Hydrogen Sulfide Influences Cellular Senescence via Splicing Mechanisms

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.

Link: https://doi.org/10.18632/aging.101500


It seems that the cells are evolved to be adapted to a certain concentration of h2s. And restoring it might be helping a bit. In the grand scene of things it is just messing with the metabolism to allow down the seneceance.

This Might be helpful in conjonction with other treatments. After all, if you have 10 approaches each helping a little , the cumulative effect cloud be big enough to matter.

Also h2s concentrations cold be a useful metabolical marker

Posted by: Cuberat at August 8th, 2018 7:47 AM

I think you're missing the essential point here Cuberat - that splicing factors are handles controlling the various mechanisms behind gene expression and cellular aging. Not that suprising when you know that splicing factors can control heteochromatin formation. This team's previous work used resveratrol analogues to achieve even more profound 'rejuvenation' of old cells. I expect in the future this work will link up epigenetic aging, telomere attrition and cancer.

So no, not just tinkering with metabolism.

Posted by: Mark at August 8th, 2018 9:51 AM

Maybe there was something to those mineral baths popular at Spas in the early 20th century.

Posted by: Tom Schaefer at August 8th, 2018 11:07 AM

I'm real impressed by the fact they have developed/found 3 different H2S donor molecules that reduce senescent blood vessel endothelial cell by about 50%, by rejuvenating mitochondria in the cells. All this research seems like it could lead to increased health span by this pathway.

Posted by: Biotechy Marcks at August 8th, 2018 1:53 PM

You might be right and I hope I am wrong. Even if translates even to modest benefit for humans it is still a step in the right direction.

Posted by: cuberat at August 8th, 2018 3:23 PM

Hi there, just a 2 cents.

Low dose H2S is benefitial because of splicing factors altering nuclear histone methylation, this ties with the DNA epigenetic clock and telomeres/telomeric DNA - all under methylation control and all chromosome related, all DNA related.
These alternative splicing factors alter nuclear lamins that control chromosome organisation. Telomeres dysfunction, global demethylation of epigenetic clock, redox loss cause senescence via aberrant cryptic splicing in lamins, creating aberrant form of lamin progerin, as seen in HGPS or in slowmo over a regular healthy lifespann. In turn, this aggregate clogs the cell and is a insta senescence trigger; senescence requires progerin (progerin is an evolved senescence 'defect' mechanism to kill host and prevent cell malignancy). Autophagy delays senescence via progerin disposal, but lipofuscin is undegraded and accumulates. Both these aggregates cause senescence by Autophagy blocking and chromosome disorganization/DNA coil loosening/decondensation/decompaction; but the one that is highly toxic is progerin, lipofuscin is stabilized it's just cumulative amalgmated junk of oxidized phospholipids/carbonyls/oxidized DNA but is mostly inert, while progerin is akin to SASP but Much much worse toxic wise and causes apoptosis, necrosis or senescence upon its production. This demonstrates that aging is DNA-disorganization caused/causing vicious circle of aggregates, which they alter chromosomal DNA organisation/function.

Just a 2 cents.

Posted by: CANanonymity at August 8th, 2018 11:55 PM

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