated with greater CVD mortality independent of classic CVD risk factors. Adding uric acid measurement to the FCRS would improve prediction in older adults.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P

Interventions which inhibit TOR activity (including rapamycin and caloric restriction) lead to downstream gene expression changes and increased lifespan in laboratory models. However, the role of mTOR signaling in human aging is unclear.We tested the expression of mTOR-related transcripts in two independent study cohorts; the InCHIANTI population study of aging and the San Antonio Family Heart Study (SAFHS). Expression of 27/56 (InCHIANTI) and 19/44 (SAFHS) genes were associated with age after correction for multiple testing. 8 genes were robustly associated with age in both cohorts. Genes involved in insulin signaling (PTEN, PI3K, PDK1), ribosomal biogenesis (S6K), lipid metabolism (SREBF1), cellular apoptosis (SGK1), angiogenesis (VEGFB), insulin production and sensitivity (FOXO), cellular stress response (HIF1A) and cytoskeletal remodeling (PKC) were inversely correlated with age, whereas genes relating to inhibition of ribosomal components (4EBP1) and inflammatory mediators (STAT3) were positively associated with age in one or both datasets.We conclude that the expression of mTOR-related transcripts is associated with advancing age in humans. Changes seen are broadly similar to mTOR inhibition interventions associated with increased lifespan in animals. Work is needed to establish whether these changes are predictive of human longevity and whether further mTOR inhibition would be beneficial in older people. © 2012 Elsevier Ireland Ltd.

Interventions which inhibit TOR activity (including rapamycin and caloric restriction) lead to downstream gene expression changes and increased lifespan in laboratory models. However, the role of mTOR signaling in human aging is unclear. We tested the expression of mTOR-related transcripts in two independent study cohorts; the InCHIANTI population study of aging and the San Antonio Family Heart Study (SAFHS). Expression of 27/56 (InCHIANTI) and 19/44 (SAFHS) genes were associated with age after correction for multiple testing. 8 genes were robustly associated with age in both cohorts. Genes involved in insulin signaling (PTEN, PI3K, PDK1), ribosomal biogenesis (S6K), lipid metabolism (SREBF1), cellular apoptosis (SGK1), angiogenesis (VEGFB), insulin production and sensitivity (FOXO), cellular stress response (HIF1A) and cytoskeletal remodeling (PKC) were inversely correlated with age, whereas genes relating to inhibition of ribosomal components (4EBP1) and inflammatory mediators (STAT3) were positively associated with age in one or both datasets. We conclude that the expression of mTOR-related transcripts is associated with advancing age in humans. Changes seen are broadly similar to mTOR inhibition interventions associated with increased lifespan in animals. Work is needed to establish whether these changes are predictive of human longevity and whether further mTOR inhibition would be beneficial in older people.

Background-Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts. Methods and Results-Continuous ABI and PAD (ABI

Declining muscle strength is a core feature of aging. Several mechanisms have been postulated, including CCAAT/enhancer-binding protein-beta (C/EBP-β)-triggered macrophage-mediated muscle fiber regeneration after micro-injury, evidenced in a mouse model. We aimed to identify in vivo circulating leukocyte gene expression changes associated with muscle strength in the human adult population. We undertook a genome-wide expression microarray screen, using peripheral blood RNA samples from InCHIANTI study participants (aged 30 and 104). Logged expression intensities were regressed with muscle strength using models adjusted for multiple confounders. Key results were validated by real-time PCR. The Short Physical Performance Battery (SPPB) score tested walk speed, chair stand, and balance. CEBPB expression levels were associated with muscle strength (β coefficient = 0.20560, P = 1.03*10(-6), false discovery rate q = 0.014). The estimated handgrip strength in 70-year-old men in the lowest CEBPB expression tertile was 35.2 kg compared with 41.2 kg in the top tertile. CEBPB expression was also associated with hip, knee, ankle, and shoulder strength and the SPPB score (P = 0.018). Near-study-wide associations were also noted for TGF-β3 (P = 3.4*10(-5) , q = 0.12) and CEBPD expression (P = 9.7*10(-5) , q = 0.18) but not for CEBPA expression. We report here a novel finding that raised CEBPB expression in circulating leukocyte-derived RNA samples in vivo is associated with greater muscle strength and better physical performance in humans. This association may be consistent with mouse model evidence of CEBPB-triggered muscle repair: if this mechanism is confirmed, it may provide a target for intervention to protect and enhance aging muscle.

[This corrects the article on p. e43378 in vol. 7.].

BACKGROUND: Successful aging depends in part on delaying age-related disease onsets until later in life. Conditions including coronary artery disease, Alzheimer's disease, prostate cancer, and type 2 diabetes are moderately heritable. Genome-wide association studies have identified many risk associated single-nucleotide polymorphisms for these conditions, but much heritability remains unaccounted for. Nevertheless, a great deal is being learned. METHODS: Here, we review age-related disease associated single-nucleotide polymorphisms and identify key underlying pathways including lipid handling, specific immune processes, early tissue development, and cell cycle control. RESULTS: Most age-related disease associated single-nucleotide polymorphisms do not affect coding regions of genes or protein makeup but instead influence regulation of gene expression. Recent evidence indicates that evolution of gene regulatory sites is fundamental to interspecies differences. Animal models relevant to human aging may therefore need to focus more on gene regulation rather than testing major disruptions to fundamental pathway genes. Recent larger scale human studies of in vivo genome-wide expression (notably from the InCHIANTI aging study) have identified changes in splicing, the "fine tuning" of protein sequences, as a potentially important factor in decline of cellular function with age. Studies of expression with muscle strength and cognition have shown striking concordance with certain mice models of muscle repair and beta-amyloid phagocytosis respectively. CONCLUSIONS: the emerging clearer picture of the genetic architecture of age-related diseases in humans is providing new insights into the underlying pathophysiological pathways involved. Translation of genomics into new approaches to prevention, tests and treatments to extend successful aging is therefore likely in the coming decades.

INTRODUCTION: Circulating inflammatory markers may play an important role in cognitive impairment at older ages. Mice deficient for the chemokine (C-C motif) receptor 2 (CCR2) develop an accelerated Alzheimer-like pathology. CCR2 is also important in neurogenesis. To identify human gene transcripts most closely associated with Mini-Mental State Examination (MMSE) scores, we undertook a genome-wide and inflammation specific transcriptome screen in circulating leukocytes from a population-based sample. METHODS: We measured in vivo transcript levels by microarray analysis in 691 subjects (mean age 72.6 years) in the InCHIANTI study (Invecchiare in Chianti, aging in the Chianti area). We assessed expression associations with MMSE performance at RNA collection and prior 9-year change in MMSE score in linear regression models. RESULTS: in genome-wide analysis, raised CCR2 expression was cross-sectionally the most strongly associated transcript with lower MMSE score (beta=-0.16, p=5.1×10(-6), false discovery rate (FDR; q=0.077). Amongst inflammatory transcripts, only CCR2 expression was associated with both MMSE score and accelerated decline in score over the preceding 9 years (beta=-0.16, p=5.1×10(-6), q=0.003; and beta=-0.13, p=5.5×10(-5), q=0.03, respectively). CCR2 expression was also positively associated with apolipoprotein E (ApoE) e4 Alzheimer disease risk haplotype. CONCLUSIONS: We show for the first time that CCR2 expression is associated with lower MMSE scores in an older human population. Laboratory models of Ccr2-mediated β-amyloid removal and regulation of neurogenesis affecting cognitive function may be applicable in humans. CCR2-mediated pathways may provide a possible focus for intervention to potentiate protective reactions to Alzheimer pathology in older people, including for people with an adverse ApoE haplotype.

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 - 10 g8). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-I °B signaling and mitochondrial dysfunction as biological processes related to timing of menopause. © 2012 Nature America, Inc. All rights reserved.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8- 1.2 ×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p

BACKGROUND: Bisphenol a is widely used in food and drinks packaging. There is evidence of associations between raised urinary bisphenol a (uBPA) and increased incidence of reported cardiovascular diagnoses. METHODOLOGY/PRINCIPAL FINDINGS: to estimate associations between BPA exposure and angiographically graded coronary atherosclerosis. 591 patients participating in the Metabonomics and Genomics in Coronary Artery Disease (MaGiCAD) study in Cambridgeshire UK, comparing urinary BPA (uBPA) with grades of severity of coronary artery disease (CAD) on angiography. Linear models were adjusted for BMI, occupational social class and diabetes status. Severe (one to three vessel) CAD was present in 385 patients, 86 had intermediate disease (n=86) and 120 had normal coronary arteries. The (unadjusted) median uBPA concentration was 1.28 ng/mL with normal coronary arteries, and 1.53 ng/mL with severe CAD. Compared to those with normal coronary arteries, uBPA concentration was significantly higher in those with severe CAD (OR per uBPA SD=5.96 ng/ml OR=1.43, CI 1.03 to 1.98, p=0.033), and near significant for intermediate disease (OR=1.69, CI 0.98 to 2.94, p=0.061). There was no significant uBPA difference between patients with severe CAD (needing surgery) and the remaining groups combined. CONCLUSIONS/SIGNIFICANCE: BPA exposure was higher in those with severe coronary artery stenoses compared to those with no vessel disease. Larger studies are needed to estimate true dose response relationships. The mechanisms underlying the association remain to be established.

The role of vitamin D in skeletal health is well established, but more recent findings have also linked vitamin D deficiency to a range of non-skeletal conditions such as cardiovascular disease, cancer, stroke and metabolic disorders including diabetes. Cognitive impairment and dementia must now be added this list. Vitamin D receptors are widespread in brain tissue, and vitamin D's biologically active form [1,25(OH)(2)D3] has shown neuroprotective effects including the clearance of amyloid plaques, a hallmark of Alzheimer's Disease. Associations have been noted between low 25-hydroxyvitamin D [25(OH)D] and Alzheimer's disease and dementia in both Europe and the US. Similarly, the risk of cognitive impairment was up to four times greater in the severely deficient elders (25(OH)D < 25 nmol/L) in comparison with individuals with adequate levels (≥ 75 nmol/L). Further studies have also shown associations between low 25(OH)D concentrations and cerebrovascular events such as large vessel infarcts, risk of cerebrovascular accident and fatal stroke. Cross-sectional studies cannot establish temporal relationships because cognitive decline and the onset of dementia itself may influence vitamin D concentrations through behavioural and dietary changes. However, two large prospective studies recently indicated that low vitamin D concentrations may increase the risk of cognitive decline. Large, well designed randomized controlled trials are now needed to determine whether vitamin D supplementation is effective at preventing or treating Alzheimer's disease and dementia.

The identification of multiple signals at individual loci could explain additional phenotypic variance ('missing heritability') of common traits, and help identify causal genes. We examined gene expression levels as a model trait because of the large number of strong genetic effects acting in cis. Using expression profiles from 613 individuals, we performed genome-wide single nucleotide polymorphism (SNP) analyses to identify cis-expression quantitative trait loci (eQTLs), and conditional analysis to identify second signals. We examined patterns of association when accounting for multiple SNPs at a locus and when including additional SNPs from the 1000 Genomes Project. We identified 1298 cis-eQTLs at an approximate false discovery rate 0.01, of which 118 (9%) showed evidence of a second independent signal. For this subset of 118 traits, accounting for two signals resulted in an average 31% increase in phenotypic variance explained (Wilcoxon P< 0.0001). The association of SNPs with cis gene expression could increase, stay similar or decrease in significance when accounting for linkage disequilibrium with second signals at the same locus. Pairs of SNPs increasing in significance tended to have gene expression increasing alleles on opposite haplotypes, whereas pairs of SNPs decreasing in significance tended to have gene expression increasing alleles on the same haplotypes. Adding data from the 1000 Genomes Project showed that apparently independent signals could be potentially explained by a single association signal. Our results show that accounting for multiple variants at a locus will increase the variance explained in a substantial fraction of loci, but that allelic heterogeneity will be difficult to define without resequencing loci and functional work.

BACKGROUND: Bisphenol a (BPA) is a synthetic estrogen commonly used in polycarbonate plastic and resin-lined food and beverage containers. Exposure of animal and cell models to doses of BPA below the recommended tolerable daily intake (TDI) of 50 μg/kg/day have been shown to alter specific estrogen-responsive gene expression, but this has not previously been shown in humans. OBJECTIVE: We investigated associations between BPA exposure and in vivo estrogenic gene expression in humans. METHODS: We studied 96 adult men from the InCHIANTI population study and examined in vivo expression of six estrogen receptor, estrogen-related receptor, and androgen receptor genes in peripheral blood leukocytes. RESULTS: the geometric mean urinary BPA concentration was 3.65 ng/mL [95% confidence interval (CI): 3.13, 4.28], giving an estimated mean excretion of 5.84 μg/day (95% CI: 5.00, 6.85), significantly below the current TDI. In age-adjusted models, there were positive associations between higher BPA concentrations and higher ESR2 [estrogen receptor 2 (ER beta)] expression (unstandardized linear regression coefficient = 0.1804; 95% CI: 0.0388, 0.3221; p = 0.013) and ESRRA (estrogen related receptor alpha) expression (coefficient = 0.1718; 95% CI: 0.0213, 0.3223; p = 0.026): These associations were little changed after adjusting for potential confounders, including obesity, serum lipid concentrations, and white cell subtype percentages. Upper-tertile BPA excretors (urinary BPA > 4.6 ng/mL) had 65% higher mean ESR2 expression than did lower-tertile BPA excretors (0-2.4 ng/mL). CONCLUSIONS: Because activation of nuclear-receptor-mediated pathways by BPA is consistently found in laboratory studies, such activation in humans provides evidence that BPA is likely to function as a xenoestrogen in this sample of adults.

BACKGROUND: facing the costs of population ageing, many governments aim to keep older people in employment for longer. Summary health measures predict early retirement, but more specific symptoms and conditions need to be identified to guide efforts to delay retirement. OBJECTIVE: to identify common symptoms and conditions that predict early work exit, at the population level. DESIGN: cohort study of community dwelling respondents to the English Longitudinal Study of Ageing. SETTING AND PARTICIPANTS: a total of 1,693 workers aged 50 and over at baseline who were younger than the contemporaneous retirement age (60 for women, 65 for men) at 4-year follow-up. RESULTS: a total of 308 (18.2%) individuals moved out of employment during the follow-up period. Advancing age, female gender, partner retirement, greater pension wealth, high alcohol consumption and fair or poor self-rated health were all associated with work exit. Accounting for these factors, reported difficulty walking a quarter mile was predictive of early work exit (odds ratio (OR) = 2.23; 95% confidence interval (CI) 1.42-3.52), especially where symptoms included lower limb pain and/or shortness of breath. Symptomatic depression (measured by Centre for Epidemiological Studies Depression scale) was also predictive of early work exit (OR = 1.52, CI 1.07, 2.18). About 50.8% of early retirees reported one or more of these specific health symptoms (depression, general pain, mobility limitations and leg pain when walking). CONCLUSION: older workers who report depressive symptoms or impaired physical mobility, especially with lower limb pain and shortness of breath, are at increased risk of early transition out of work. Health interventions targeting these conditions may enable older workers to remain in the labour force.

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands-yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10-36), SULT2A1 (rs2637125; p = 2.61×10-19), ARPC1A (rs740160; p = 1.56×10-16), TRIM4 (rs17277546; p = 4.50×10-11), BMF (rs7181230; p = 5.44×10-11), HHEX (rs2497306; p = 4.64×10-9), BCL2L11 (rs6738028; p = 1.72×10-8), and CYP2C9 (rs2185570; p = 2.29×10-8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.

Aging is a major risk factor for chronic disease in the human population, but there are little human data on gene expression alterations that accompany the process. We examined human peripheral blood leukocyte in-vivo RNA in a large-scale transcriptomic microarray study (subjects aged 30-104 years). We tested associations between probe expression intensity and advancing age (adjusting for confounding factors), initially in a discovery set (n= 58), following-up findings in a replication set (n=240). We confirmed expression of key results by real-time PCR. of 16,571 expressed probes, only 295 (2%) were robustly associated with age. Just six probes were required for a highly efficient model for distinguishing between young and old (area under the curve in replication set; 95%). The focused nature of age-related gene expression may therefore provide potential biomarkers of aging. Similarly, only 7 of 1065 biological or metabolic pathways were age-associated, in gene set enrichment analysis, notably including the processing of messenger RNAs (mRNAs); [P

BACKGROUND: the prevalence of psychological distress and common mental disorders has been shown to peak in midlife but analyses have ignored the association of poor material circumstances with prevalence. This study aimed to test the hypothesis that the midlife prevalence peak occurs only in lower-income households. METHOD: Pooled data were used from the annual Health Survey for England, a nationally representative cross-sectional study, on community-dwelling individuals aged ≥ 16 years from years 1997 to 2006 (n=100 457). 12-item General Health Questionnaire scores, reported mental illness diagnoses and receipt of relevant medication were assessed in relation to household income and age. Analyses were separated by gender and adjusted for age, ethnicity, smoking, social class, education and co-morbidities. RESULTS: Prevalence of psychological distress, diagnoses and treatments rose with age until early middle age and declined subsequently. In analyses conducted separately by income categories, this pattern was marked in low-income groups but absent in high-income groups. Income-related inequalities in the prevalence of psychological distress were greatest in midlife; for example, in men aged 45-54 years the odds ratio of receiving psychiatric medication in the lowest income group compared with the highest was 7.50 [95% confidence interval (CI) 4.24-13.27] and in women aged 45-54 years the odds ratio of reporting mental illness was 10.25 (95% CI 6.16-17.05). CONCLUSIONS: an increased prevalence of psychological distress, common mental disorder diagnoses and treatment in midlife is not a universal phenomenon but is found only in those in low-income households. This implies the phenomenon is not inevitable but is potentially manageable or preventable.

