Living longer without simultaneously extending years spent in good health ("health span") is an increasing societal burden, demanding new therapeutic strategies. Hydrogen sulfide (H2S) can correct disease-related mitochondrial metabolic deficiencies, and supraphysiological H2S concentrations can pro health span. However, the efficacy and mechanisms of mitochondrion-targeted sulfide delivery molecules (mtH2S) administered across the adult life course are unknown. Using a Caenorhabditis elegans aging model, we compared untargeted H2S (NaGYY4137, 100 µM and 100 nM) and mtH2S (AP39, 100 nM) donor effects on life span, neuromuscular health span, and mitochondrial integrity. H2S donors were administered from birth or in young/middle-aged animals (day 0, 2, or 4 postadulthood). RNAi pharmacogenetic interventions and transcriptomics/network analysis explored molecular events governing mtH2S donor-mediated health span. Developmentally administered mtH2S (100 nM) improved life/health span vs. equivalent untargeted H2S doses. mtH2S preserved aging mitochondrial structure, content (citrate synthase activity) and neuromuscular strength. Knockdown of H2S metabolism enzymes and FoxO/daf-16 prevented the positive health span effects of mtH2S, whereas DCAF11/wdr-23 - Nrf2/skn-1 oxidative stress protection pathways were dispensable. Health span, but not life span, increased with all adult-onset mtH2S treatments. Adult mtH2S treatment also rejuvenated aging transcriptomes by minimizing expression declines of mitochondria and cytoskeletal components, and peroxisome metabolism hub components, under mechanistic control by the elt-6/elt-3 transcription factor circuit. H2S health span extension likely acts at the mitochondrial level, the mechanisms of which dissociate from life span across adult vs. developmental treatment timings. The small mtH2S doses required for health span extension, combined with efficacy in adult animals, suggest mtH2S is a potential healthy aging therapeutic.

National space agencies have announced planned long-duration crewed missions beyond Low Earth Orbit. It is critical to understand the impact of long-duration microgravity and especially deep-space radiation exposure on humans. There is a knowledge gap concerning the impact of the space environment on humans, our human microbiome and associated Earth biology needed to support human activities in space. Cranfield University and its partners have been developing a bioCubeSat concept named BAMMsat. The term bioCubeSat refers to a CubeSat with a biological payload on-board. BAMMsat stands for Bioscience, Astrobiology, Medical, Material science on CubeSats. The versatile platform builds upon the typical functional requirements of these scientific fields, such as i) the need to house multiple samples, ii) maintain viable samples in an appropriate space environment, iii) the need to artificially perturb the samples and (iv) the need to monitor the samples. Cranfield University and University of Exeter are currently involved in a technology demonstration of a second-generation design of a BAMMsat payload for flight on a large stratospheric balloon due to be flown in Oct 2021. The mission will launch under the REXUS/BEXUS programme realised under the remit of the Swedish National Space Agency (SNSA), German Aerospace Centre (DLR), and European Space Agency (ESA). The work presents the current BAMMsat technological status, development stages and opportunity to advance bioscience research in space.

Significance
.
. Duchenne muscular dystrophy (DMD) is a fatal degenerative disease without a cure. Current standard pharmacological treatment is corticosteroids. Their prolonged use is associated with several undesirable side effects. Using
. Caenorhabditis elegans
. we have identified pharmacological treatments that supplement hydrogen sulfide (H
. 2
. S). One, sodium GYY4137, largely acts like prednisone to improve neuromuscular health; the other, AP39, targets H
. 2
. S delivery to mitochondria. As these are not steroids, they are unlikely to produce steroid-induced side effects. Additionally, as DMD mice show a decline in total sulfide, our results pave the way for evaluation of cellular and/or mitochondrial H
. 2
. S in DMD pathology and warrant further investigation of selective H
. 2
. S delivery approaches in
. mdx
. mice and/or higher animal models of DMD.
.

Biology experiments in space seek to increase our understanding of what happens to life beyond Earth and how we can safely send life beyond Earth. Spaceflight is associated with many (mal)adaptations in physiology, including decline in musculoskeletal, cardiovascular, vestibular, and immune systems. Biological experiments in space are inherently challenging to implement. Development of hardware and validation of experimental conditions are critical to ensure the collection of high-quality data. The model organism Caenorhabditis elegans has been studied in space for more than 20 years to better understand spaceflight-induced (patho)physiology, particularly spaceflight-induced muscle decline. These experiments have used a variety of hardware configurations. Despite this, hardware used in the past was not available for our most recent experiment, the Molecular Muscle Experiment (MME). Therefore, we had to design and validate flight hardware for MME. MME provides a contemporary example of many of the challenges faced by researchers conducting C. elegans experiments onboard the International Space Station. Here, we describe the hardware selection and validation, in addition to the ground-based experiment scientific validation testing. These experiences and operational solutions allow others to replicate and/or improve our experimental design on future missions.

Mitochondrial dysfunction impairs muscle health and causes subsequent muscle wasting. This study explores the role of mitochondrial dysfunction as an intramuscular signal for the extracellular matrix (ECM)-based proteolysis and, consequentially, muscle cell dystrophy. We found that inhibition of the mitochondrial electron transport chain causes paralysis as well as muscle structural damage in the nematode Caenorhabditis elegans. This was associated with a significant decline in collagen content. Both paralysis and muscle damage could be rescued with collagen IV overexpression, matrix metalloproteinase (MMP), and Furin inhibitors in Antimycin A-treated animal as well as in the C. elegans Duchenne muscular dystrophy model. Additionally, muscle cytosolic calcium increased in the Antimycin A-treated worms, and its down-regulation rescued the muscle damage, suggesting that calcium overload acts as one of the early triggers and activates Furin and MMPs for collagen degradation. In conclusion, we have established ECM degradation as an important pathway of muscle damage.-Sudevan, S. Takiura, M. Kubota, Y. Higashitani, N. Cooke, M. Ellwood, R. A. Etheridge, T. Szewczyk, N. J. Higashitani, A. Mitochondrial dysfunction causes Ca2+ overload and ECM degradation-mediated muscle damage in C. elegans.