Gene expression and alternative splicing in ageing

Ageing is a major risk factor for chronic disease, but the factors that underpin why some people age well and others succumb to certain diseases are, to date, unclear. Elucidating the biological mechanisms underlying human ageing is therefore crucial to the understanding of age-related chronic disease.

The InCHIANTI study is a population-based study in which participants were originally enrolled in 1998-2000 and were interviewed and examined every three years. The recent 9-year follow-up exam involved 733 participants and whole genome expression profiling of RNA samples was performed.

Focused changes in a small subset of genes with age (295 out of 16,571, 2%), which are predominantly related to splicing pathways, have been identified. This led to the hypothesis that alterations in core splicing machinery may result in changes to the amount or nature of mRNA transcripts.

In a small scale study within the InCHIANTI DNA microarray data it was identified that the majority of genes expressed differences in the ratios of mRNA isoform expression with age. Further to this, total RNA was Reverse Transcribed and used for Taqman Low Density Array (TLDA) analysis for transcripts of selected genes. The genes were selected on the basis that they had alternatively expressed isoforms in the top 250 associations with age in the previous microarray study. TLDA analysis validated previous findings.

Change in the balance of alternative mRNA isoforms with age has been identified, implicating disturbances to alternative splicing as a fundamental mechanism of ageing. Further work is now necessary to define the molecular basis for this observation.