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count-3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

OBJECTIVES: to identify predictors of extraordinary survival. DESIGN: Longitudinal study of a cohort of elderly people followed up until almost all have died. SETTING: Two counties in Iowa; a part of the Established Populations for Epidemiologic Study of the Elderly. PARTICIPANTS: Two thousand eight hundred ninety community-dwelling citizens aged 65 to 85 at baseline and surviving at least 3 years. MEASUREMENTS: Data relating to age, sex, birth order, parental longevity, marital status, education, family income, social support, self-reported health, chronic diseases, blood pressure, body mass index, physical ability, exercise, life attitude and mental health were obtained. Extraordinary survivors (ESs) were defined to include approximately 10% of the longest survivors in their sex group. RESULTS: the 253 ESs were far more likely never to have smoked. In models adjusted for age, sex, and smoking, the earlier-life factors such as parental longevity, being earlier in the birth order (in women only), and body mass index at age 50 were associated with extraordinary survival. In similar models for predictors at age 65 to 85, extraordinary survival was associated with excellent self-reported health, fewer chronic diseases, better physical mobility and memory, and positive attitude toward life, but it was not associated with depression, anxiety, or sleep quality. In multivariable models, attitude toward life was not an independent predictor. Women in the top third of a cumulative score of independent predictors were 9.3 (95% confidence interval=4.4-19.6, P

The Second International Workshop on CMV & Immunosenescence was held in Cambridge, UK, 2-4th December, 2010. The presentations covered four separate sessions: cytomegalovirus and T cell phenotypes; T cell memory frequency, inflation and immunosenescence; cytomegalovirus in aging, mortality and disease states; and the immunobiology of cytomegalovirus-specific T cells and effects of the virus on vaccination. This commentary summarizes the major findings of these presentations and references subsequently published work from the presenter laboratory where appropriate and draws together major themes that were subsequently discussed along with new areas of interest that were highlighted by this discussion. © 2011 Wills et al; licensee BioMed Central Ltd.

Background: Studies have suggested that CMV infection may influence cardiovascular disease (CVD) risk and mortality. However, there have been no large-scale examinations of these relationships among demographically diverse populations. The inflammatory marker C-reactive protein (CRP) is also linked with CVD outcomes and mortality and may play an important role in the pathway between CMV and mortality. We utilized a U.S. nationally representative study to examine whether CMV infection is associated with all-cause and CVD-related mortality. We also assessed whether CRP level mediated or modified these relationships. Methodology/Principal Findings: Data come from subjects ≥25 years of age who were tested for CMV and CRP level and were eligible for mortality follow-up on December 31st, 2006 (N = 14153) in the National Health and Nutrition Examination Survey (NHANES) III (1988-1994). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for all-cause and CVD-related mortality by CMV serostatus. After adjusting for multiple confounders, CMV seropositivity remained statistically significantly associated with all-cause mortality (HR 1.19, 95% CI: 1.01, 1.41). The association between CMV and CVD-related mortality did not achieve statistical significance after confounder adjustment. CRP did not mediate these associations. However, CMV seropositive individuals with high CRP levels showed a 30.1% higher risk for all-cause mortality and 29.5% higher risk for CVD-related mortality compared to CMV seropositive individuals with low CRP levels. Conclusions/Significance: CMV was associated with a significant increased risk for all-cause mortality and CMV seropositive subjects who also had high CRP levels were at substantially higher risk for both for all-cause and CVD-related mortality than subjects with low CRP levels. Future work should target the mechanisms by which CMV infection and low-level inflammation interact to yield significant impact on mortality. © 2011 Simanek et al.

BACKGROUND: Common variation at chromosome 9p21 (marked by rs10757278 or rs1333049) is associated with coronary artery disease (CAD) and peripheral vascular disease. A decreasing effect at older age was suggested, and effects on long-term mortality are unclear. We estimated 9p21 associations with CAD and all-cause mortality in a CAD diagnosis-free older population. We also estimated classification gains on adding the variant to the Framingham Risk Score (FRS) for CAD. METHODS AND RESULTS: DNA was from an Established Populations for Epidemiological Study of the Elderly-Iowa cohort from 1988 (participants >71 years), with death certificates obtained to 2008 for 92% of participants. Cox regression models were adjusted for confounders and CAD risk factors. of 1095 CAD diagnosis-free participants, 52% were heterozygous (CG) and 22% were homozygous (CC) for the risk C allele rs1333049. Unadjusted CAD-attributed death rates in the CC group were 30 vs 22 per 1000 person-years for the GG group. The C allele was associated with all-cause (hazard ratio, 1.19; 95% CI, 1.08-1.30) and CAD (hazard ratio, 1.29; 95% CI, 1.08-1.56) mortality, independent of CAD risk factors. There was no association with stroke deaths. Variant associations with CAD mortality were attenuated after the age of 80 years (age-interaction term P=0.05). In age group 71 to 80 years, FRS classified as high risk 21% of respondents who died of CAD within 10 years; adding 9p21 identified 27% of respondents. CONCLUSIONS: in 71- to 80-year-old subjects free of CAD diagnoses, 9p21 is associated with excess mortality, mainly attributed to CAD mortality. Adding 9p21 to the FRS may improve the targeting of CAD prevention in older people, but validation in independent samples is needed for confirmation.

Background: Recent European studies suggest that vitamin D deficiency may be associated with increased odds of cognitive impairment in older persons, although findings from the United States are equivocal. Our objective was to investigate the association between vitamin D deficiency and cognitive impairment in the elderly U.S. population. Methods: Three thousand and three hundred twenty-five adults aged 65 years or more completed cognitive assessments, medical examinations, and physical performance measures and provided blood samples in the Third National Health and Nutrition Examination Survey, a nationally representative cross-sectional study of the U.S. noninstitutionalized population. We determined whether low levels of serum 25-hydroxyvitamin D (25(OH)D) were associated with increased odds of cognitive impairment using logistic regression models. Cognitive impairment was assessed using measures of immediate and delayed verbal memory, orientation, and attention (impairment was defined as the worst 10% of the distribution of combined scores). Results: the multivariate adjusted odds ratios (95% confidence interval) of cognitive impairment in participants who were 25(OH)D insufficient (≥50 < 75 nmol/L), deficient (≥25 < 50 nmol/L), and severely deficient (

BACKGROUND: Recent European studies suggest that vitamin D deficiency may be associated with increased odds of cognitive impairment in older persons, although findings from the United States are equivocal. Our objective was to investigate the association between vitamin D deficiency and cognitive impairment in the elderly U.S. population. METHODS: Three thousand and three hundred twenty-five adults aged 65 years or more completed cognitive assessments, medical examinations, and physical performance measures and provided blood samples in the Third National Health and Nutrition Examination Survey, a nationally representative cross-sectional study of the U.S. noninstitutionalized population. We determined whether low levels of serum 25-hydroxyvitamin D (25(OH)D) were associated with increased odds of cognitive impairment using logistic regression models. Cognitive impairment was assessed using measures of immediate and delayed verbal memory, orientation, and attention (impairment was defined as the worst 10% of the distribution of combined scores). RESULTS: the multivariate adjusted odds ratios (95% confidence interval) of cognitive impairment in participants who were 25(OH)D insufficient (≥ 50 < 75 nmol/L), deficient (≥ 25 < 50 nmol/L), and severely deficient (

BACKGROUND: Perfluorooctanoic acid (PFOA, also known as C8) and perfluorooctane sulfonate (PFOS) are stable compounds with many industrial and consumer uses. Their persistence in the environment plus toxicity in animal models has raised concern over low-level chronic exposure effects on human health. OBJECTIVES: We estimated associations between serum PFOA and PFOS concentrations and thyroid disease prevalence in representative samples of the U.S. general population. METHODS: Analyses of PFOA/PFOS versus disease status in the National Health and Nutrition Examination Survey (NHANES) for 1999-2000, 2003-2004, and 2005-2006 included 3,974 adults with measured concentrations for perfluorinated chemicals. Regression models were adjusted for age, sex, race/ethnicity, education, smoking status, body mass index, and alcohol intake. RESULTS: the NHANES-weighted prevalence of reporting any thyroid disease was 16.18% (n = 292) in women and 3.06% (n = 69) in men; prevalence of current thyroid disease with related medication was 9.89% (n = 163) in women and 1.88% (n = 46) in men. In fully adjusted logistic models, women with PFOA >or= 5.7 ng/mL [fourth (highest) population quartile] were more likely to report current treated thyroid disease [odds ratio (OR) = 2.24; 95% confidence interval (CI), 1.38-3.65; p = 0.002] compared with PFOA or= 36.8 ng/mL (quartile 4) versus

BACKGROUND: Bisphenol a (BPA) is a high production volume chemical widely used in food and drinks packaging. Associations have previously been reported between urinary BPA concentrations and heart disease, diabetes and liver enzymes in adult participants of the National Health and Nutrition Examination Survey (NHANES) 2003/04. We aimed to estimate associations between urinary BPA concentrations and health measures in NHANES 2005/06 and in data pooled across collection years. METHODOLOGY AND FINDINGS: a cross-sectional analysis of NHANES: subjects were n = 1455 (2003/04) and n = 1493 (2005/06) adults aged 18-74 years, representative of the general adult population of the United States. Regression models were adjusted for age, sex, race/ethnicity, education, income, smoking, BMI, waist circumference, and urinary creatinine concentration. Main outcomes were reported diagnoses of heart attack, coronary heart disease, angina and diabetes and serum liver enzyme levels. Urinary BPA concentrations in 2005/06 (geometric mean 1.79 ng/ml, 95% CI: 1.64 to 1.96) were lower than in 2003/04 (2.49 ng/ml, CI: 2.20 to 2.83, difference p-value = 0.00002). Higher BPA concentrations were associated with coronary heart disease in 2005/06 (OR per z-score increase in BPA = 1.33, 95%CI: 1.01 to 1.75, p = 0.043) and in pooled data (OR = 1.42, CI: 1.17 to 1.72, p = 0.001). Associations with diabetes did not reach significance in 2005/06, but pooled estimates remained significant (OR = 1.24, CI: 1.10 to 1.40, p = 0.001). There was no overall association with gamma glutamyl transferase concentrations, but pooled associations with alkaline phosphatase and lactate dehydrogenase remained significant. CONCLUSIONS: Higher BPA exposure, reflected in higher urinary concentrations of BPA, is consistently associated with reported heart disease in the general adult population of the USA. Studies to clarify the mechanisms of these associations are urgently needed.

BACKGROUND: the baby-boom generation is entering retirement. Having experienced unprecedented prosperity and improved medical technology, they should be the healthiest generation ever. METHODS: We compared prevalence of disease and risk factors at ages 50-61 years in baby boomers with the preceding generation and attributed differences to period or cohort effects. Data were from the Health Survey for England (HSE) from 1994 to 2007 (n = 48,563). Logistic regression models compared health status between birth cohorts. Age-period-cohort models identified cohort and period effects separately. RESULTS: Compared to the wartime generation, the baby-boomer group was heavier (3.02 kg; 95% confidence interval [CI], 2.42-3.63; p < 0.001) and reported more diagnoses of hypertension (odds ratio [OR] = 1.48; CI, 1.27-1.72; p < 0.001), diabetes (OR = 1.71; CI, 1.37-2.12; p < 0.001), and mental illness (OR = 1.90; CI, 1.54-2.53; p < 0.001). Baby boomers reported fewer heart attacks (OR = 0.61; CI, 0.47-0.79; p < 0.001) and had lower measured blood pressures (systolic -9.51 mmHg; CI, -8.7 to -10.31; p

BACKGROUND: Bisphenol a (BPA) is a high production volume chemical widely used in packaging for food and beverages. Numerous studies have demonstrated that BPA can alter endocrine function in animals, yet human studies remain limited. OBJECTIVE: We estimated daily excretion of BPA among adults and examined hypothesized associations with serum estrogen and testosterone concentrations. METHODS: We conducted cross-sectional analyses using data from the InCHIANTI Study, a prospective population-based study of Italian adults. Our study included 715 adults between 20 and 74 years old. BPA concentrations were measured by liquid chromatography-mass spectrometry in 24-hr urine samples. The main outcome measures were serum concentrations of total testosterone and 17beta-estradiol. RESULTS: Geometric mean urinary BPA concentration was 3.59 ng/mL [95% confidence interval (CI), 3.42-3.77 ng/mL], and mean excretion was 5.63 microg/day (5th population percentile, 2.1 microg/day; 95th percentile, 16.4 microg/day). We found higher excretion rates among men, younger respondents, and those with increasing waist circumference (p = 0.013) and weight (p = 0.003). Higher daily BPA excretion was associated with higher total testosterone concentrations in men, in models adjusted for age and study site (p = 0.044), and in models additionally adjusted for smoking, measures of obesity, and urinary creatinine concentrations (beta = 0.046; 95% CI, 0.015-0.076; p = 0.004). We found no associations with the other serum measures. We also found no associations with the primary outcomes among women, but we did find an association between BPA and SHBG concentrations in the 60 premenopausal women. CONCLUSION: Higher BPA exposure may be associated with endocrine changes in men. The mechanisms involved in the observed cross-sectional association with total testosterone concentrations need to be clarified.

A correlation between national pig-meat consumption and mortality rates from chronic liver disease (CLD) across developed countries was reported in 1985. One possible mechanism explaining this may be hepatitis E infection spread via pig meat. We aimed to re-examine the original association in more recent international data. Regression models were used to estimate associations between national pig-meat consumption and CLD mortality, adjusting for confounders. Data on CLD mortality, alcohol consumption, hepatitis B virus (HBV) and hepatitis C virus (HCV) seroprevalence for 18 developed countries (1990-2000) were obtained from WHO databases. Data on national pig-meat and beef consumption were obtained from the UN database. Univariate regression showed that alcohol and pig-meat consumption were associated with mortality from CLD, but beef consumption, HBV and HCV seroprevalence were not. A 1 litre per capita increase in alcohol consumption was associated with an increase in mortality from CLD in excess of 1.6 deaths/100,000 population. A 10 kg higher national annual average per capita consumption of pork meat was associated with an increase in mortality from CLD of between 4 and 5 deaths/100,000 population. Multivariate regression showed that alcohol, pig-meat consumption and HBV seroprevalence were independently associated with mortality from CLD, but HCV seroprevalence was not. Pig-meat consumption remained independently associated with mortality from CLD in developed countries in the 1990-2000 period. Further work is needed to establish the mechanism.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

A recent genome-wide association (GWA) study of late-onset Alzheimer's disease (LOAD) identified 15 novel single nucleotide polymorphisms (SNPs) independent of ApoE. We hypothesised that variants associated with LOAD are also associated with poor cognitive function in elderly populations. We measured additive associations between the five most strongly associated LOAD SNPs and grouped Mini Mental State Examination (MMSE) scores. Variants were genotyped in respondents (mean age 79 years) from the Oxford Healthy Ageing project (OHAP) and other sites of the MRC Cognitive Function and Ageing Study (MRC-CFAS). In adjusted ordinal logistic models, two variants were associated with poorer cognitive function: rs11622883 (OR=1.14, 95% CI: 1.01-1.28, p=0.040) and rs505058 (OR=1.29, 95% CI: 1.02-1.64, p=0.036). These SNPs are close to a SERPINA gene cluster and within LMNA, respectively. The mechanisms underlying the associations with cognitive impairment and LOAD require further elucidation, but both genes are interesting candidates for involvement in age-related cognitive impairment.

BACKGROUND: to our knowledge, no prospective study has examined the association between vitamin D and cognitive decline or dementia. METHODS: We determined whether low levels of serum 25-hydroxyvitamin D (25[OH]D) were associated with an increased risk of substantial cognitive decline in the InCHIANTI population-based study conducted in Italy between 1998 and 2006 with follow-up assessments every 3 years. A total of 858 adults 65 years or older completed interviews, cognitive assessments, and medical examinations and provided blood samples. Cognitive decline was assessed using the Mini-Mental State Examination (MMSE), and substantial decline was defined as 3 or more points. The Trail-Making Tests a and B were also used, and substantial decline was defined as the worst 10% of the distribution of decline or as discontinued testing. RESULTS: the multivariate adjusted relative risk (95% confidence interval [CI]) of substantial cognitive decline on the MMSE in participants who were severely serum 25(OH)D deficient (levels /=75 nmol/L) was 1.60 (95% CI, 1.19-2.00). Multivariate adjusted random-effects models demonstrated that the scores of participants who were severely 25(OH)D deficient declined by an additional 0.3 MMSE points per year more than those with sufficient levels of 25(OH)D. The relative risk for substantial decline on Trail-Making Test B was 1.31 (95% CI, 1.03-1.51) among those who were severely 25(OH)D deficient compared with those with sufficient levels of 25(OH)D. No significant association was observed for Trail-Making Test A. CONCLUSION: Low levels of vitamin D were associated with substantial cognitive decline in the elderly population studied over a 6-year period, which raises important new possibilities for treatment and prevention.

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10-8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10-19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10-8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10-6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10-3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk. © 2009 Richards et al.

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P <. or =5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P <. or =0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19) for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8), n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5x10(-6), n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3), n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.

Exposure to heavy metals promotes oxidative stress and damage to cellular components, and may accelerate age-related disease and disability. Physical mobility is a validated biomarker of age-related disability and is predictive of hospitalization and mortality. Our study examined associations between selected heavy metals and impaired lower limb mobility in a representative older human population. Data for 1615 adults aged 60 yr from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 were used to identify associations between urinary concentrations of 10 metals with self-reported and measured significant walking impairments. Models were adjusted for confounding factors, including smoking. In models adjusted for age, gender, and ethnicity, elevated levels of cadmium, cobalt, and uranium were associated with impairment of the ability to walk a quarter mile. In fully adjusted models, cobalt was the only metal that remained associated: the odds ratio (OR) for reporting walking problems with a 1-unit increase in logged cobalt concentration (g/L) was 1.43 (95% CI 1.12 to 1.84). Cobalt was also the only metal associated with a significant increased measured time to walk a 20-ft course. In analyses of disease categories to explain the mobility finding, cobalt was associated with physician diagnosed arthritis (1-unit increase OR = 1.22 (95% CI 1.00 to 1.49). Low-level cobalt exposure, assessed through urinary concentrations of this essential heavy metal, may be a risk factor for age-related physical impairments. Independent replication is needed to confirm this association.

