Fisetin failed to extend lifespan, and did not appear to reduce senescent cells with the markers they looked at.
This seems like it should cause some re-evaluation of the senolytics idea.
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I still think senescent cells are an ssue.
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Just because one senolytic fails doesn’t mean they all do. I think we have enough evidence to believe that Dasatanib and Quercetin works.
We can probably avoid fisetin though.
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I am taking a large number of HDAC inhibitors. One of them is fisetin.
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What evidence is that?
If you are asking me. I would say my response is not really evidence in itself.
Fistin is an HDACi. I have an overall protocol. I do a lot of testing. I provide information about the testing results. I think my protocol on the whole (which includes intermittent rapamycin) helps to improve health at a cellular level.
I don’t mind discussing the test results, but I need some questions really.
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That study found no evidence of fisetin being senolytic in the first place. So it’s not really the senolytic idea that needs to be reevaluated based on the results, but rather the idea that fisetin counts as one.
To be clear – the senolytic hypothesis needs to be elaborated – there are many cellular behaviours that fall under the general rubric of senescence, depending on who you ask – and rigorously tested. Unfortunately, this trial did not provide the kind of test folks hoped for.
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I don’t have the citations to hand, but AFAIK Fisetin is an HDACi. That clearly has some effect on transcription.
But it didn’t have an effect on lifespan nor on senescence in mice. Either it doesn’t work in-vivo or it’s not a strong HDACi or your whole theory is wrong or not a limiting aspect for lifespan.
FWIW
As I have posted in another thread;
“Azithromycin and Roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts”
This is an interesting and well designed study carried out by what appear to be competent research teams. Some weakness in the execution of the study was created by combining the data from unrelated teams working with the mice in different labs managed by different people. Given that a heterogeneous mouse strain was employed, cell sizes need to be very large to test for potential significance. I note that results were not consistent across locations.
With respect to fisetin, so far as I know there is no compelling evidence as to the extent, if any, that research on mice generalizes to humans. In contrast, there is limited but decent human clinical evidence as well as human tissue evidence that fisetin possesses a number of beneficial properties including targeted senolytic activity (whereas there is some evidence that dasatinib also kills healthy cells) and the reduction of neuroinflammation. Bioavailability is a significant challenge in dealing with the human consumption of fisetin. One wonders if this was addressed adequately in the mouse research.
At this point, I see nothing in this new mouse research suggesting that fisetin does not hold promise for several human uses, including longevity.
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HDACi as I see it has relatively minor positive effects. The most positive effects come from citrate.
Which classes of HDACi are most important is a good question I have no answer to, but in the end I am trying to find a protocol that improves/extends healthspan. If I have test results that imply I have done that I am a happy bunny.
Bounce, bounce, bounce.
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Some weakness in the execution of the study was created by combining the data from unrelated teams working with the mice in different labs managed by different people
That is not a weakness, but a strength.
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In principle, diversity across treatment settings and conditions might contribute to the strength of findings. In this case, sample size was increased to accommodate the genetic diversity of the mice but does not appear to have been increased to accommodate the variance and error terms potentially introduced by different lab managers, administration and oversight teams, etc. as they respond to the unique nature and daily variance of each rodent population and environment. I don’t know but the strategy of spreading this research across different labs was likely based on financial and other resource considerations. In any event, this was a relatively small and subordinate point.
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