This is some speculative dot joining but do we know the mechanism through which Fisetin acts as a senolytic? I don't recall having read so.
I was looking through the fisetin thread trying to find an old post and discovered one post I'd linked, likely barely read and forgotten to the following study:
https://www.ncbi.nlm...om=groupmessage
"Chronic fisetin treatment of HF at physiological concentrations resulted in shorter telomeres compared to control cells, indicating reduced telomere stability and enhanced biological aging of these cells. Under the assumption that it is healthy, fisetin is often added to nutritional supplements at relatively high concentrations. Since the biological effects of regular consumption of high doses of fisetin (and also flavonoids in general) are not known, thorough safety evaluation is warranted with respect to these nutritional supplements. Chronic minocycline treatment also enhanced telomere shortening. This implies that precaution should be taken when minocycline is subscribed as a chronic treatment.
However, under conditions of chronic oxidative stress, both fisetin and minocycline appeared to reduce the rate of telomere shortening. Since our study was limited to testing the effects of fisetin and minocycline in an in vitro model with HF cells that were chronically exposed to oxidative stress more research is needed to evaluate possible positive effects of fisetin and minocycline in chronic inflammatory diseases.
It can be concluded that chronic administration of pharmaceuticals or nutraceuticals with PARP inhibiting activity appears to be beneficial in conditions of chronic oxidative stress, but may be detrimental under relatively normal conditions."
i haven't read through this yet, but note catching DMSO was used with the fisetin, which would certainly be confounding - and is in vitro.
But I wonder, if the case, if this might explain why fisetin acts as a senolytic?
Senescent cells have shorter telomeres, and obviously shortened telomeres appear to induce apoptosis too:
https://www.ncbi.nlm...les/PMC5514392/
"Secondly, mouse models where telomere function has been compromised, suggest a role in the ageing process. Telomerase knock-out (mTERC−/−) mice which carry a homozygous deletion of the RNA component of telomerase show a generation-dependent telomere shortening, which results in critically short telomeres and both senescence and apoptosis . In these mice, dysfunctional telomeres have been shown to impact on the function of stem cells, organ regeneration and lifespan . Moreover, it has been shown that reintroduction of telomerase activity in telomerase-deficient mice is able to revert the premature ageing phenotype observed in tissues such as the spleen, intestine and testes"
So might fisetin trigger apoptosis in senescent cells through further shortening telomere length?
Recently there was a controlled study with wild mice dosed with fisetin apparently refuting earlier evidence of senescent cell clearance with the flavanoid with inbred mice.
https://www.longecit...-36#entry915639
There were complaints that fisetin was administered in water and so not especially bioavaialble. Mice of course have extremely long telomeres, so I assume, stoo attempt to induce apoptosis or senescence through some telomere shortening intervention might not be as successful, as with other species, or possible too it would seem, with inbred mice: for house sparrows, at least, inbreeding is a deleterious for telomere length:
https://link.springe...592-022-01441-x
So might fisetin induce senescent cell clearance by triggering apoptosis through further shortening the telomeres of sensecent cells? And too might that explain why wild mice fisetin studies compare unfavourably with those of the shorter telomered inbred mice?
Edited by ambivalent, 21 September 2022 - 08:27 PM.