Exposure to heavy metals promotes oxidative stress and damage to cellular components, and may accelerate age-related disease and disability. Physical mobility is a validated biomarker of age-related disability and is predictive of hospitalization and mortality. Our study examined associations between selected heavy metals and impaired lower limb mobility in a representative older human population. Data for 1615 adults aged >or=60 yr from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 were used to identify associations between urinary concentrations of 10 metals with self-reported and measured significant walking impairments. Models were adjusted for confounding factors, including smoking. In models adjusted for age, gender, and ethnicity, elevated levels of cadmium, cobalt, and uranium were associated with impairment of the ability to walk a quarter mile. In fully adjusted models, cobalt was the only metal that remained associated: the odds ratio (OR) for reporting walking problems with a 1-unit increase in logged cobalt concentration (mug/L) was 1.43 (95% CI 1.12 to 1.84). Cobalt was also the only metal associated with a significant increased measured time to walk a 20-ft course. In analyses of disease categories to explain the mobility finding, cobalt was associated with physician diagnosed arthritis (1-unit increase OR = 1.22 (95% CI 1.00 to 1.49). Low-level cobalt exposure, assessed through urinary concentrations of this essential heavy metal, may be a risk factor for age-related physical impairments. Independent replication is needed to confirm this association.

AIMS/HYPOTHESIS: Circulating beta-carotene levels are inversely associated with risk of type 2 diabetes, but the causal direction of this association is not certain. In this study we used a Mendelian randomisation approach to provide evidence for or against the causal role of the antioxidant vitamin beta-carotene in type 2 diabetes. METHODS: We used a common polymorphism (rs6564851) near the BCMO1 gene, which is strongly associated with circulating beta-carotene levels (p = 2 x 10(-24)), with each G allele associated with a 0.27 standard deviation increase in levels. We used data from the InCHIANTI and Uppsala Longitudinal Study of Adult Men (ULSAM) studies to estimate the association between beta-carotene levels and type 2 diabetes. We next used a triangulation approach to estimate the expected effect of rs6564851 on type 2 diabetes risk and compared this with the observed effect using data from 4549 type 2 diabetes patients and 5579 controls from the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium. RESULTS: a 0.27 standard deviation increase in beta-carotene levels was associated with an OR of 0.90 (95% CI 0.86-0.95) for type 2 diabetes in the InCHIANTI study. This association was similar to that of the ULSAM study (OR 0.90 [0.84-0.97]). In contrast, there was no association between rs6564851 and type 2 diabetes (OR 0.98 [0.93-1.04], p = 0.58); this effect size was also smaller than that expected, given the known associations between rs6564851 and beta-carotene levels, and the associations between beta-carotene levels and type 2 diabetes. CONCLUSIONS/INTERPRETATION: Our findings in this Mendelian randomisation study are in keeping with randomised controlled trials suggesting that beta-carotene is not causally protective against type 2 diabetes.

AIMS: There are a large number of common genetic variants that have been robustly associated with low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride concentrations. The majority of these have been identified or confirmed in recent genome-wide association studies, but few studies have assessed the combined effect of known lipid variants. We hypothesized that these variants would influence both the need for interventions and myocardial infarction (MI) outcomes. We aimed to estimate combined effects of proven SNPs on LDL, HDL, and triglyceride concentrations and MI history in a representative older population. METHODS AND RESULTS: in the InCHIANTI Study of Aging (age >or=65 years), we calculated individual dyslipidaemia risk allele counts for increased LDL (range 4-14, n = 594), reduced HDL (5-16, n = 635), and increased triglycerides (7-16, n = 611). Lipid levels were compared with ATPIII National Cholesterol Education Panel (NCEP) intervention guidelines. Individual variants and the APOE haplotype explained

Low plasma levels of carotenoids and tocopherols are associated with increased risk of chronic disease and disability. Because dietary intake of these lipid-soluble antioxidant vitamins is only poorly correlated with plasma levels, we hypothesized that circulating carotenoids (vitamin A-related compounds) and tocopherols (vitamin E-related compounds) are affected by common genetic variation. By conducting a genome-wide association study in a sample of Italians (n = 1190), we identified novel common variants associated with circulating carotenoid levels and known lipid variants associated with alpha-tocopherol levels. Effects were replicated in the Women's Health and Aging Study (n = 615) and in the alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) study (n = 2136). In meta-analyses including all three studies, the G allele at rs6564851, near the beta-carotene 15,15'-monooxygenase 1 (BCMO1) gene, was associated with higher beta-carotene (p = 1.6 x 10(-24)) and alpha-carotene (p = 0.0001) levels and lower lycopene (0.003), zeaxanthin (p = 1.3 x 10(-5)), and lutein (p = 7.3 x 10(-15)) levels, with effect sizes ranging from 0.10-0.28 SDs per allele. Interestingly, this genetic variant had no significant effect on plasma retinol (p > 0.05). The SNP rs12272004, in linkage disequilibrium with the S19W variant in the APOA5 gene, was associated with alpha-tocopherol (meta-analysis p = 7.8 x 10(-10)) levels, and this association was substantially weaker when we adjusted for triglyceride levels (p = 0.002). Our findings might shed light on the controversial relationship between lipid-soluble anti-oxidant nutrients and human health.

Avoiding age-related disease until late in life is key to 'successful' ageing. Over 300 genome-wide association study papers have been published. Over 50 variants have already been identified as associated with four key age-related diseases, namely cardiovascular disease, type 2 diabetes, osteoporosis and prostate cancer. We review these findings with reference to pathways linked to ageing, including cell cycle control or cell senescence, oxidative stress, insulin, IGF1 and other endocrine signalling, and inflammation. Many variants are disease specific or of unknown function. of the remainder, those with functions likely to be relevant to ageing are predominantly in cell cycle control and therefore tissue repair. Three loci associated with two or more age-related diseases have been identified, two apparently related to cell cycle control. The third shared locus (near TERT), may be involved in telomerase activity and is associated with several environmentally caused age-related cancers. These findings challenge current ideas, suggesting large numbers of cell type specific effects, often driven by regulatory rather than coding changes. They also confirm the central role of cell cycle and re-growth as a key pathway underlying the human variation in successful ageing.

BACKGROUND: Levels of the proinflammatory cytokine interleukin-18 (IL-18) are raised in old age and are associated with reduced physical functioning. Previous studies have indicated that the C allele of the rs5744256 polymorphism in the IL-18 gene is strongly associated with reduced circulating IL-18 levels. This variant has previously been associated with improved locomotor performance in old age, but the finding requires independent replication. METHODS: We examined the association between the IL-18 polymorphism rs5744256 and physical functioning in three cohorts with a total of 4,107 participants aged 60-85 years: the English Longitudinal Study of Ageing, Caerphilly, and Boyd Orr. We meta-analyzed (N = 6,141) the results with data from the original paper reporting this association: Iowa-Established Populations for Epidemiological Study of the Elderly and InCHIANTI cohorts. Physical functioning was assessed by timed walks or the get up and go test. As locomotor performance tests differed between the cohorts and the distributions of times to complete the test (in seconds) were positively skewed, we used the reciprocal transformation and computed study-specific z scores. RESULTS: Based on the three new studies, the estimated linear regression coefficient per C allele was 0.011 (95% confidence interval [95% CI]: -0.04 to 0.06). A meta-analysis that pooled the data from all studies showed weak evidence of an effect, with a regression coefficient of 0.047 (95% CI: 0.010 to 0.083). CONCLUSIONS: We did not replicate an association between the IL-18 rs5744256 polymorphism and the physical function in people aged 60-85 years. However, pooling data from all studies suggested a weak association of the C allele of the rs5744256 single nucleotide polymorphism on improving walking times in old age.

OBJECTIVES: to assess how individual socioeconomic status and neighborhood deprivation affect frailty. DESIGN: Nationally representative population-based study, the English Longitudinal Study of Aging (ELSA), analyzed cross-sectionally. PARTICIPANTS: Four thousand eight hundred eighteen individuals aged 65 and older. MEASUREMENTS: Outcome was a frailty index (FI), based on 58 potential deficits, with a theoretical range from 0 to 1; exposures were individual wealth and neighborhood deprivation (lack of local resources, financial and otherwise), based on a set of standard indicators. RESULTS: the FI score varied independently according to wealth and neighborhood deprivation. The mean FI score for an individual in the highest 20% of wealth and least deprived 20% of neighborhoods was 0.09 (95% confidence interval (CI)=0.09-0.09) and for an individual in the lowest 20% of wealth and most deprived 20% of neighborhoods was 0.17 (95% CI=0.16-0.17). CONCLUSION: Frailty in older adults is independently associated with individual and neighborhood socioeconomic factors. Older adults who are poor and live in deprived neighborhoods are most vulnerable. Policies and interventions intended to prevent or reduce frailty must take into account individual circumstances and the broader social settings in which individuals are located.

OBJECTIVES: We sought to identify the income-disability prevalence relationship among older Brazilians. METHODS: Data were from 63,985 individuals 60 years and older from the 1998 and 2003 Brazilian National Household Surveys. Generalized additive logistic models with cubic regression splines were used to estimate the disability-income relationships. RESULTS: There was a strong linear relationship between increased income and reduced disability prevalence for most of the income distribution. Benefits were still present above the 90th percentile of income but were more modest. Because incomes among the wealthiest few are disproportionately large, odds ratios of disability nevertheless showed marked improvements, even across the very highest income groups. CONCLUSIONS: Among older Brazilians, reduced disability is associated with higher income, and these associations are present even above the 90th percentile of income. In addition to understanding mechanisms of disability reduction among impoverished individuals, work is needed to understand these mechanisms in middle- and high-income groups.

BACKGROUND: a common variant at chromosome 9p21 (tagged by the rs1333049 or rs10757278 single-nucleotide polymorphism) is strongly associated with myocardial infarction and major arterial aneurysms. An association with peripheral arterial disease (PAD) was also reported in a sample younger than 75 years, but this disappeared on removal of respondents with a myocardial infarction history, resulting in an odds ratio of 1.09 for PAD (P=0.075). We aimed at estimating the association of this variant with an Ankle-Brachial Index (ABI) and PAD in 3 older populations. METHODS AND RESULTS: We used data from the InCHIANTI, Baltimore Longitudinal Study of Aging, and Health, Aging, and Body Composition studies. In 2630 white individuals (mean age, 76.4 years), the C allele at rs1333049 was associated with lower mean ABI measures and with an increased prevalence of PAD. These associations remained after removal of baseline and incident myocardial infarction cases over a 6-year follow-up for both ABI (-0.017 ABI units; 95% CI, -0.03 to -0.01; P = 1.3 x 10(-4)) and PAD (per allele odds ratio, 1.29; 95% CI, 1.06 to 1.56; P = 0.012). These associations also remained after adjustment for known atherosclerosis risk factors, including diabetes mellitus, smoking, hypercholesterolemia, and hypertension. CONCLUSIONS: the C allele at rs1333049 is associated with an increased prevalence of PAD and lower mean ABI. This association was independent of the presence of diagnosed myocardial infarction and atherosclerotic risk factors in 3 older white populations.

BACKGROUND: the human paraoxonase (PON1) protein detoxifies certain organophosphates, and the PON1 Q192R polymorphism (rs662) affects PON1 activity. Groups with higher dose exposure to organophosphate sheep dips or first Gulf War nerve toxins reported poorer health if they had 192R, and these associations have been used to exemplify Mendelian randomization analysis. However, a reported association of 192R with depression in a population-based study of older women recently cast doubt on the specificity of the higher dose findings. We aimed to examine associations between the PON1 Q192R polymorphism and self-reported poor health and depression in two independent population-based studies. METHODS: We used logistic regression models to examine the associations in men and women aged 60-79 years from the English Longitudinal Study of Ageing (ELSA, n = 3158) and InCHIANTI (n = 761) population studies. Outcomes included the Center for Epidemiologic Studies Depression (CES-D) scale, self-rated general health status and (in ELSA only) diagnoses of depression. RESULTS: the PON1 Q192R polymorphism was not associated with self-reported poor health {meta-analysis: odds ratio (OR) = 1.01 [confidence interval (CI) 0.91-1.13], P = 0.80} or depressive symptoms in either study or in meta-analyses [CES-D: OR = 1.01 (CI 0.87-1.17), P = 0.90]. There was also no association with histories of diagnosed depression in ELSA [OR = 1.03 (CI 0.82-1.30), P = 0.80]. CONCLUSIONS: We found no evidence of an association between the PON1 Q192R polymorphism and poor general or mental health in two independent population-based studies. Neither the claimed Q192R association with depression in the general population nor its theoretical implications were supported.

INTRODUCTION: Genetic factors influence circulating thyroid hormone levels, but the common gene variants involved have not been conclusively identified. The genes encoding the iodothyronine deiodinases are good candidates because they alter the balance of thyroid hormones. We aimed to thoroughly examine the role of common variation across the three deiodinase genes in relation to thyroid hormones. METHODS: We used HapMap data to select single-nucleotide polymorphisms (SNPs) that captured a large proportion of the common genetic variation across the three deiodinase genes. We analyzed these initially in a cohort of 552 people on T(4) replacement. Suggestive findings were taken forward into three additional studies in people not on T(4) (total n = 2513) and metaanalyzed for confirmation. RESULTS: a SNP in the DIO1 gene, rs2235544, was associated with the free T(3) to free T(4) ratio with genome-wide levels of significance (P = 3.6 x 10(-13)). The C-allele of this SNP was associated with increased deiodinase 1 (D1) function with resulting increase in free T(3)/T(4) ratio and free T(3) and decrease in free T(4) and rT(3). There was no effect on serum TSH levels. None of the SNPs in the genes coding for D2 or D3 had any influence on hormone levels. CONCLUSIONS: This study provides convincing evidence that common genetic variation in DIO1 alters deiodinase function, resulting in an alteration in the balance of circulating free T(3) to free T(4). This should prove a valuable tool to assess the relative effects of circulating free T(3) vs. free T(4) on a wide range of biological parameters.

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8x10(-57)), CCL4L1 (p = 3.9x10(-21)), IL18 (p = 6.8x10(-13)), LPA (p = 4.4x10(-10)), GGT1 (p = 1.5x10(-7)), SHBG (p = 3.1x10(-7)), CRP (p = 6.4x10(-6)) and IL1RN (p = 7.3x10(-6)) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8x10(-40)), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.

CONTEXT: Bisphenol a (BPA) is widely used in epoxy resins lining food and beverage containers. Evidence of effects in animals has generated concern over low-level chronic exposures in humans. OBJECTIVE: to examine associations between urinary BPA concentrations and adult health status. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of BPA concentrations and health status in the general adult population of the United States, using data from the National Health and Nutrition Examination Survey 2003-2004. Participants were 1455 adults aged 18 through 74 years with measured urinary BPA and urine creatinine concentrations. Regression models were adjusted for age, sex, race/ethnicity, education, income, smoking, body mass index, waist circumference, and urinary creatinine concentration. The sample provided 80% power to detect unadjusted odds ratios (ORs) of 1.4 for diagnoses of 5% prevalence per 1-SD change in BPA concentration, or standardized regression coefficients of 0.075 for liver enzyme concentrations, at a significance level of P <. 05. MAIN OUTCOME MEASURES: Chronic disease diagnoses plus blood markers of liver function, glucose homeostasis, inflammation, and lipid changes. RESULTS: Higher urinary BPA concentrations were associated with cardiovascular diagnoses in age-, sex-, and fully adjusted models (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.18-1.63; P =. 001 with full adjustment). Higher BPA concentrations were also associated with diabetes (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.21-1.60; P <. 001) but not with other studied common diseases. In addition, higher BPA concentrations were associated with clinically abnormal concentrations of the liver enzymes gamma-glutamyltransferase (OR per 1-SD increase in BPA concentration, 1.29; 95% CI, 1.14-1.46; P <. 001) and alkaline phosphatase (OR per 1-SD increase in BPA concentration, 1.48; 95% CI, 1.18-1.85; P =. 002). CONCLUSION: Higher BPA exposure, reflected in higher urinary concentrations of BPA, may be associated with avoidable morbidity in the community-dwelling adult population.

OBJECTIVE: Common variation in the FTO gene is associated with BMI and type 2 diabetes. Increased BMI is associated with diabetes risk factors, including raised insulin, glucose, and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits. RESEARCH DESIGN AND METHODS: We tested the association between FTO genotype and 10 metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO-BMI and BMI-trait associations. RESULTS: Each copy of the FTO rs9939609 a allele was associated with higher fasting insulin (0.039 SD [95% CI 0.013-0.064]; P = 0.003), glucose (0.024 [0.001-0.048]; P = 0.044), and triglycerides (0.028 [0.003-0.052]; P = 0.025) and lower HDL cholesterol (0.032 [0.008-0.057]; P = 0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine aminotransferase, gamma-glutamyl-transferase, LDL cholesterol, A1C, and systolic and diastolic blood pressure were in the expected direction but did not reach P < 0.05. For all metabolic traits, effect sizes were consistent with those expected for the per allele change in BMI. FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio 1.17 [95% CI 1.10-1.25]; P = 3 x 10(-6)). CONCLUSIONS: FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of >12,000 individuals were needed to detect associations at P < 0.05. Our findings highlight the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions.

OBJECTIVE: to identify socio-economic, behavioural and disease status risks for impaired balance or self-reported dizziness in older people from a large population-based study. METHODS: data were from the English Longitudinal Study of Ageing (ELSA), for 2,925 participants, aged 65+. Multivariate models were used to assess the associations between balance and dizziness and disease status, health behaviours, grip strength and socio-economic markers. RESULTS: there were 21.5% (n = 619) participants with impaired balance and 11.1% (n = 375) reported dizziness. Impaired balance was statistically significantly associated with age, diabetes (OR = 1.53), arthritis (OR = 1.33), eyesight (OR = 1.94) and grip strength. The wealthiest 20% of participants were less likely to have impaired balance than the poorest 20% (OR = 0.46). Dizziness problems were not associated with age, gender or wealth, but were significantly associated with an abnormal heart rhythm (OR = 1.85), hearing (OR = 1.81), eyesight (OR = 1.72) and grip strength. CONCLUSION: the epidemiology of impaired balance differs from that of dizziness, and risk assessment approaches to prevent falls may need to elicit information on different problem-specific factors. Impaired balance test performance in older people may be added to the many outcomes showing strong socio-economic gradients.

