In this open access paper, researchers report that compounds delivering hydrogen sulfide into cells slow the pace at which those cells become senescent in culture. The mechanisms involved are not fully explored but involve splicing factors, proteins that have a strong influence over gene expression. As the biochemistry of cellular senescence is explored, and researchers find ways to potentially hold back the transition of cells into the senescent state, we might ask whether or not this is a good idea. Lingering cellular senescence is a cause of aging, but most cells become senescent for a good reason - they are damaged, potentially cancerous, have replicated too many times for continued safety, or the surrounding environment is toxic. Most self-destruct rather than remaining to contribute to the aging process.
Will it be helpful rather than harmful to prevent senescence? Current approaches to senescent cells involve destroying them, which seems the better path forward. Cells that become senescent are not, on balance, the sort of cell that one would want to keep around. Better to remove them, I think. So how to interpret the evidence here regarding the influence of hydrogen sulfide on cellular senescence and aging in general? It seems positive and also suppresses cellular senescence. What does it actually achieve under the hood, what is the full balance of relevant mechanisms? It is perhaps a little early to say, and we should continue to watch the accumulation of evidence on this topic.
The biochemical and functional pathways most dysregulated by age in the human peripheral blood transcriptome are enriched for transcripts encoding the regulatory machinery that governs splice site choice. Changes in splicing regulation have also been linked with lifespan in both mammalian and invertebrate model systems. Evidence that these changes are functional is provided by the observation that large-scale dysregulation of patterns of alternative splicing is characteristic of many age related diseases.
The accumulation of senescent cells is emerging as an important driving factor of the ageing process in multiple species. Senescent cells do not divide, are viable and metabolically active, but have altered physiology. This includes the secretion of the SASP, a cocktail of pro-inflammatory cytokines and tissue remodelling factors that induces senescence in neighbouring cells in a paracrine manner. Senescent cells also show dysregulation of splicing regulator expression in vitro, and restoration of splicing factor expression to levels comparable with those seen in younger cells has recently been demonstrated to be associated with reversal of multiple senescence phenotypes in senescent human primary fibroblasts.
There is now enormous interest in compounds with the potential to kill senescent cells or ameliorate their effects. The endogenous gaseous mediator hydrogen sulfide (H2S) has been described to exert a protective effect against cellular senescence and ageing phenotypes, and accordingly, to have protective effects against several age related diseases, although many of these studies have been carried out using non-physiological conditions, using very high levels of H2S. Plasma H2S level declines with age, is associated with hypertension in animals and humans and shows a significant inverse correlation with severity of coronary heart disease.
Here, we aimed to assess the effect of the H2S donor Na-GYY4137, and since mitochondria are a source and a target of H2S, three novel H2S donors, AP39, AP123, and RT01 previously demonstrated to be targeted specifically to the mitochondria, on splicing regulatory factor expression and cell senescence phenotypes in senescent primary human endothelial cells. Treatment with Na-GYY4137 resulted in an almost global upregulation of splicing factor expression in treated cells. Conversely, H2S donors targeted to the mitochondria also resulted in rescue from senescence but each demonstrated a very specific upregulation of transcripts encoding the splicing activator protein SRSF2 and the splicing inhibitor protein HNRNPD.
Abolition of either SRSF2 or HNRNPD expression in primary endothelial cells in the absence of any treatment resulted in increased levels of cellular senescence. None of the H2S donors were able to reduce senescent cell load in cells in which SRSF2 or HNRNPD expression had been abrogated. These data strongly suggest that mitochondria-targeted H2S is capable of rescuing senescence phenotypes in endothelial cells through mechanisms that specifically involve SRSF2 and HNRNPD.