Mitochondrial targeted Hydrogen Sulfide as a regulator of ageing in Caenorhabditis elegans.

Abstract

Introduction: Ageing remains a highly elusive process, with its associated physical and molecular decline continuing to place financial strain on UK healthcare systems. Mitochondrial function is known to play an important role in the ageing phenotype, where it has gained attention as an attractive therapeutic target in attempts to alleviate these pathologies. The current work presents a panel of novel H2S compounds and their effects on C. elegans survival. Methods: Using the model organism C. elegans we tested dosing of five compounds across the life-course (1μM, 100nM and 10nM, with respective controls for both the compound (i.e. cellular targeting motif alone) and DMSO alone. with age-synchronysed animals exposed from L1 larval stage. Survival assays were performed using a high-throughput microfluidic platform and scored every day for being alive or dead. To infer a putative prole of mitochondrial preservation in any compound-induced lifespan extension, transgenic animals expressing mitochondrial green fluorescent protein (for RT163 only) were also examined for mitochondrial structure across the life-course. Results: All mitochondrial H2S donors extended C. elegans lifespan. RT163 showed the most prominent effects at a dose of 100nM, with 100 nM also proving an efficacious dose in both RTC1 and RTA302. The endoplasmic reticulum targeting drug, RTER88, failed to extended lifespan versus control conditions. Mitochondrial structure was also assessed in animals exposed to 100nM of RT163 against 100nM of the compound control and DMSO. RT163 was able to preserve networking up to 6 days post-adulthood, highlighting the improved survival is likely mitochondrially mediated. Conclusion: Mitochondria play an integral role in the ageing process, with strategies to augment its age-dependent extending lifespan. Here we report that H2S targeted to mitochondria increases survival proportions, with some insight into preservation of mitochondrial structure potentially the causal role. Importantly, these effects are seen at orders of magnitude lower than traditional sulfide donors, emphasising the potential that these compounds have to be clinically relevant drugs.