BACKGROUND: the relationship between stroke risk and cognitive function has not previously been examined in a large community living sample other than the Framingham cohort. The objective of this study was to examine the relationship between 10-year risk for incident stroke and cognitive function in a large population-based sample. METHODS: Participants were 7377 adults aged 50 years and over of the 2002 wave of the English Longitudinal Study of Ageing, a prospective cohort study. A modified version of the Framingham Stroke Risk Profile (incorporating age, sex, systolic blood pressure, antihypertensive medication, diabetes, smoking status, cardiovascular disease, and atrial fibrillation) was used to assess 10-year risk of stroke. Linear regression models were used to determine the cross-sectional relationship of stroke risk to global cognitive function and performance in multiple cognitive domains. RESULTS: in unadjusted models 10 percentage point increments of 10-year stroke risk were associated with poor global cognitive function (-0.40 SD units, 95% CI -0.43 - -0.38), and lowered performance in all cognitive domains. After statistical adjustment for age, sex, testing interval and other correlates of cognitive function the association with stroke risk was attenuated though remained significant for global cognitive function (-0.06 SD units, 95% CI -0.09 - -0.03), immediate and delayed verbal memory, semantic verbal fluency and processing speed. CONCLUSION: in individuals free from a history of stroke or dementia, high subclinical cerebrovascular disease burden was associated with worse cognitive function in multiple domains.

AIMS/HYPOTHESIS: There are strong associations between measures of inflammation and type 2 diabetes, but the causal directions of these associations are not known. We tested the hypothesis that common gene variants known to alter circulating levels of inflammatory proteins, or known to alter autoimmune-related disease risk, influence type 2 diabetes risk. METHODS: We selected 46 variants: (1) eight variants known to alter circulating levels of inflammatory proteins, including those in the IL18, IL1RN, IL6R, MIF, PAI1 (also known as SERPINE1) and CRP genes; and (2) 38 variants known to predispose to autoimmune diseases, including type 1 diabetes. We tested the associations of these variants with type 2 diabetes using a meta-analysis of 4,107 cases and 5,187 controls from the Wellcome Trust Case Control Consortium, the Diabetes Genetics Initiative, and the Finland-United States Investigation of NIDDM studies. We followed up associated variants (p < 0.01) in a further set of 3,125 cases and 3,596 controls from the UK. RESULTS: We found no evidence that inflammatory or autoimmune disease variants are associated with type 2 diabetes (at p

The clinical utility of newly identified genetic variants associated with common diseases needs evaluation

OBJECTIVES: to assess the relationship between cognitive function, socioeconomic status, and neighborhood deprivation (lack of local resources of all types, financial and otherwise). DESIGN: Nationally representative cross-section. SETTING: the English Longitudinal Study of Ageing (ELSA). PARTICIPANTS: Seven thousand one hundred twenty-six community-dwelling individuals aged 52 and older and resident in urban areas. MEASUREMENTS: Individual cognitive function score and index of multiple deprivation (IMD) at the Super Output Area level, adjusting for health, lifestyle, and sociodemographic confounders. Analyses were conducted separately according to sex and age group (52-69 and > or = 70). RESULTS: IMD affected cognitive function independent of the effects of education and socioeconomic status. For example, in fully adjusted models, women aged 70 and older had a standardized cognitive function score (z-score) that was 0.20 points (95% confidence interval (CI)=0.01-0.39) lower in the bottom 20% of wealth than the top 20%, 0.44 points (95% CI=0.20-0.69) lower in the least-educated group than in the most educated, and 0.31 points (95% CI 0.15-0.48) lower if resident lived in an area in the bottom 20% of IMD than in the top 20%. CONCLUSION: in community-based older people in urban neighborhoods, neighborhood deprivation--living in a neighborhood with high levels of deprivation, compared with national levels--is associated with cognitive function independent of individual socioeconomic circumstances. The mechanisms underlying this relationship are unclear and warrant further investigation.

BACKGROUND: Appropriate dental care is an important part of maintaining good oral health. We examined the relationship between socioeconomic status, neighbourhood deprivation levels and older people's dental service use. METHODS: We used logistic regression analysis to assess the relationship between self-reported dental service use and neighbourhood deprivation, adjusting for individual socioeconomic and health factors, in individuals aged 65+ in the 2005 Health Survey for England (n = 4240). RESULTS: Among dentulous respondents, 69.9% reported attending for regular check-ups, 6.2% occasional check-ups, 18.4% only saw a dentist when in trouble and 5.6% never went to a dentist. In our adjusted model age, sex, region, education level, occupational social class, self-reported health and smoking status, but not degree of urbanization, were associated with use of dental services. Following adjustment for these other factors those living in the most deprived 20% of neighbourhoods, compared with those in the least deprived, had a relative risk ratio of 2.25 (95% confidence interval 1.59-3.17) of using dental services only when symptomatic, rather than going for regular or occasional check-ups. When alternative outcomes of reporting having recently seen a doctor or been a hospital inpatient were assessed these deprivation-related patterns in service use were not evident. CONCLUSION: Levels of neighbourhood deprivation are associated with the use of dental services by older people. Action is needed to ensure older people in deprived communities access appropriate and comprehensive dental services.

OBJECTIVE: to assess whether incident mobility disability and neighbourhood deprivation in older people are associated independent of the effects of individual socio-economic status, health behaviours and health status. METHODS: prospective cohort study with a 2-year follow-up. SETTING: the English Longitudinal Study of Ageing (ELSA), a national probability sample of non-institutionalised older people. PARTICIPANTS: 4,148 participants aged 60 years and over. MEASUREMENTS: exposure was a census-based index of neighbourhood deprivation [the Index of Multiple Deprivation (IMD)]; outcomes were measured and self-reported incident mobility difficulties. RESULTS: neighbourhood deprivation had a statistically significant effect on physical function following adjustment for individual socio-economic factors, health behaviours and health status. Compared to those living in the least deprived 20% of neighbourhoods, those in the most deprived neighbourhoods had a risk ratio (RR) of incident self-reported mobility difficulties of 1.75 (95% CI 1.14-2.70) and RR of incident-impaired gait speed of 1.63 (95% CI 1.01-2.62). In adjusted models, 4.0 per 100 (95% CI 3.0-5.4) older adults in neighbourhoods in the least deprived 20% had incident mobility difficulties over a 2-year period, whereas 13.6 per 100 (95% CI 10.5-17.4) older adults had incident mobility difficulties in neighbourhoods in the most deprived 20%. CONCLUSIONS: older people living in deprived neighbourhoods are significantly more likely to experience incident mobility difficulties than those in less-deprived neighbourhoods. The mechanisms underlying this relationship are unclear and research to identify mechanisms and appropriate interventions is needed.

OBJECTIVES: to estimate the effects of excess body weight on objective and subjective physical function and mortality risks in noninstitutionalized older adults. DESIGN: Population-based cohort study. SETTING: the English Longitudinal Study of Ageing (ELSA). PARTICIPANTS: Three thousand seven hundred ninety-three participants in the ELSA aged 65 and older followed up for 5 years. MEASUREMENTS: Analyses compared the risks of impaired physical function and mortality for subjects who were at the recommended weight (body mass index (BMI)=20.0-24.9) with those who were overweight (BMI=25.0-29.9), obese (BMI=30.0-34.9) or severely obese (BMI>or=35.0). Outcome measures were difficulties with activities of daily living (ADLs), score on the Short Physical Performance Battery, and mortality. RESULTS: Participants in higher BMI categories had greater risk of impaired physical function at follow-up but little or no greater risk of mortality. For example, compared with men of recommended weight, obese men (BMI=30.0-34.9) had relative risk ratios of difficulties with ADLs of 1.99 (95% confidence interval (CI)=1.42-2.78), of measured functional impairment of 1.51 (95% CI=1.05-2.16), and of mortality of 0.99 (95% CI=0.60-1.61). Findings were robust when excluding those who lost weight, smoked, or had poor self-rated health. CONCLUSION: Excess body weight in people aged 65 and older is associated with greater risk of impaired physical function but not with greater mortality risk. Societies with growing numbers of overweight and obese older people are likely to face increasing burdens of disability-associated health and social care costs.

Plasma liver-enzyme tests are widely used in the clinic for the diagnosis of liver diseases and for monitoring the response to drug treatment. There is considerable evidence that human genetic variation influences plasma levels of liver enzymes. However, such genetic variation has not been systematically assessed. In the present study, we performed a genome-wide association study of plasma liver-enzyme levels in three populations (total n = 7715) with replication in three additional cohorts (total n = 4704). We identified two loci influencing plasma levels of alanine-aminotransferase (ALT) (CPN1-ERLIN1-CHUK on chromosome 10 and PNPLA3-SAMM50 on chromosome 22), one locus influencing gamma-glutamyl transferase (GGT) levels (HNF1A on chromosome 12), and three loci for alkaline phosphatase (ALP) levels (ALPL on chromosome 1, GPLD1 on chromosome 6, and JMJD1C-REEP3 on chromosome 10). In addition, we confirmed the associations between the GGT1 locus and GGT levels and between the ABO locus and ALP levels. None of the ALP-associated SNPs were associated with other liver tests, suggesting intestine and/or bone specificity. The mechanisms underlying the associations may involve cis- or trans-transcriptional effects (some of the identified variants were associated with mRNA transcription in human liver or lymphoblastoid cells), dysfunction of the encoded proteins (caused by missense variations at the functional domains), or other unknown pathways. These findings may help in the interpretation of liver-enzyme tests and provide candidate genes for liver diseases of viral, metabolic, autoimmune, or toxic origin. The specific associations with ALP levels may point to genes for bone or intestinal diseases.

BACKGROUND: Hip and knee joint replacement rates vary by demographic group. This article describes the epidemiology of need for joint replacement, and of subsequent receipt of a joint replacement by those in need. METHODS: Data from the Health and Retirement Study were used to assess need for hip or knee joint replacement in a total of 14,807 adults aged 60 years or older in 1998, 2000, and 2002 and receipt of needed surgery 2 years later. "Need" classification was based on difficulty walking, joint pain, stiffness, or swelling and receipt of treatment for arthritis, without contraindications to surgery. RESULTS: Need in 2002 was greater in participants who were older than 74 years (vs 60-64: adjusted odds ratio 2.06; 95% confidence interval, 1.68-2.53), women (vs men: 1.81; 1.53-2.14), less educated (vs college educated: 1.27; 1.06-1.52), in the poorest third (vs richest: 2.20; 1.78-2.72), or obese (vs nonobese: 2.39; 2.02-2.81). One hundred sixty-eight participants in need received a joint replacement, with lower receipt in black or African American participants (vs white: 0.47; 0.26-0.83) or less educated (vs college educated: 0.65; 0.44-0.96). These differences were not explained by current employment, access to medical care, family responsibilities, disability, living alone, comorbidity, or exclusion of those younger than Medicare eligibility age. CONCLUSIONS: After taking variations in need into consideration, being black or African American or lacking a college education appears to be a barrier to receiving surgery, whereas age, sex, relative poverty, and obesity do not. These disparities maintain disproportionately high levels of pain and disability in disadvantaged groups.

OBJECTIVE: to assess the receipt of effective healthcare interventions in England by adults aged 50 or more with serious health conditions. DESIGN: National structured survey questionnaire with face to face interviews covering medical panel endorsed quality of care indicators for both publicly and privately provided care. SETTING: Private households across England. PARTICIPANTS: 8688 participants in the English longitudinal study of ageing, of whom 4417 reported diagnoses of one or more of 13 conditions. MAIN OUTCOME MEASURES: Percentage of indicated interventions received by eligible participants for 32 clinical indicators and seven questions on patient centred care, and aggregate scores. RESULTS: Participants were eligible for 19 082 items of indicated care. Receipt of indicated care varied substantially by condition. The percentage of indicated care received by eligible participants was highest for ischaemic heart disease (83%, 95% confidence interval 80% to 86%), followed by hearing problems (79%, 77% to 81%), pain management (78%, 73% to 83%), diabetes (74%, 72% to 76%), smoking cessation (74%, 71% to 76%), hypertension (72%, 69% to 76%), stroke (65%, 54% to 76%), depression (64%, 57% to 70%), patient centred care (58%, 57% to 60%), poor vision (58%, 54% to 63%), osteoporosis (53%, 49% to 57%), urinary incontinence (51%, 47% to 54%), falls management (44%, 37% to 51%), osteoarthritis (29%, 26% to 32%), and overall (62%, 62% to 63%). Substantially more indicated care was received for general medical (74%, 73% to 76%) than for geriatric conditions (57%, 55% to 58%), and for conditions included in the general practice pay for performance contract (75%, 73% to 76%) than excluded from it (58%, 56% to 59%). CONCLUSIONS: Shortfalls in receipt of basic recommended care by adults aged 50 or more with common health conditions in England were most noticeable in areas associated with disability and frailty, but few areas were exempt. Efforts to improve care have substantial scope to achieve better health outcomes and particularly need to include chronic conditions that affect quality of life of older people.

This review surveys the developing market for direct-to-consumer (DTC) genetic tests and examines the range of companies and tests available, the regulatory landscape, the concerns raised about DTC testing, and the calls for enhanced oversight. We provide a comparative overview of the situation, particularly in the United States and Europe, by exploring the regulatory frameworks for medical devices and clinical laboratories. We also discuss a variety of other mechanisms such as general controls on advertising and consumer law mechanisms.

Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.

Interleukin-6 (IL-6) is a key inflammatory cytokine, signalling to most tissues by binding to a soluble IL-6 receptor (sIL-6r), making a complex with gp130. We used 1273 subjects (mean age 68 years) from the InCHIANTI Italian cohort to study common variation in the IL-6r locus and associations with interleukin 6 receptor (IL-6r), IL-6, gp130 and a battery of inflammatory markers. The rs4537545 single nucleotide polymorphism (SNP) tags the functional non-synonymous Asp358Ala variant (rs8192284) in IL-6r (r(2)=0.89, n=343). Individuals homozygous for the rs4537545 SNP minor allele (frequency 40%) had a doubling of IL-6r levels (132.48 pg/ml, 95% CI 125.13-140.27) compared to the common allele homozygous group (68.31 pg/ml, 95% CI 65.35-71.41): in per allele regression models, the rs4537545 SNP accounted for 20% of the variance in sIL-6r, with P=5.1 x 10(-62). The minor allele of rs4537545 was also associated with higher circulating IL-6 levels (P=1.9 x 10(-4)). There was no association of this variant with serum levels of gp130 or with any of the studied pro- and anti-inflammatory markers. A common variant of the IL-6r gene results in major changes in IL-6r and IL-6 serum levels, but with no apparent effect on gp130 levels or on inflammatory status in the general population.

p16(INK4a) is active in cell senescence, ageing and tumor suppression. Deletion of the small p16(INK4a)/ARF/p15(INK4b) region occurs in many cancers. We screened 25 common polymorphisms across the region and three related genes for associations with physical functioning in older people. In an initial sample of 938 (aged 65-80 years) from the EPIC study (Norfolk, UK), the rs2811712 SNP minor allele (located between the shared p16(INK4a)/ARF locus and p15(INK4b)) was associated with reduced physical impairment. This association remained after testing an additional 1319 EPIC-Norfolk samples (p-value=0.013, total n=2257), and on independent replication in the InCHIANTI study (n=709, p=0.015), and at one-sided significance in Iowa-EPESE (n=419, p=0.079). Overall (n=3372), the prevalence of severely limited physical function was 15.0% in common homozygotes and 7.0% in rare homozygotes (per minor allele odds ratio=1.48, 95% CI: 1.17-1.88, p=0.001, adjusted for age, sex and study). This estimate was similar excluding screening set 1 (OR=1.45, 95% CI: 1.09-1.92, p=0.010, n=2434). These findings require further replication, but provide the first direct evidence that the p16(INK4a)/ARF/p15(INK4b) genetic region and the senescence machinery are active in physical ageing in heterogeneous human populations. The mechanism involved may be via greater cellular restorative activity and reduced stem cell senescence.

BACKGROUND: the proinflammatory cytokine interleukin-18 (IL-18) is associated with major disabling conditions, although whether as byproduct or driver is unclear. The role of common variation in the IL-18 gene on serum concentrations and functioning in old age is unknown. METHODS: We used 1671 participants aged 65-80 years from two studies: the InCHIANTI study and wave 6 of the Iowa-Established Populations for Epidemiological Study of the Elderly (EPESE). We tested three common polymorphisms against IL-18 concentration and measures of functioning. RESULTS: in the InCHIANTI study, a 1 standard deviation increase in serum IL-18 concentrations was associated with an increased chance of being in the 20% of slowest walkers (odds ratio 1.45; 95% confidence interval, 1.17-1.80; p =.0007) and 20% of those with poorest function based on the Short Physical Performance Battery Score (odds ratio 1.52; 95% confidence interval, 1.22-1.89; p =.00016) in age sex adjusted logistic regression models. There was no association with Activities of Daily Living (p =.26) or Mini-Mental State Examination score (p =.66). The C allele of the IL-18 polymorphism rs5744256 reduced serum concentrations of IL-18 by 39 pmol/mL per allele (p =.00001). The rs5744256 single nucleotide polymorphism was also associated with shorter walk times in InCHIANTI (n = 662, p =.016) and Iowa-EPESE (n = 995, p =.026). In pooled ranked models rs5744256 was also associated with higher SPPB scores (n = 1671, p =.019). Instead of adjusting for confounders in the IL-18 walk time association, we used rs5744256 in a Mendelian randomization analysis: the association remained in instrumental variable models (p =.021). CONCLUSION: IL-18 concentrations are associated with physical function in 65- to 80-year-olds. A polymorphism in the IL-18 gene alters IL-18 concentrations and is associated with an improvement in walk speed. IL-18 may play an active role in age-related functional impairment, but these findings need independent replication.

Interleukin-1-receptor antagonist (IL-1RA) modulates the biological activity of the proinflammatory cytokine interleukin-1 (IL-1) and could play an important role in the pathophysiology of inflammatory and metabolic traits. We genotyped seven single nucleotide polymorphisms (SNPs) that capture a large proportion of common genetic variation in the IL-1RN gene in 1256 participants from the Invecchiare in Chianti study. We identified five SNPs associated with circulating IL-1RA levels with varying degrees of significance (P-value range=0.016-4.9 x 10(-5)). We showed that this association is likely to be driven by one haplotype, most strongly tagged by rs4251961. This variant is only in weak linkage disequilibrium (r(2)=0.25) with a previously reported variable number of tandem repeats polymorphism (VNTR) in intron-2 although a second variant, rs579543, that tags the VNTR (r(2)=0.91), may also be independently associated with IL-1RA levels (P=0.03). We found suggestive evidence that the C allele at rs4251961 that lowers IL-1RA levels is associated with an increased IL-1beta (P=0.03) level and may also be associated with interferon -gamma (P=0.03), alpha-2 macroglobulin (P=0.008) and adiponectin (P=0.007) serum levels. In conclusion, common variation across the IL-1RN gene is strongly associated with IL-1RA levels.

BACKGROUND: This study aims to establish the extent of educational differences in the disability transitions of incidence, recovery and mortality in people aged 65 years and over, whether these can be explained by differentials in disease burden and their relative contribution to educational differences in prevalence and disability-free life expectancy (DFLE). METHODS: a stratified random sample of 13 004 participants in five areas in England and Wales were interviewed in 1991-94 and followed up at 2, 6 (one centre only) and 10 years. Two levels of disability were analysed: mobility difficulty and activities of daily living (ADL) disability. We fitted logistic regression models to model educational differences in disability prevalence, incidence, recovery and mortality transitions. DFLE was calculated to assess the combined effect of the dynamic transitions. RESULTS: Those with < or =9 years education had higher ADL and mobility disability prevalence and higher incidence and lower recovery of mobility disability. Differences in disability incidence remained after adjustment for comorbidity. Women with the lowest education had shorter life expectancies (1.7 years less at the age of 65 years) than the most educated and had even shorter DFLE (1.9 years free of ADL disability and 2.8 years free of mobility difficulty at the age of 65 years). CONCLUSIONS: Differentials in education continue to contribute to prevalence of disability at ages beyond 65 years in both men and women and independently of diseases. These appear to be driven predominantly by differentials in disability incidence that also compound to produce greater differentials in DFLE between education groups than in total years lived.

The genetics of aging has seen extraordinary progress over the last few decades, with animal models suggesting key roles for a number of metabolic pathways. However, humans outlive laboratory models many times over, and only evidence from humans can ultimately identify the drivers of human aging. In this article we thematically review progress in identifying human genetic variants associated with longevity. We also look at the bigger picture of progress in identifying genetic associates of disease and functioning and healthy aging in older people. Although much of the existing evidence is fragmentary, recent exciting findings and robust methods are taking the field rapidly forward.

BACKGROUND: There is evidence of a U-shaped association between alcohol consumption and physical health outcomes in older people, such that moderate drinking is associated with better outcomes than abstinence or heavy drinking, but whether moderate drinking in older people is associated with better cognition and mental health than non-drinking has not been explored. OBJECTIVE: to assess the relationship between drinking and cognitive health in middle-aged and older people. DESIGN: Prospective observational study. SETTING/PARTICIPANTS: Six thousand and five individuals aged 50 and over who participated in Wave 1 of the English Longitudinal Study of Ageing (ELSA) and who were not problem drinkers. Exposure and outcome variables: we examined cognitive function, subjective well-being, and depressive symptoms, and compared the risks associated with having never drunk alcohol, having quit drinking, and drinking at

OBJECTIVES: to assess the association between physical activity and subsequent physical functioning in middle-aged adults across a range of body mass index (BMI) categories. DESIGN: Prospective nationally representative cohort studies. SETTING: the United States and England. PARTICIPANTS: Eight thousand seven hundred two individuals in the United States and 1,507 in England aged 50 to 69 and free of impairment at baseline, followed up for 6 years. MEASUREMENTS: Self-reported and measured BMI and self-reported level of physical activity. Outcome measures were score on a physical performance battery and self-reported mobility impairment. RESULTS: in both studies, being overweight and being obese were associated with greater risk of impairment (than being of recommended weight). In all weight categories and both countries, higher levels of physical activity were associated with lower risks of mobility impairment. For example, U.S. respondents of recommended weight (BMI 20-25) who were active on 3 or more days per week had a relative risk (RR) of incident mobility difficulties, compared with those who were less active, of 0.56 (95% confidence interval (CI)=0.40-0.78); for those who were obese (BMI >/=30) the corresponding RR was 0.59 (95% CI=0.45-0.76). CONCLUSION: Excess bodyweight is a risk factor for impaired physical function in middle-aged and older people. Physical activity is protective of impaired physical functioning in this age group in subjects with recommended weight, overweight, and obesity. Older adults should be encouraged to engage in appropriate levels of physical activity irrespective of their weight.

BACKGROUND: Transitions such as retirement may represent points at which changes in health behaviour occur. OBJECTIVE: to assess whether transition into retirement is associated with increased rates of smoking cessation. DESIGN: Population-based prospective cohort study in England. SETTING AND PARTICIPANTS: One thousand seven hundred and twelve smokers aged 50 years and over, followed up for 5 to 6 years. MEASUREMENTS: Work status (working/retired) and smoking status (non-smoker/smoker) at baseline and follow-up. RESULTS: at baseline, 381 (22.2%) of our respondents had retired, 444 (25.9%) were working and remained in work at follow-up, and 167 (9.8%) transitioned from work to retirement. Seven hundred and twenty (42.1%) had some other status (e.g. unpaid work/unemployment). A total of 42.5% (95% CI 34.9-50.1) of those who retired quit smoking; for those remaining in employment this figure was 29.3% (95% CI 25.0-33.6), and for those already retired it was 30.2% (95% CI 25.5-34.9). In adjusted regression analyses, those aged 55-70 who retired were more than twice as likely (fully adjusted odds ratio 2.50 (95% CI 1.35-4.62)) to quit smoking as those who continued to work. Results were robust when those who retired for reasons of ill-health were excluded. CONCLUSIONS: Our results suggest individuals who undergo the transition into retirement are more likely to quit smoking than those who do not. Interventions should be developed to specifically target those who are retiring, or soon to retire, and those who are due to retire should be helped to incorporate smoking cessation into their retirement planning.

OBJECTIVES: to assess whether there is a relationship between smoking and levels of overall quality of life, or with the pleasure domain of quality of life, in lower socio-economic groups (SES). STUDY DESIGN: Cohort study involving 9176 individuals aged 50 years and over who participated in the Health Survey for England and were followed up in Wave 1 of the English Longitudinal Study of Ageing in 2002. METHODS: We classified smokers as never-smokers, ex-smokers and current smokers, and used household wealth as a marker for socio-economic position. Pleasure was assessed using the pleasure subscale of the CASP-19 instrument, a 19-point measure of quality of life that covers four theoretical domains: control, autonomy, self-realization and pleasure. RESULTS: We found that the odds ratio for experiencing lower than median levels of pleasure for smokers with low SES was 1.42 (95% CI 1.16-1.74), and for all smokers was 1.33 (95% CI 1.17-1.51). The same pattern of associations was found when the outcome was total CASP-19 score or positive GHQ-12 score. CONCLUSIONS: We found no evidence to support a claim that smoking is associated with heightened levels of pleasure, either in people with low SES or in the general population. In fact, our results suggest the opposite: that smoking is associated with lower levels of pleasure and poorer overall quality of life. Policy decisions on smoking should consider its potentially harmful effect on quality of life and pleasure as well as on other aspects of health.

OBJECTIVES: to estimate disability plus mortality risks in older people according to level of alcohol intake. DESIGN: Two population-based cohort studies. SETTING: the Health and Retirement Study (United States) and the English Longitudinal Study of Aging (England). PARTICIPANTS: Thirteen thousand three hundred thirty-three individuals aged 65 and older followed for 4 to 5 years. MEASUREMENTS: Difficulties with activities of daily living (ADLs), instrumental activities of daily living (IADLs), poor cognitive function, and mortality. RESULTS: One-tenth (10.8%) of U.S. men, 28.6% of English men, 2.9% of U.S. women, and 10.3% of English women drank more than the U.S. National Institute on Alcohol Abuse and Alcoholism recommended limit for people aged 65 and older. Odds ratios (ORs) of disability, or disability plus mortality, in subjects drinking an average of more than one to two drinks per day were similar to ORs in subjects drinking an average of more than none to one drink per day. For example, those drinking more than one to two drinks per day at baseline had an OR of 1.0 (95% confidence interval (CI)=0.8-1.2) for ADL problems, 0.7 (95% CI=0.6-1.0) for IADL problems, and 0.8 (95% CI=0.6-1.1) for poor cognitive function. Findings were robust across alternative models. The shape of the relationship between alcohol consumption and risk of disability was similar in men and women. CONCLUSION: Functioning and mortality outcomes in older people with alcohol intakes above U.S. recommended levels for the old but within recommendations for younger adults are not poor. More empirical evidence of net benefit is needed to support screening and intervention efforts in community-living older people with no specific contraindications who drink more than one to two drinks per day.

Fasting glucose is associated with future risk of type 2 diabetes and ischemic heart disease and is tightly regulated despite considerable variation in quantity, type, and timing of food intake. In pregnancy, maternal fasting glucose concentration is an important determinant of offspring birth weight. The key determinant of fasting glucose is the enzyme glucokinase (GCK). Rare mutations of GCK cause fasting hyperglycemia and alter birth weight. The extent to which common variation of GCK explains normal variation of fasting glucose and birth weight is not known. We aimed to comprehensively define the role of variation of GCK in determination of fasting glucose and birth weight, using a tagging SNP (tSNP) approach and studying 19,806 subjects from six population-based studies. Using 22 tSNPs, we showed that the variant rs1799884 is associated with fasting glucose at all ages in the normal population and exceeded genomewide levels of significance (P=10-9). rs3757840 was also highly significantly associated with fasting glucose (P=8x10-7), but haplotype analysis revealed that this is explained by linkage disequilibrium (r2=0.2) with rs1799884. A maternal a allele at rs1799884 was associated with a 32-g (95% confidence interval 11-53 g) increase in offspring birth weight (P=.002). Genetic variation influencing birth weight may have conferred a selective advantage in human populations. We performed extensive population-genetics analyses to look for evidence of recent positive natural selection on patterns of GCK variation. However, we found no strong signature of positive selection. In conclusion, a comprehensive analysis of common variation of the glucokinase gene shows that this is the first gene to be reproducibly associated with fasting glucose and fetal growth.

BACKGROUND: a polymorphism in the transcription factor 7-like 2 (TCF7L2) gene has been found to be associated with type 2 diabetes in case-control studies. We aimed to estimate associations of the marker rs7903146 (C/T) polymorphism with fasting glucose, lipids, diabetes prevalence and complications in an older general population. METHODS: in total, 944 subjects aged > or = 65 years from the population representative InCHIANTI study were enrolled in this study. Those with fasting blood glucose of > or = 7 mmol/l or physician diagnosis were considered diabetic. Cut-off points for impaired fasting glucose (IFG) were > or = 5.6 mmol/l to < 7 mmol/l. RESULTS: in the general population sample, minor (T) allele carriers of rs7903146 had higher fasting blood glucose (FBG) (p = 0.028) but lower fasting insulin (p = 0.030) and HOMA2b scores (p = 0.001), suggesting poorer beta-cell function. T allele carriers also had smaller waist circumference (p = 0.009), lower triglyceride levels (p = 0.006), and higher high-density lipoprotein cholesterol (p = 0.008). The prevalence of diabetes or IFG was 32.4% in TT carriers and 23.3% in CC carriers; adjusted OR = 1.67 (95% confidence interval 1.05 to 2.65, p = 0.031). Within the diabetic and IFG groups, fewer T allele carriers had metabolic syndrome features (p = 0.047) or had experienced a myocardial infarction (p = 0.037). Conversely, T allele carriers with diabetes had poorer renal function (reduced 24-hour creatinine clearance, p = 0.013), and possibly more retinopathy (p = 0.067). Physician-diagnosed dementia was more common in the T carriers (in diabetes p = 0.05, with IFG p = 0.024). CONCLUSION: the TCF7L2 rs7903146 polymorphism is associated with lower insulin levels, smaller waist circumference, and lower risk lipid profiles in the general elderly population. Patients with diabetes who are carriers of the minor allele are less likely to have metabolic-syndrome features, but may experience more microvascular complications, although the number of cases was small. If replicated, these findings may have implications for developing treatment approaches tailored by genotype.

BACKGROUND: Common mental disorder prevalence decreases substantially around the conventional retirement age for men in the UK, but trends for older women are more continuous. Prevalence changes in depression and anxiety around retirement are less clear, as is the role of risk factors. The aim of this study was to establish whether work status, age or other known risk factors account for the reduced prevalence of depressive episode and anxiety disorder around retirement ages for men and for women. METHOD: the British Psychiatric Morbidity Survey (BPMS) 2000 was analysed, including 1875 men and 2253 women aged 45-75 years. Diagnoses were from the Revised Clinical Interview Schedule (CIS-R). Logistic models were adjusted for sociodemographic factors, social network, work status, life events, physical illness and disability. RESULTS: There are marked reductions in the prevalence of depressive episode after 60 years for women [60% lower prevalence, 95% confidence interval (CI) 40-80] and 65 years for men (90% lower prevalence, 95% CI 70-100), compared to the youngest age groups. For anxiety disorder, the reduction in prevalence was 80% (95% CI 60-90) for men and 40% (95% CI 20-60) for women. In fully adjusted multivariate models, the strong association between diagnoses and age groups remained, for both genders. Work status was a significant factor for men but not for women. CONCLUSION: There is a discontinuity in the prevalence of depressive episode for both men and women, coinciding with statutory retirement ages. No studied risk factor reduced the associations between age group and disorders. This population scale recovery may provide a model for understanding non-genetic factors.

BACKGROUND: Analysis of the Psychiatric Morbidity Survey of Great Britain showed that the prevalence of common mental disorders was lower amongst men at or above Britain's state pension age of 65, relative to younger men. Retirees below this age had consistently higher rates of mental disorders than working men. In contrast, the low prevalence of mental disorders amongst retirees aged 65 and older was similar to that of their working peers. The aim of this analysis was to investigate this pattern of results in a national sample of Australian men, and the mediating role of socio-demographic factors. METHOD: Data were from the Household, Income and Labour Dynamics (HILDA) in Australia survey (2003). The analyses included men aged 45-74 years who were active in the labour force (n = 1309), or retired (n = 635). Mental health was assessed using the mental health scale from the Short-Form 36 Health Questionnaire. RESULTS: Retirees were more likely to have mental health problems than their working peers, however this difference was progressively smaller across age groups. For retirees above, though not below, the age of 55 this difference was explained by poorer physical functioning. When age at retirement was considered it was found that early retirees who were now at or approaching the conventional retirement age did not display the substantially elevated rates of mental health problems seen in their younger counterparts. Further, men who had retired at age 60 or older did not display an initially elevated rate of mental health problems. CONCLUSIONS: the association between retirement and mental health varies across older adulthood. Retired British and Australian men below the conventional retirement age of 65 are more likely to have mental health problems relative to their working peers, and retirees above this age. However, poor mental health appears to be linked to being retired below this age rather than an enduring characteristic of those who retire early.

BACKGROUND: Lower limb mobility disabilities are well understood in older people, but the causes in middle age have attracted little attention. OBJECTIVES: to estimate the prevalence of mobility disabilities among noninstitutionalized adults in England and to compare the disabling symptoms reported by middle-aged and older people. DESIGN: Cross-sectional data from the 2002 English Longitudinal Study of Ageing (ELSA). Mobility disability was identified by level of reported difficulty walking a quarter mile. PARTICIPANTS: Eleven thousand two hundred sixteen respondents aged 50 years and older living in private households in 2002. RESULTS: the prevalence of difficulty walking a quarter mile increases sharply with age, but even in the middle-aged (50 to 64 years age-group) 18% (95% confidence interval [CI]: 16% to 19%) of men and 19% (95% CI: 17% to 20%) of women reported some degree of difficulty. of the 16 main symptoms reported as causing mobility disability in middle age, 2 dominated: pain in the leg or the foot (43%; 95% CI: 40% to 46%) and shortness of breath/dyspnea (21%; 95% CI: 18% to 23%). Fatigue or tiredness, and stability problems were cited by only 5% and 6%, respectively. These proportions were slightly different from those in the 65 to 79-year age group: 40%, 23%, 6%, and 8%, respectively. CONCLUSIONS: Mobility (walking) disabilities in the middle-aged are relatively common. The symptoms reported as causes in this age group differ little from those reported by older groups, and are dominated by lower limb pain and shortness of breath. More clinical attention paid to disabling symptoms may lead to disability reductions in later life.

OBJECTIVES: Hip and knee joint replacements are effective, and yet little is known about how closely the need for joint replacement matches supply in different population groups. Our objective was to compare the prevalence of existing joint replacements with that of need in population groups in England. METHODS: a total of 7101 people aged 60 yrs or older, representative of the population of England, were interviewed. Participants were asked about both receipt and need for joint replacement, socio-economic status and co-morbidity. 'Need' classification was based on hip or knee pain and difficulty walking, with adjustment for potential surgical contraindications. Associations between participants' characteristics and both need and receipt were estimated. RESULTS: the prevalence of existing joint replacement (receipt) was 6% [95% confidence intervals (CI) 5, 6], and this was lower in the North than the South [adjusted odds ratio (OR) 0.72, CI 0.53, 0.96]. In contrast, the prevalence of estimated need was higher in the North (OR 1.27, CI 1.03, 1.58). Need was greater in women than men (OR 1.30, CI 1.09, 1.53), and showed an increasing gradient from the wealthiest to poorest quintile (ORs 1.00, 1.52, 2.18, 2.49, 3.23). In contrast, receipt did not differ significantly by sex or socio-economic group. CONCLUSIONS: People living in the North of England, women and the less wealthy experience relatively high levels of need, yet do not receive relatively more hip and knee joint replacements.

Nation-wide research on mental health problems amongst men and women during the transition from employment to retirement is limited. This study sought to explore the relationship between retirement and mental health across older adulthood, whilst considering age and known risk factors for mental disorders. Data were from the 1997 National Survey of Mental Health and Well-being, a cross-sectional survey of 10,641 Australian adults. The prevalence of depression and anxiety disorders was analysed in the sub-sample of men (n = 1928) and women (n = 2261) aged 45-74 years. Mental health was assessed using the Composite International Diagnostic Instrument. Additional measures were used to assess respondents' physical health, demographic and personal characteristics. The prevalence of common mental disorders diminished across increasing age groups of men and women. Women aged 55-59, 65-69, and 70-74 had significantly lower rates of mental disorders than those aged 45-49. In contrast, only men aged 65-69 and 70-74 demonstrated significantly lower prevalence compared with men aged 45-49. Amongst younger men, retirees were significantly more likely to have a common mental disorder relative to men still in the labour force; however, this was not the case for retired men of, or nearing, the traditional retirement age of 65. Men and women with poor physical health were also more likely to have a diagnosable mental disorder. The findings of this study indicate that, for men, the relationship between retirement and mental health varies with age. The poorer mental health of men who retire early is not explained by usual risk factors. Given current policy changes in many countries to curtail early retirement, these findings highlight the need to consider mental health, and its influencing factors, when encouraging continued employment amongst older adults.

BACKGROUND: Klotho has an important role in insulin signalling and the development of ageing-like phenotypes in mice. The common functional "KL-VS" variant in the KLOTHO (KL) gene is associated with longevity in humans but its role in type 2 diabetes is not known. We performed a large case-control and family-based study to test the hypothesis that KL-VS is associated with type 2 diabetes in a UK Caucasian population. METHODS: We genotyped 1793 cases, 1619 controls and 1616 subjects from 509 families for the single nucleotide polymorphism (SNP) F352V (rs9536314) that defines the KL-VS variant. Allele and genotype frequencies were compared between cases and controls. Family-based analysis was used to test for over- or under-transmission of V352 to affected offspring. RESULTS: Despite good power to detect odds ratios of 1.2, there were no significant associations between alleles or genotypes and type 2 diabetes (V352 allele: odds ratio = 0.96 (0.84-1.09)). Additional analysis of quantitative trait data in 1177 healthy control subjects showed no association of the variant with fasting insulin, glucose, triglycerides, HDL- or LDL-cholesterol (all P > 0.05). However, the HDL-cholesterol levels observed across the genotype groups showed a similar, but non-significant, pattern to previously reported data. CONCLUSION: This is the first large-scale study to examine the association between common functional variation in KL and type 2 diabetes risk. We have found no evidence that the functional KL-VS variant is a risk factor for type 2 diabetes in a large UK Caucasian case-control and family-based study.

OBJECTIVE: to measure the risk of periretirement age disability associated with five different anthropometric measures of body mass and shape, and to compare the measures in this group, the peak age group of obesity prevalence. DESIGN: Longitudinal study of Health Survey for England 1998 respondents followed-up in the English Longitudinal Study of Ageing in 2002. SUBJECTS: National population sample of 1030 women and 888 men aged 55-74 years. MEASUREMENTS: Five baseline exposure measures (weight (WT), body mass index (BMI), waist circumference (WC), hip circumference (HC), and waist-hip ratio (WHR)) at baseline, and disability outcomes (measured gait speed, self-reported mobility problems, instrumental and ordinary activities of daily living (I/ADLs)) after 5 years. RESULTS: Individually, the heaviest quartile of WC and WHR predicted disability using all outcomes in men. In women, the heaviest category of each of the five exposure measures predicted disability, for each of the outcomes. In competing measures models, WC was included in the best fit model of tested mobility disability in men (odds ratio (OR) 2.4; 95% confidence interval (CI) 1.4-4.1; P

Objective: to estimate disability rates and explore associations, identifying the most significant socioeconomic markers associated with the prevalence of mobility disability among elderly women. Methods: National mobility disability rates were estimated based on information from the 1998 National Household Survey (PNAD), conducted by the Instituto Brasileiro de Geografia e Estatistica. The present study analyzes the elderly women population, totaling 16,186 subjects. Logistic regression models were constructed considering 'difficulty walking 100 meters' as the dependent variable. Results: the prevalence of markers of mild, moderate and severe disability was greater among women, and increased with age. In logistic regression analysis, markers most strongly associated with increased prevalence of mobility disability were age, gender low schooling, and low income. Rural residence was also associated with reduced prevalence. Conclusions: Our results suggest potential risk factors for the development of functional decline in elderly women, given that the associations encountered were consistent with those reported by other studies in the literature.

BACKGROUND: Mobility (locomotor) disability is an early marker of disability progression, health care utilisation and institutionalisation in older people. Whether mobility disability has different causes in the middle-aged has received limited attention. OBJECTIVES: to examine associations of mobility disability with sociodemographic, behaviour and disease status and to contrast these with associations in older groups. DESIGN: Cross-sectional interview data from the 2002 English Longitudinal Study of Ageing. Mobility status based on reported difficulty walking a quarter of a mile (402 m). PARTICIPANTS: a total of 11,392 community-living respondents aged 50 years and over. RESULTS: in the middle-aged, 8% (95% CI 7-9%) of women and 9% (95% CI 8-11%) of men reported having much difficulty or being unable to walk a quarter of a mile, equating to 787,000 (95% CI 700,000-831,000) people in England. Factors which at least doubled odds of mobility disability in the middle-aged were chronic obstructive lung disease, angina, stroke, recently treated cancer, comorbidity, lower limb and back pain. Factors associated with mobility disability in older groups were similar. Thirty-eight per cent of mobility disability in the middle-aged population was related to high levels of lower limb pain and 15% to high levels of back pain. CONCLUSIONS: Mobility disability in the middle-aged is relatively common. The associated conditions in the middle-aged are similar to those in older people. Lower limb and back pain make dominant population contributions to mobility disability. Prevention of later disability progression may require more attention being paid to mobility difficulties and its causes in the middle-aged.

Pharmacogenetics involves genetic testing of individual patients to guide drug treatment. Proponents argue that pharmacogenetics will achieve major gains in drug safety and efficacy, and revolutionise marketing. Pharmacogenetics also raises several policy concerns, including the need for sound information for clinical decision-making on drug-genetic test combinations. Currently, the pharmacogenetics science base and the rate of emergence of clinical applications are uncertain. Most commentary on pharmacogenetics focuses on new compounds, yet older drugs cause most adverse events. Test regulation in the USA appears fundamentally different from Europe, where evidence of safety or efficacy may not be required. Genetics research is needed as part of post-marketing surveillance systems. In routine clinical practice, computer-based health records with relevant decision support systems will also be needed. Without health policy action, pharmacogenetics could produce a new generation of poorly evaluated tests and drugs, with medicine becoming significantly less evidence-based, leading to rising costs, patient hazard and exclusions of drug-related 'genetic minorities' from evaluated treatments.

OBJECTIVE: Reports of increased rates of psychosis in prisons could be due to sampling and ascertainment differences. The authors compared two samples of subjects 16-64 years of age: those from the general population of residents in Great Britain and prisoners in England and Wales. METHOD: a random sample of remanded and sentenced male and female prisoners (N=3,142) and a two-phase, cross-sectional random sample of household residents (N=10,108) were assessed with structured questionnaires and the semistructured Schedules for Clinical Assessment in Neuropsychiatry. RESULTS: the weighted prevalence of probable functional psychosis in the past year was 4.5 per thousand (95% CI=3.1 to 5.8) in the household survey. In the prison survey, the weighted prevalence was over 10 times greater: 52 per thousand (95% CI=45 to 60). One in four prisoners with a psychotic disorder had psychotic symptoms attributed to toxic or withdrawal effects of psychoactive substances. The proportion of subjects with specific types of hallucinations or delusions did not differ between prison and household psychosis cases. CONCLUSIONS: This large study using standardized comparisons showed that the prevalence of psychosis in prisons is substantially higher than in the community and is deserving of greater attention to treatment and prevention. Apart from a minority of prisoners with symptoms attributable to psychoactive substances, the clinical symptom profile of psychosis is the same in both settings. Longitudinal research is needed to better understand these prevalence differences.

BACKGROUND: the apolipoprotein E (ApoE) e4 polymorphism is linked to increased mortality rates, Alzheimer's disease, and cardiovascular disease in older people, but previous studies have largely failed to detect an effect on self-reported mobility disability. We hypothesized that poor performance on mobility-related tests may provide a better measure of effects, and we aimed to estimate the extent to which the ApoE e4 allele increases risks of poor performance on measured mobility and self-reported mobility disability compared to e3/3, in a medium-sized population cohort. METHODS: Data were from 1262 people at baseline older than 65 years from the Longitudinal Aging Study Amsterdam (LASA), followed up for 6 years. Age- and sex-adjusted logistic regression models were used to explore associations. RESULTS: at baseline, those individuals with an e4 allele had an odds ratio of 2.26 (95% confidence interval, 1.31-3.90) for poor performance on gait speed testing ( or =20 s), compared to those with e3/3 status. At follow-up, associations between e4 status and incident poor performance on the chair stand test was significant. Associations with self-reported inability or need for help walking for 5 minutes or for climbing 15 steps were nonsignificant throughout. CONCLUSIONS: the ApoE e4 polymorphism is associated with a substantial excess of mobility limitation. The impact is detectable by performance testing, but not by self-reports. Poor results on mobility performance tests may provide a phenotype of ageing.

BACKGROUND: the social class distribution of the common mental disorders (mostly anxiety and/or depression) has been in doubt until recently. This paper reviews the evidence of associations between the prevalence of the common mental disorders in adults of working age and markers of socio-economic disadvantage. METHODS: Work is reviewed which brings together major population surveys from the last 25 years, together with work trawling for all European population studies. Data from more recent studies is examined, analysed and discussed. Because of differences in methods, instruments and analyses, little can be compared precisely, but internal associations can be examined. FINDINGS: People of lower socio-economic status, however measured, are disadvantaged, and this includes higher frequencies of the conditions now called the 'common mental disorders' (mostly non-psychotic depression and anxiety, either separately or together). In European and similar developed populations, relatively high frequencies are associated with poor education, material disadvantage and unemployment. CONCLUSION: the large contribution of the common mental disorders to morbidity and disability, and the social consequences in working age adults would justify substantial priority being given to addressing mental health inequalities, and deprivation in general, within national and European social and economic policy.

BACKGROUND: There is intense political interest in retaining older workers in the workforce, to fund lengthening retirements. While health is important in early exit from work, the health of early retirees has been little studied. OBJECTIVE: the aim of this study was to compare the health status of economically active 50- to 64-year-olds with economically inactive former workers (termed early retirees). METHODS: a total of 1,875 respondents to the 2000 Psychiatric Morbidity Survey of Great Britain were included in the analysis. Current common mental (neurotic) disorder presence was based on the revised Clinical Interview Schedule (CIS-R). RESULTS: Results in all, 71.2% of men and 66.4% of women early retirees reported having a long-standing illness. of early retired men, 22.2% have a common mental disorder compared to 8.2% of those still in work (p value of difference

OBJECTIVE: to estimate disability rates and explore associations, identifying the most significant socioeconomic markers associated with the prevalence of mobility disability among elderly women. METHODS: National mobility disability rates were estimated based on information from the 1998 National Household Survey (PNAD), conducted by the Instituto Brasileiro de Geografia e Estatística. The present study analyzes the elderly women population, totaling 16,186 subjects. Logistic regression models were constructed considering 'difficulty walking 100 meters' as the dependent variable. RESULTS: the prevalence of markers of mild, moderate and severe disability was greater among women, and increased with age. In logistic regression analysis, markers most strongly associated with increased prevalence of mobility disability were age, gender, low schooling, and low income. Rural residence was also associated with reduced prevalence. CONCLUSIONS: Our results suggest potential risk factors for the development of functional decline in elderly women, given that the associations encountered were consistent with those reported by other studies in the literature.

BACKGROUND: the impact of social transitions that might improve mental health, such as retirement, has attracted limited attention. Adverse occupational conditions and involuntary exit from work are linked to high rates of common mental disorders, but voluntary retirement is associated with improved mental health. AIMS: We aimed to estimate the prevalence of common mental disorders around the conventional retirement age and to identify the associated factors that might explain differences in rates. METHODS: Data were from the Psychiatric Morbidity Survey of Great Britain (2000), covering a sample of 8,580 respondents aged 16-74 years. Current common mental (neurotic) disorder presence was based on the revised Clinical Interview Schedule. RESULTS: Prevalence rates for having any common mental disorder in men aged 65-69 years (5%; 95% CI: 2.7-7.3) were dramatically lower than in the agegroup 60-64 years (14.5%; 95 % CI: 10.6-18.5). This pattern applied to individual disorders and to the prevalence of very high symptoms counts. Prevalence rates in women peaked at age 50 and declined thereafter, but no large changes in prevalence are evident around age 60 or 65 years. In men leaving work early (aged 50-64 years), prevalence of common mental disorders remains high until the conventional retirement age. There is little change in exposure to other studied risk factors capable of explaining prevalence reduction, with the exception of decreased economic hardship in the older group. CONCLUSION: in the general population aged 50-74 years,there is a dramatic improvement in mental health in men after the conventional retirement age, but not in women. In men who leave work earlier, prevalence remains relatively high until after age 65.

BACKGROUND: Measurement of the quality of health care is essential for quality improvement, and patients are an underused source of data about quality of care. We describe the adaptation of a set of USA quality indicators for use in patient interview surveys in England, to measure the extent to which older patients receive a broad range of effective health care interventions in both primary and secondary care. METHOD: One hundred and nineteen quality indicators covering 16 clinical areas, based on a set of indicators for the care of vulnerable elderly patients in the USA, were reviewed by a panel of 10 clinical experts in England. A modified version of the RAND/UCLA appropriateness method was used and panel members were supplied with literature reviews summarising the evidence base for each quality indicator. The indicators were sent for comment before the panel meeting to UK charitable organisations for older people. RESULTS: the panel rated 102 of the 119 indicators (86%) as valid for use in England; 17 (14%) were rejected as invalid. All 58 indicators about treatment or continuity and follow up were rated as valid compared with just over half (13 of 24) of the indicators about screening. CONCLUSIONS: These 102 indicators are suitable for use in patient interview surveys, including the English Longitudinal Study of Ageing (ELSA). The systematic measurement of quality of care at the population level and identification of gaps in quality is essential for quality improvement. There is potential for transfer of quality indicators between countries, at least for the health care of older people.

Background Cholinesterase inhibitors produce small improvements in cognitive and global assessments in Alzheimer's disease. We aimed to determine whether donepezil produces worthwhile improvements in disability, dependency, behavioural and psychological symptoms, carers' psychological wellbeing, or delay in institutionalisation. If so, which patients benefit, from what dose, and for how long? Methods 565 community-resident patients with mild to moderate Alzheimer's disease entered a 12-week run-in period in which they were randomly allocated donepezil (5 mg/day) or placebo. 486 who completed this period were rerandomised to either donepezil (5 or 10 mg/day) or placebo, with double-blind treatment continuing as long as judged appropriate. Primary endpoints were entry to institutional care and progression of disability, defined by loss of either two of four basic, or six of 11 instrumental, activities on the Bristol activities of daily living scale (BADLS). Outcome assessments were sought for all patients and analysed by logrank and multilevel models. Findings Cognition averaged 0·8 MMSE (mini-mental state examination) points better (95% CI 0·5-1·2; p

INTRODUCTION: Socio-economic differences in mobility disability prevalence in old age have been reported from the US and Europe. Brazil is characterised by gross socio-economic inequalities, but there have been no previous national data on disability prevalence. AIM: This study aimed to estimate disability rates and explore associations identifying the most significant socio-economic markers associated with mobility disability prevalence in old age in Brazil. SUBJECTS AND METHODS: a nationally representative sample of 28,943 people aged 60 years or over was interviewed, in the 1998 National Household Survey (PNAD), conducted by the Brazilian Institute of Geography and Statistics. RESULTS: the prevalence rates of markers of mild, moderate and severe disability were higher in women than men, and increased with age. Prevalence rates of difficulty with personal care and medium distance walking were broadly similar to England, but far more Brazilians reported difficulty climbing stairs. In logistic regression analyses, the strongest markers associated with increased mobility disability prevalence were age, gender, lack of education and low income. Rural residence was also associated with reduced prevalence. Limited differences by region were present, and there were mixed effects for self-reported racial group for women. CONCLUSIONS: Disability in the older population of Brazil shows familiar prevalence patterns by age and gender. Disparity in income and educational attainment in Brazil are the most important markers associated with group differences in mobility disability prevalence in old age.

BACKGROUND: Trends in health treatments and outcomes in the general population may be used to monitor achievement of health targets. AIMS: to investigate changes in mental health services and treatment in Britain over a 7-year period. METHOD: National surveys of psychiatric morbidity were completed in 1993 and 2000 in households throughout Great Britain. Standardised interviews were used to establish psychiatric case status and service and treatment utilisation in adults aged 16-64 years. RESULTS: Use of psychotropic medication doubled in those designated as psychiatric cases. In the non-case-status population antidepressant use rose from 0.16% in 1993 (95% CI 0.07-0.25) to 2.02% in 2000 (95% CI 1.69-2.35). However, the overall prevalence of neurotic and psychotic disorder hardly changed from 1993 to 2000. Use of specialised 'talking treatments'did not increase significantly, except in the non-case group. CONCLUSIONS: Treatment with psychotropic medication alone is unlikely to improve the overall mental health of the nation. A policy based almost exclusively on treatment of identified cases should be augmented by preventive approaches.

BACKGROUND: Disability questions require older people to report difficulties with everyday activities, using broad categorical responses. Relatively little is known about population group differences in the thresholds for reporting difficulty or inability with medium-distance mobility against tested mobility-related performance. We aimed to estimate the thresholds on tested performance at which self-reports change from one category to another, across a range of sociodemographic subgroups. We also aimed to compare reported and tested performance across two national population studies. METHODS: the samples were from the third U.S. National Health and Nutrition Examination Study (NHANES III) and the Longitudinal Aging Study Amsterdam (LASA). Measures of gait speed, chair stands, and peak expiratory flow rate in both studies yielded the validated index of mobility-related physical limitations (MOBLI). Latent probit models were used to estimate cutpoints (thresholds) on the index for reporting difficulty or inability to walk a medium distance. RESULTS: Thresholds for reporting difficulty or inability were studied by age, sex, race, educational level, and income in NHANES III. In models adjusting for the other factors, performance thresholds for reporting disability categories varied by age and income. The younger elderly persons in NHANES III on average reported difficulties or inabilities only when they reached a more severe level of tested limitation compared with older old persons. A similar pattern exists for those on higher incomes. For race, differences in threshold were present only for reporting inability, but not difficulty. Significant differences in thresholds were not present between groups defined by sex or for years of education. Comparisons between the NHANES and LASA studies show that lower reported mobility difficulty or inability prevalence in the Dutch sample is attributable both to reporting at higher levels of limitation and to better functioning. CONCLUSIONS: There is evidence of differences in thresholds for reporting mobility disability, especially across age and income groups in older Americans. Further work is needed to understand the perceptual, attitudinal, or environmental factors that cause these reporting differences.

BACKGROUND: in contrast to acute treatment, delivery of aftercare to depressed patients has not been well studied. Poor care may contribute to poor outcomes for treated depression. METHODS: One hundred and two patients discharged from hospital with unipolar depression were followed up 18 months later and were interviewed in detail regarding aftercare and treatment received. Unmet needs were assessed on the community version of the MRC Needs for Care Assessment. RESULTS: in the first month after discharge approximately 70 % of subjects received contacts with mental health services and in the first 3 months over 80 % received at least one contact. About 40 % were in contact with mental health services at 18 months. Needs assessment found comparatively low unmet needs, reaching highest levels (around 25 % in any 6-month period) for medication. Two-thirds of unmet needs for medication and psychotherapy were due to patient refusal or non-compliance. Aftercare levels were higher in those with more previous admissions and were unrelated to presence of personality disorder. CONCLUSIONS: There were some deficiencies in service aftercare for depressed patients in a British NHS setting, although unmet need was not high. Some aftercare failures reflect patient reluctance to receive further treatment, representing a challenge to overcome in patients entitled to autonomous choices.

The new genetics is stimulating the development of genetic testing of patients to help choose the best drug, adjust doses and avoid side effects. Proponents say that this personalized medicine will revolutionize drug development and healthcare. In a series of group meetings, 48 leading experts from regulatory agencies, industry, academia and consumer interests gave their opinions on the public policy priorities. Most believed that pharmacogenetics would have a clear impact on care within 15 years and that a public policy response was needed. The establishment of a good clinical evidence base should be a priority, together with addressing the needs of drug response gene minorities. A total of 72% also believed that postmarketing surveillance systems should be collecting DNA from patients experiencing moderate or severe adverse events.

BACKGROUND AND AIMS: Hip and knee replacements have become increasingly common in the older population but the prevalence of these procedures and the potential impact on functioning towards the end of life have not been previously described. The aim of this study was to estimate the rates and distribution of hip and knee joint replacements and hip implants (surgical pins, screws, rods, plates, etc.) in people aged 65 and over who died in the US in 1993, and to measure mobility outcomes during their last year of life. METHODS: Data were drawn from the 1993 National Mortality Followback Survey; 7684 deaths in people aged 65 years or over were included. From these data full informant interviews were available for 6586 (86%). Three hundred and forty-four decedents had hip joint replacements, 357 had hip implants, and 102 had knee joint replacements. Replicate methods were used to obtain weighted estimates for all decedents in the 1993 US base population. RESULTS: of female and male decedents, 15.5% (95% CI: 14.3-16.7) and 6.1% (95% CI: 3.9-8.2), respectively, had received the studied devices. About 80% of these had been implanted more than a year before death. There were large differences in the risks of receiving a hip joint replacement or a hip implant depending on gender, education and race. About 60% of recipients either had no difficulty in getting around their own homes during the last year of life or had difficulty lasting less than 6 months. CONCLUSIONS: Implanted hip and knee devices were common in older people who died in the US in 1993. Large sociodemographic differences in those who received vs those who did not were present at the end of life. While difficulty in walking is the main indication for joint replacements, a majority of those receiving replacements experienced less than 6 months of mobility difficulties in their own homes during the last year of their lives.

BACKGROUND: Interpreting self-reported disability differences between diverse older populations is complicated by differences in attitudes and environment. We have previously reported on the index of mobility-related limitation tests (MOBLI), and shown that it predicts mortality over 4 years. In this article, we examine whether the index is responsive to changes in self-reported mobility disability. METHODS: Data on gait speed, time to complete 5 chair stands, and peak expiratory flow rate, with self-reported difficulty walking for 5 minutes, were available from the baseline and two 3-year follow-ups in the Longitudinal Aging Study Amsterdam. Analysis used data on changes in the index (or walking speed alone) and corresponding change over 3 years in self-reported difficulty or inability with a medium-distance walk. RESULTS: During all follow-ups, groups reporting deterioration in functioning had relatively larger changes in gait speed and MOBLI score than did the "no deterioration" groups. In comparative analyses of responsiveness, the MOBLI score had a larger responsiveness index, higher odds ratios, and larger receiving operating characteristic area than gait speed alone. CONCLUSIONS: the MOBLI index of mobility-related physical limitation tests is responsive to changes in self-reported mobility disability over two 3-year periods, and performs better than gait speed alone. This property is strongly supportive of its validity for epidemiological comparison of older populations across countries or over longer periods of time.

BACKGROUND: of two large-scale government-commissioned studies of common mental disorders in the UK, one found occupational social class to be the strongest marker of risk while the other showed no clear relationship. This study reviews the published evidence on the links between conventional markers of social position and the common mental disorders in developed countries. METHODS: Inclusion criteria covered general population based studies with broad social class variation; samples of 3,000 or more adults of working age; identification of mental illness by validated instruments; social position identified by explicit standard markers; fieldwork undertaken since 1980; published output on key areas of interest. Incompatible study methods and concepts made statistical pooling of results invalid. RESULTS: of nine studies, eight provide evidence of an association between one or more markers of less privileged social position and higher prevalence of common mental disorders. For some individual indicators in particular studies, no clear trend was evident, but no study showed a contrary trend for any indicator. The more consistent associations were with unemployment, less education and low income or material standard of living. Occupational social class was the least consistent marker. CONCLUSIONS: Common mental disorders are significantly more frequent in socially disadvantaged populations. More precise indicators of education, employment and material circumstances are better markers of increased rates than occupational social class.

BACKGROUND: Published studies linking the common mental disorders with social disadvantage lack basic comparability. This project aimed to estimate effect sizes and independence of social position markers as risk factors for common mental disorders. Disorders with disability were examined to identify groups with high clinical and policy priority. METHODS: Data from the 1993 household survey of psychiatric morbidity in Great Britain were analysed using logistic regression models, using traditional and more specific markers of social position. RESULTS: of those with a common mental disorder, 22 % reported difficulty doing at least one activity of daily living, linked to their mental symptoms. In comprehensive statistical analyses, having two or more physical illnesses was associated with an odds ratio of 6.42 (95 % CI 4.34-9.51) for common mental disorder with disability, while odds ratios of 3 or more were present for being economically inactive or having had two or more recent adverse life events. Occupational social class was not an independent marker of raised rates of disorder. Similar patterns of result were present for common mental disorders irrespective of disability, although odds ratios were smaller. CONCLUSIONS: Several specific markers of less privileged status are independently associated with raised rates of common mental disorders, with or without disability. There may be scope to target specific high-risk groups within comprehensive programmes to reduce mental health inequalities.

BACKGROUND: self-reported disability reflects physical, environmental and attitudinal factors. We have previously reported the empirical identification of three simple tests to provide an index of (ambulatory) mobility-related physiological limitations (MOBLI). Evidence of the MOBLI 's responsiveness over time has been presented. Evidence of the predictive validity of the index is needed. OBJECTIVE: we aimed to measure the predictive validity for future mortality of the MOBLI and of self-reported mobility disability in a longitudinal cohort study. METHODS: data are from the sixth annual interview for two sites in the Established Populations for Epidemiologic Studies of the Elderly study. Included were 3,040 people, with information about self-reported walking difficulties, walking speed, time to complete five chair stands and peak expiratory flow. Age- and sex-adjusted death rates over a 4-year follow-up were computed, and proportional hazards regression models were used in the analysis. RESULTS: the MOBLI score is associated with subsequent mortality over 4 years, with evidence of a 'dose-response' relationship. The predictive value for mortality of the MOBLI score is similar to that of self-reported mobility disability in the studied population. CONCLUSIONS: the 'objective' MOBLI index has predictive validity as a continuous or dichotomised measure of the physiological component of mobility limitation in older populations. Given its empirical basis and face validity, predictive validity and responsiveness to change, MOBLI should be considered for local validation and use in epidemiological comparisons of older populations across countries or over longer periods of time.

BACKGROUND: at the lower end of IQ distributions in general populations, there is a clear excess of cases, representing the distinct pathology of severe learning disability. This study aimed to establish whether such a subpopulation exists in distributions of common mental disorder and depression symptom scores, above epidemiological 'case' cut-offs. METHOD: Data from 9556 non-psychotic respondents to the 1993 OPCS (Office of Population Censuses and Surveys) National Household Psychiatric Morbidity Survey were analysed. The distribution of total neurotic symptom and depression scores from the revised Clinical Interview Schedule were examined. Automated least squares methods were used to fit the best single statistical distribution to the data. RESULTS: a single exponential curve provided the best fit for the whole population, but floor effects produced deviations at symptom counts of 0-3. After truncation, exponential distributions fitted excellently. Proportions of the population above conventional cut-offs of > or = 12 symptoms differed by < 12% from expected for a range of low and high prevalence groups. The single exponential model also fitted the depression score. CONCLUSIONS: Symptom counts for the common mental disorders fall within single population distributions, with little apparent numerical excess in the case range. High and low prevalences of these disorders appear to be population characteristics, with shifts in exponential means predicting proportions above case cut-offs.

BACKGROUND: Disability reflects physiological limitations, social and environmental barriers, and "sickness" behavior. Being able to measure these influences separately would greatly assist interpretation of disability comparisons over time or between populations. This study aimed to identify an index of mobility-related limitations composed of physiological measures that are most closely associated with reported mobility disability in elders. METHODS: Data from the Third National Health and Nutrition Examination Survey (NHANES III) were used. Participants aged 60 and older were included in this analysis. Participants included 6596 respondents who were interviewed in their homes, and 5724 (87%) of these attended a further examination. Domains of measurements included body measurements, bone densitometry, physical examination, spirometry, fundus photography, and physical performance measures. Multivariate models were developed on a random half subsample of the data and were validated on the other half. Receiver operating characteristic (ROC) areas and logit rank slopes were used to evaluate sets of measures. RESULTS: in weighted logistic regression models, six and five measures were significantly associated with difficulty and inability in walking a quarter of a mile, respectively. These mainly included measures of lower extremity and lung function. A relatively minimal loss of sensitivity and specificity occurred from using more economical models, employing a subset of the identified measures. CONCLUSIONS: Subsets of measures associated with reported mobility disability could provide objective indices of mobility-related limitation for comparing populations or long-term population health monitoring.

OBJECTIVES: Older people with less education have substantially higher prevalence rates of mobility disability. This study aimed to establish the relative contributions of incidence, recovery rates, and death to prevalence differences in mobility disability associated with educational status. METHODS: Data were from 3 sites of the Established Populations for Epidemiological Study of the Elderly, covering 8,871 people aged 65-84 years who were followed for up to 7 years. Participants were classified on years of education received and as disabled if they needed help or were unable to walk up or down stairs or walk half a mile. A Markov model computed relative risks, adjusting for the effects of repeated observations on the same individuals. RESULTS: Differences between education groups in person-years lived with disability were large. The relative risk of incident disability in men with 0-7 years of education (vs. those with 12 or more years) was 1.65 (95% CI = 1.37-1.97) and in women was 1.70 (95% CI = 1.15-2.53). Both recovery risks and risks of death in those with disability were not significantly different across education groups in either gender. DISCUSSION: Higher incidence of disability is the main contributor to the substantially higher prevalence of disability in older people of lower socioeconomic status. Efforts to reduce the disparity in disability rates by socioeconomic status in old age should focus mainly on preventing disability, because differences in the course of mobility disability after onset appear to play a limited role in the observed prevalence disparities.

OBJECTIVES: to estimate the prevalence of problem behavior in the last year of life in older people and to explore risk factors and assess the effect of behaviors on access to care. DESIGN: Retrospective analysis of data from the 1993 National Mortality Followback Survey, conducted by the National Center for Health Statistics (NCHS). SETTING: Persons who resided and died in the United States (except South Dakota) in 1993. PARTICIPANTS: Seven thousand six hundred and eighty-four deaths in people age 65 and older were included, from which full informant interview data were available for 6,748 decedents (88%). MEASUREMENTS: Informant data were collected on frequency of complaints about behavior from family members, complaints from others in the community, bizarre behavior, destroying property, violent threats or attempts, and temper tantrums. RESULTS: Overall, 20% of decedents were reported as having any of the problem behaviors sometimes or often in the last year of life. Rates differed little by age at death or gender. Risks of having problem behaviors were higher for those with clinically diagnosed dementia, mental illness, alcohol abuse, and bronchitis or emphysema. A diagnosis of dementia had been made in 27% of those with behavior problems. Nursing homes or healthcare facilities were the usual residence of 32% of people with any behavior problems sometimes or often during their last year of life. Informants for decedents who had destroyed property or made violent threats were 2.3 times (95% confidence interval (CI) = 1.2-4.4) more likely to report that the subject had not received the care they had needed during the last year of life. CONCLUSION: Problem behavior is relatively common in older people in the last year of life and is not confined to nursing home residents or people suffering from dementia.

BACKGROUND: Alzheimer's disease is the most common cause of dementia and is a primary degenerative disease of the brain of unknown cause. Onset is usually late in life with increasing impairment of memory, developing gradually into a global impairment of cognition, orientation, linguistic ability and judgement. The clinical course is accompanied by growing disability and dependency on care. One of the characteristic features of the disease is the widely variable rate of progression seen in different patients. Acetylcholine is an important neurotransmitter associated with memory, and abnormalities in cholinergic neurones (including cell loss) are among the many neurological and neurochemical abnormalities that develop in AD. One approach to lessening the impact of these abnormalities is to inhibit the breakdown of acetylcholine by blocking the relevant enzyme. Tacrine was the first compound approved as a treatment for AD in the US and worked in this way, but caused severe side effects. E2020 (donepezil, Aricept) is a second generation cholinesterase inhibitor and appears to be highly specific, with relatively few side effects. OBJECTIVES: the objective of this review is to assess whether or not donepezil improves the well-being of patients with mild or moderate Alzheimer's disease. SEARCH STRATEGY: the Cochrane Dementia and Cognitive Impairment Group Register of Clinical Trials, was searched using the terms 'donepezil', 'E2020' and 'ARICEPT'. Medline, PsychLIT and EMBASE electronic databases were searched with the above terms. Members of the Donepezil Study Group and Eisai Inc were contacted. SELECTION CRITERIA: all unconfounded, double-blind, randomised controlled trials in which treatment with donepezil was administered for more than a day and compared with placebo in patients with Alzheimer's disease. DATA COLLECTION AND ANALYSIS: Data were extracted independently by the reviewers (JSB & DB), pooled where appropriate and possible, and the weighted or standardised mean differences or Peto odds ratios (95%CI) estimated. Where possible, intention-to-treat data were used. MAIN RESULTS: There are 4 included trials, covering treatment of 12 or 24 weeks duration in highly selected patients. The only information available on one trial (Gauthier 1998) is a conference abstract which reports no usable results. Available outcome data cover domains including cognitive function and global clinical state, but data on several important dimensions of outcome are not available. The results of three trials suggest a small beneficial effect of donepezil in improving cognitive function: at a 5mg/day dose, improvements measured -2.6 points (95%CI -3.5 -- -1.8) on weighted mean difference, in the midrange of the 70 point ADAS-Cog scale. The results of two trials show some improvement in global clinical state (assessed by an independent clinician) in those treated with donepezil compared to placebo. The patient's own rating of their Quality of Life showed no benefit of donepezil compared with placebo. There were significantly more withdrawals before the end of treatment from the 10mg/d (but not the 5mg/d) donepezil group compared with placebo, which may have resulted in some overestimation of beneficial changes at 10mg/d in progressively declining characteristics, as last available measures were used in analyses. A variety of adverse effects were recorded, but very few patients left a trial as a direct result of the intervention. REVIEWER'S CONCLUSIONS: in selected patients with mild or moderate Alzheimer's disease treated for periods of 12 or 24 weeks, donepezil produced modest improvements in cognitive function and study clinicians rated global clinical state more positively in treated patients. No improvements were present on patient self-assessed quality of life and data on many important outcomes are not available. The practical importance of these changes to patients and carers is unclear.

BACKGROUND: Alzheimer's disease is the most common cause of dementia and is a primary degenerative disease of the brain of unknown cause. Onset is usually late in life with increasing impairment of memory, developing gradually into a global impairment of cognition, orientation, linguistic ability and judgement. The clinical course is accompanied by growing disability and dependency on care. One of the characteristic features of the disease is the widely variable rate of progression seen in different patients. Acetylcholine is an important neurotransmitter associated with memory, and abnormalities in cholinergic neurones (including cell loss) are among the many neurological and neurochemical abnormalities that develop in AD. One approach to lessening the impact of these abnormalities is to inhibit the breakdown of acetylcholine by blocking the relevant enzyme. Tacrine was the first compound approved as a treatment for AD in the US and worked in this way, but caused severe side effects. E2020 (donepezil, Aricept) is a second generation cholinesterase inhibitor and appears to be highly specific, with relatively few side effects. OBJECTIVES: the objective of this review is to assess whether or not donepezil improves the well-being of patients with mild or moderate Alzheimer's disease. SEARCH STRATEGY: the Cochrane Dementia and Cognitive Impairment Group Register of Clinical Trials, was searched using the terms 'donepezil', 'E2020' and 'ARICEPT'. Medline, PsychLIT and EMBASE electronic databases were searched with the above terms. Members of the Donepezil Study Group and Eisai Inc were contacted. SELECTION CRITERIA: all unconfounded, double-blind, randomised controlled trials in which treatment with donepezil was administered for more than a day and compared with placebo in patients with Alzheimer's disease. DATA COLLECTION AND ANALYSIS: Data were extracted independently by the reviewers (JSB & DB), pooled where appropriate and possible, and the weighted or standardised mean differences or Peto odds ratios (95%CI) estimated. Where possible, intention-to-treat data were used. MAIN RESULTS: There are 4 included trials, covering treatment of 12 or 24 weeks duration in highly selected patients. The only information available on one trial (Gauthier 1998) is a conference abstract which reports no usable results. Available outcome data cover domains including cognitive function and global clinical state, but data on several important dimensions of outcome are not available. The results of three trials suggest a small beneficial effect of donepezil in improving cognitive function: at a 5mg/day dose, improvements measured -2.6 points (95%CI -3.5 -- -1.8) on weighted mean difference, in the midrange of the 70 point ADAS-Cog scale. The results of two trials show some improvement in global clinical state (assessed by an independent clinician) in those treated with donepezil compared to placebo. The patient's own rating of their Quality of Life showed no benefit of donepezil compared with placebo. There were significantly more withdrawals before the end of treatment from the 10mg/d (but not the 5mg/d) donepezil group compared with placebo, which may have resulted in some overestimation of beneficial changes at 10mg/d in progressively declining characteristics, as last available measures were used in analyses. A variety of adverse effects were recorded, but very few patients left a trial as a direct result of the intervention. REVIEWER'S CONCLUSIONS: in selected patients with mild or moderate Alzheimer's disease treated for periods of 12 or 24 weeks, donepezil produced modest improvements in cognitive function and study clinicians rated global clinical state more positively in treated patients. No improvements were present on patient self-assessed quality of life and data on many important outcomes are not available. The practical importance of these changes to patients and carers is unclear.

BACKGROUND: Alzheimer's disease is the most common cause of dementia in older people. One of the aims of therapy is to inhibit the breakdown of a chemical neurotransmitter, acetylcholine, by blocking the relevant enzyme. This can be done by a group of chemicals known as cholinesterase inhibitors. However, some (like tacrine) are associated with adverse effects such as hepatotoxicity, but E2020 (donepezil, Aricept) is thought to be more specific in its action, and safer. OBJECTIVES: the objective of this review is to assess whether or not donepezil improves the well-being of patients with mild or moderate Alzheimer's disease. SEARCH STRATEGY: the Cochrane Dementia and Cognitive Improvement Group specialized register was searched using the terms 'donepezil', 'E2020' and 'Aricept'. Members of the Donepezil Study Group and Eisai Inc were contacted. SELECTION CRITERIA: all unconfounded, double-blind, randomized controlled trials in which treatment with donepezil was compared with placebo for patients with Alzheimer's disease. DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer (JSB ), pooled where appropriate and possible, and the weighted mean differences or Peto odds ratios (95%CI) estimated. Where possible, intention-to-treat (ITT) data were used. MAIN RESULTS: Eight trials are included, involving 2664 participants. The trials were of 12, 24 or 52 weeks duration in selected patients. Available outcome data cover domains including cognitive function and global clinical state, but data on several important dimensions of outcome are not available. For cognition there is a statistically significant improvement for both 5 and 10 mg/day of donepezil at 24 weeks compared to placebo (1.9 points on the ADAS-Cog scale, WMD 1.86, 95%CI -2.60 to -1.11; 2.9 points on the ADAS-Cog scale, WMD -2.91, 95% CI -3.65 to -2.16)and for 10mg/day donepezil compared to placebo at 52 weeks (1.7 MMSE points, 95% CI, -2.59 to -0.82). The results of three studies show some improvement in global clinical state (assessed by an independent clinician) in those treated with 5 and 10mg/day of donepezil compared with placebo at 12 and 24 weeks. The patients' own ratings of their Quality of Life showed no benefit of donepezil compared with placebo. There were significantly more withdrawals before the end of treatment from the 10mg/day (but not the 5mg/day) donepezil group compared with placebo which may have resulted in some overestimation of beneficial changes at 10mg/day a variety of adverse effects were recorded, with more incidents of nausea, vomiting, diarrhoea and anorexia in the 10mg/day group compared with placebo and the 5mg/day group, but very few patients left a trial as a direct result of the intervention. REVIEWER'S CONCLUSIONS: in selected patients with mild or moderate Alzheimer's disease treated for periods of 12, 24 or 52 weeks, donepezil produced modest improvements in cognitive function and study clinicians rated global clinical state more positively in treated patients. No improvements were present on patient self-assessed quality of life and data on many important outcomes are not available. The practical importance of these changes to patients and carers is unclear.

OBJECTIVES: the longer life expectancy in old age of more privileged socioeconomic groups is well established, but less clear is whether the net effect of additional years of life is a lengthened, stable or reduced duration of disability. Estimates of healthy and disabled life expectancy (using definitions including dependency in activities of daily living and cognitive impairment) were made, contrasting occupational classes I and II (professional and managerial) with the rest. DESIGN: Disability prevalence was estimated from the Medical Research Council Cognitive Function and Ageing study. Sullivan's method was used to calculate health expectancy. SUBJECTS: 10,377 people aged 65 years or over in Cambridgeshire, Newcastle, Nottingham and Oxford. Subjects were classified as disabled if they had evidence of dementia (using the Automated Geriatric Examination Computer Assisted Taxonomy) or scored 11 or more on the modified Townsend Disability scale, at baseline screen. RESULTS: the prevalence of disability overall and need for "constant care" was lower in both men and women in social classes I and II compared with the rest. Men aged 65 to 69 in classes I and II can expect nearly 14 years of life free of disability compared with 11.5 years for those in classes III to V: for women the equivalent expectations are 15.5 and 13.8 years. Men aged 65 to 69 in classes I and II can also expect a shorter duration of disability: 1 year compared with 1.6 years for classes III to V. In women expectation of disability is higher overall, but shows little difference by occupational class. CONCLUSIONS: Relatively privileged socioeconomic groups in England, especially men, can expect fewer years of disability despite longer overall life expectancy. These findings lend weight to optimistic scenarios for the future numbers of older people with disability.

BACKGROUND: Referral rates from general practitioners to hospital services vary up to 25-fold, and several studies have sought reasons for this apparent inconsistency in clinical practice. However, few studies have concentrated on, or indeed included, psychiatric patients or psychiatric referral rates. AIM: to determine the effect of population, general practice, and mental health service factors on use of specialist mental health services by general practices. METHOD: Cross-sectional data from computerized records used in managing clinical care on all patients aged 16 to 64 years who had been in contact with any mental health service staff over a two-year period. Twenty-three practices in Huntingdon Health District were studied, with a list population of 87,643 patients aged 16 to 64 years, served by one inpatient ward and three community mental health teams. The main outcome measures were the relation between age-standardized utilization ratio and markers of morbidity, deprivation, community mental health provision, and practice prescribing. RESULTS: Variation between practices in the use of mental health services was relatively limited, especially compared with the use of other secondary medical and surgical services. Three factors together explained 60.8% of the variance in use between practices: a census-based index of long-term limiting illness in females registered with the practice, use of one of the three community mental health teams, and average quarterly defined daily doses of hypnotics prescribed per practice population. Relatively high prescribing of hypnotics was associated with lower service use. CONCLUSION: Population morbidity and factors in the mental health service explain a substantial part of the variation in the use of mental health services between practices. Further work is needed to replicate these findings and explore why team factors and prescribing patterns influence utilization ratios. This study underlines the importance of examining population, practice, and specialist service factors in explaining variation in the use of secondary care by general practices.

Background: the adequacy of pharmacotherapy received in practice by patients after an acute episode of depression has been little studied. Aims: to describe and assess adequacy of drug continuation and maintenance in patients with depression. Method: Patients with depression were interviewed 18 months after discharge from hospital. Quantitative assessments of drug treatment doses and compliance were made monthly over this period, and qualitative ratings in continuation and maintenance phases. Results: About 20% of patients were prescribed low drug doses after discharge and 10% were prescribed no drugs at all. Reported compliance was around 70%. About 30% failed to receive adequate longer-term treatment, mostly due to the continuation phase being too short. Deficiencies of dosage and compliance were greater in patients who never achieved full recovery. Patient refusal was the most common reason for not using antidepressants. Further episodes of depression were not particularly associated with inadequate treatment. Conclusions: There were deficiencies in drug treatment that did not appear to be the principal cause of further episodes but may be important in non- recovery. Patient fears require discussion. Declaration of interest: Study supported by the East Anglian Regional Health Authority.

BACKGROUND: the adequacy of pharmacotherapy received in practice by patients after an acute episode of depression has been little studied. AIMS: to describe and assess adequacy of drug continuation and maintenance in patients with depression. METHOD: Patients with depression were interviewed 18 months after discharge from hospital. Quantitative assessments of drug treatment doses and compliance were made monthly over this period, and qualitative ratings in continuation and maintenance phases. RESULTS: About 20% of patients were prescribed low drug doses after discharge and 10% were prescribed no drugs at all. Reported compliance was around 70%. About 30% failed to receive adequate longer-term treatment, mostly due to the continuation phase being too short. Deficiencies of dosage and compliance were greater in patients who never achieved full recovery. Patient refusal was the most common reason for not using antidepressants. Further episodes of depression were not particularly associated with inadequate treatment. CONCLUSIONS: There were deficiencies in drug treatment that did not appear to be the principal cause of further episodes but may be important in non-recovery. Patient fears require discussion.

OBJECTIVES: to provide estimates of the numbers of cognitively impaired and physically disabled elderly people in England and Wales, subdivided by a range of sociodemographic, dependency, care receipt, and survival variables, to support debates on the form and funding of health and welfare programmes. DESIGN: Interviews at baseline and 2 year follow up plus data on resource use extracted from records for those with disability. SUBJECTS: 10 377 people aged 65 years and over in Cambridgeshire, Newcastle, Nottingham, and Oxford. All estimates weighted to population of England and Wales in 1996. RESULTS: 11% of men and 19% of women aged 65 and over were disabled, totalling 1.3 million people; 38% of these were aged 85 or over and a similar percentage were cognitively impaired. Overall, more than 80% of elderly disabled people needed help on at least a daily basis. Over a third of people with limitations to daily activity living in private households were wholly or partly dependent on formal services for help. 63% of disabled elderly people used acute hospitals during the 2 year follow up, 43% as inpatients. 53% of those with cognitive impairment and limitations to daily activity were living in institutions. CONCLUSIONS: Very elderly people and those with cognitive impairment make up a large proportion of those in need of long term care. A large proportion of even the most disabled elderly people currently live outside institutions and depend on formal services as well as informal care givers. Disabled elderly people use acute hospitals extensively, underlining the interrelations between acute and long term care.

INTRODUCTION: Variations in local population age structure have attracted less attention than national population ageing. As moderate and severe cognitive impairment is a major cause of need for long-term care, population-based estimates of the numbers and characteristics of this group were calculated, to explore the effects of local differences. METHOD: the UK Office of Population Census and Surveys (OPCS) study of disability in adults (N > 14000) was reanalysed. A group with moderate or severe cognitive impairments was identified and age-specific estimators of sociodemographic characteristics, household types, disabilities and service use were combined with population estimates for district health authorities in England and Wales. RESULTS: the proportion of the 65 plus population who are 85 plus varies from 8% to 15% across districts, equivalent to national population projections for 1986 and 2031 respectively. The estimated prevalence of the study group varies from 53 to 70 per 1000 population aged 65 plus, with 34-48% of cases aged 85 plus. Curiously, the proportion with severe disabilities varies little across districts. If national norms applied, local rates of institutionalization would vary from 18 to 27 per 1000 aged 65 plus. CONCLUSION: Local differences in population age structure age large compared to national changes over decades. Local differences have substantial effects on overall prevalence and on the proportion of the cognitively impaired who would be institutionalized if national patterns applied. Service design should be influenced by these complex variations, with estimates modified by local surveys.

BACKGROUND: Although the desirability of reducing prescribing of hypnotics and anxiolytics has long been recognized, variation between practices in patterns of psychotropic drug prescribing has received little attention; factors underlying such variation are poorly understood. AIM: the study aimed to describe the extent of variation between general practices in the prescribing of hypnotics, anxiolytics and antidepressants; it also aimed to analyse the influence of measures of practice population and general practice and general practitioner characteristics on any variation in prescribing volumes. METHOD: Routinely collected prescribing data and practice population data, from April 1992 to March 1993, from all 61 practices in the Cambridge and Huntingdon Health Commission were analysed. Prescribing was measured as annual defined daily doses per 1000 practice population for each drug class. Data on variables relating to practice structure and general practitioner characteristics were obtained and analysed. Potentially influencing variables were investigated by multiple regression. RESULTS: Between the highest and lowest prescribing practices there was an 11-fold difference, a 13-fold difference and an eightfold difference in the annual defined daily doses per 1000 practice population prescribed for hypnotics, for anxiolytics and for antidepressants, respectively. Strong positive correlations existed between volumes of prescribing of each drug class. The drugs prescribed in the greatest volumes were hypnotics. Practice population structure had some influence on psychotropic drug prescribing with high prescribing being associated with the proportions of temporary residents and women aged 65 years and over in the practice for all three classes of drug. Other factors, including presence of a practice counsellor, were not found to have a significant influence on psychotropic drug prescribing. CONCLUSION: the degree of variation in prescribing volumes of psychotropic drugs between practices raises serious concerns. Further study is needed, but progress will be hampered until there is more clarity over the effectiveness and appropriateness of using these substances in the various illness, symptom and life-stress presentations seen in primary care.

OBJECTIVES: to report outcome of targeting community mental health services to people with schizophrenia in an inner London district who had been shown, one year after discharge, to have high levels of psychotic symptomatology and social disability but very low levels of supported housing and structured day activity. DESIGN: Repeat interview survey of symptoms, disability, and receipt of care four years after index discharge. SETTING: Inner London health district with considerable social deprivation and a mental hospital in the process of closure. SUBJECTS: 51 patients originally aged 20-65 years who satisfied the research diagnostic criteria for schizophrenia. MAIN OUTCOME MEASURES: Contact with services during the three months before interview, levels of symptoms (from present state examination), global social disability rating. RESULTS: 65% (33/51) of the study group had been readmitted at least once in the three years between surveys. Recent contacts with community psychiatric nurses and rates of hospital admission increased (8 at one year v 24 at four years, p < 0.01; 5 v 13, p < 0.06). Conversely, fewer patients were in contact with social workers (17 v 7, p < 0.03). Proportions in supported housing, day care, or sheltered work did not change. Unemployment rates remained very high. A considerable reduction (almost a halving) in psychiatric symptoms was observed, but there was no significant change in mean levels of social disability. CONCLUSIONS: the policy of targeting the long term mentally ill resulted in significant increases in professional psychiatric input to the cohort but failed to improve access to social workers or suitable accommodation. Improvements in social functioning did not follow from reductions in the proportions of patients with psychotic mental states. Social interventions are likely to be crucial to achieving the Health of the Nation target of improving social functioning for the seriously mentally ill, as improving mental state seems in itself to be insufficient.

OBJECTIVES: to document the circumstances and care of patients with schizophrenia who had recently been discharged from local psychiatric inpatient services, and to establish the extent to which misgivings about community care might be justified. DESIGN: Cross sectional surveys with review of case notes. Follow up interviews with questionnaires administered one year after discharge. SETTING: Two inner London districts (West Lambeth and Lewisham) with high levels of social deprivation and at different stages of developing community services. PATIENTS: 90 and 50 patients in the two services respectively, aged 18 to 65, who satisfied the Research Diagnostic Criteria for schizophrenia and who were discharged from inpatient services. MAIN OUTCOME MEASURES: Diagnosis elicited by present state examination, global social disability rating, use of services during the three months before interview. RESULTS: 89 of the 140 patients (64%) had been ill for five or more years, yet few were former long stay inpatients. 55% (50/91; 95% confidence interval 45% to 65%) of those interviewed had current psychotic mental states and 22% (27/124; 16% to 31%) were functioning socially at very poor or severely maladjusted levels. 86% (107/124) were unemployed. The majority of patients had seen a mental health or social service professional, yet only 16% (20/124) were in specialised accomodation (excluding hospitals) and only 23% (17/73) of those eligible had used day care. Small numbers of people had experienced homelessness (two) or imprisonment (four over six months). CONCLUSIONS: Many schizophrenic patients leaving local psychiatric inpatient care have active symptomatology and profound social disabilities. Community care was characterised by high rates of contact with service professionals but little supported accommodation or day activity. This group of clients may require dedicated provision, which would actively encourage them to use services protected from the demands of those with less severe illness.

This paper offers a comprehensive framework for service evaluation relevant to a new respite care unit, and reports some results of its application. On existing evidence the planning assumption of a preventive effect of respite care, in avoiding admission to institutional care, is argued to be unjustifiable. The results indicate that this unit had a high non-attendance and fall-out rate, and no incentives to co-operate with alternative services or to operate efficiently. Broad estimates of cost parities revealed that attenders at the unit sacrificed considerable amounts of alternative forms of care.

Several factors are shaping the need and demand for health care; these include demographic change, the differential improvement in the survival of those with chronic conditions, and the mismatch between personal income and health. Also, medical uncertainty results in vast variations in medical practice and costs. The scope for increasing the supply of medical care, selectively to the rich or across the board, is already vast and growing. It is argued that efficient financing systems can operate only at a level at which the health benefits of interventions are measurable, i.e. the population level. Systems of individual payment are based on inevitable ignorance about expected benefits and must therefore introduce perverse (and necessarily inefficient) incentives. Population based monitoring of outcome, with coupled incentives to efficient producers, would appear to be the only method of encouraging the production of maximum social benefit from the resources used for health.

Data from the England and Wales national congenital malformation notification scheme were examined for associations of male genital tract malformations. For some of the malformations comparison of notification rates with the literature suggested gross undernotification. There was also evidence suggesting bias: examination of the relationships of the malformations to birth weight, maternal parity, and maternal age at delivery showed some highly significant trends in risk, most of which were at variance with findings in the literature, and several potential mechanisms for bias could be adduced. Direct investigation is needed, for this and other similar data sets, of the extent and mechanisms of biased undernotification.