Time-restricted eating, enabling a daily period of ketosis is what I've read and put into practice for many years as a means to starve senescent cells (as per Dr Rhonda Patrick and others), coupled with quality sleep and hydration and home-cooked meals I hope to add to that body of anecdotal evidence.
Good point. Daily fasting should increase autophagy and help to increase the clearance of senescent cells. (A little bit - here's a study that puts numbers to it: https://pmc.ncbi.nlm.nih.gov/articles/PMC11616606/)
Fixing the cleanup crew instead of killing the cells one by one is a much better shaped idea than senolytics, and it explains why the quercetin and dasatinib results kept underdelivering outside of a dish.
The part i would add is the human end. everything here is mice, which is fine for mechanism, but the underlying premise has already been tested in people. cantos randomized 10,061 post heart attack patients to an antibody against il-1 beta. hs-crp fell 54% by four years. ldl cholesterol did not fall at all, it drifted up 1.7%. cardiovascular events still dropped, hazard ratio 0.85. that is the cleanest evidence going that the inflammation is doing damage on its own rather than riding along.
Which also means there is a number you can actually watch. hs-crp runs somewhere between $25 and $70 depending on the lab, and unlike most things in longevity it moves on a timescale of weeks rather than decades.
The catch is that it is the noisiest common marker there is. a 2024 meta-analysis of repeat measurements put the median within person coefficient of variation at 44%, spread from 27% to 76% across studies. run that through the standard reference change calculation and you need a swing of well over 100% before it counts as a real change. so if you start curcumin, retest, and watch 1.8 come back as 1.1, you have measured nothing at all. that is an ordinary week for hs-crp.
Which is why anyone testing one of these compounds on themselves wants three readings before they start, not one. an average of three is the only baseline stable enough to compare anything against.
Otherwise the supplement takes credit for the noise.
Your footnote 3 is a study I think its impotent to highlight and that I want to spend more time in with some research and writing.
Inside that same pilot, adding fisetin to dasatinib plus quercetin blunted the epigenetic clock acceleration to non significant, which nobody selling senolytic stacks seems to mention in either direction (PMID 38393697, 19 people, marker data, hold it loosely).
And the convergence with the new Mayo Nature paper I am writing about tomorrow is striking: that one found the senescent cell's own damaged mitochondria fuel the inflammatory secretions from the inside, and your piece covers the clearance failing on the outside. Senescence keeps looking like a complicated circuit (like so much in systems biology) before just an off/off switch. Killing the cells might not be the answer after all.
The distinction between targeting senescent cells directly and improving the body's own clearance mechanisms is an interesting one. As this research progresses, what do you think will be the biggest challenge in translating these findings from animal models to human aging?
This is an excellent breakdown, and the efferocytosis framing is the part worth sitting with.
The pivot from senolytics to restoring macrophage clearance quietly reframes what senescent-cell accumulation even is. If aged tissue piles up senescent neutrophils mainly because the EP2 brake stalls the clearance crew, then the accumulation looks less like the primary driver and more like a downstream symptom of efferocytosis decline. That would explain the disappointing senolytic results you cite: killing the cells is bailing water while the leak is the clearance system itself.
Time-restricted eating, enabling a daily period of ketosis is what I've read and put into practice for many years as a means to starve senescent cells (as per Dr Rhonda Patrick and others), coupled with quality sleep and hydration and home-cooked meals I hope to add to that body of anecdotal evidence.
Good point. Daily fasting should increase autophagy and help to increase the clearance of senescent cells. (A little bit - here's a study that puts numbers to it: https://pmc.ncbi.nlm.nih.gov/articles/PMC11616606/)
Sorry, I got a 404 on your link
The garbage collector slowing down while the trash keeps piling up is the whole story. Enjoyed this one.
Very good description!
Fixing the cleanup crew instead of killing the cells one by one is a much better shaped idea than senolytics, and it explains why the quercetin and dasatinib results kept underdelivering outside of a dish.
The part i would add is the human end. everything here is mice, which is fine for mechanism, but the underlying premise has already been tested in people. cantos randomized 10,061 post heart attack patients to an antibody against il-1 beta. hs-crp fell 54% by four years. ldl cholesterol did not fall at all, it drifted up 1.7%. cardiovascular events still dropped, hazard ratio 0.85. that is the cleanest evidence going that the inflammation is doing damage on its own rather than riding along.
Which also means there is a number you can actually watch. hs-crp runs somewhere between $25 and $70 depending on the lab, and unlike most things in longevity it moves on a timescale of weeks rather than decades.
The catch is that it is the noisiest common marker there is. a 2024 meta-analysis of repeat measurements put the median within person coefficient of variation at 44%, spread from 27% to 76% across studies. run that through the standard reference change calculation and you need a swing of well over 100% before it counts as a real change. so if you start curcumin, retest, and watch 1.8 come back as 1.1, you have measured nothing at all. that is an ordinary week for hs-crp.
Which is why anyone testing one of these compounds on themselves wants three readings before they start, not one. an average of three is the only baseline stable enough to compare anything against.
Otherwise the supplement takes credit for the noise.
Your footnote 3 is a study I think its impotent to highlight and that I want to spend more time in with some research and writing.
Inside that same pilot, adding fisetin to dasatinib plus quercetin blunted the epigenetic clock acceleration to non significant, which nobody selling senolytic stacks seems to mention in either direction (PMID 38393697, 19 people, marker data, hold it loosely).
And the convergence with the new Mayo Nature paper I am writing about tomorrow is striking: that one found the senescent cell's own damaged mitochondria fuel the inflammatory secretions from the inside, and your piece covers the clearance failing on the outside. Senescence keeps looking like a complicated circuit (like so much in systems biology) before just an off/off switch. Killing the cells might not be the answer after all.
The distinction between targeting senescent cells directly and improving the body's own clearance mechanisms is an interesting one. As this research progresses, what do you think will be the biggest challenge in translating these findings from animal models to human aging?
This is an excellent breakdown, and the efferocytosis framing is the part worth sitting with.
The pivot from senolytics to restoring macrophage clearance quietly reframes what senescent-cell accumulation even is. If aged tissue piles up senescent neutrophils mainly because the EP2 brake stalls the clearance crew, then the accumulation looks less like the primary driver and more like a downstream symptom of efferocytosis decline. That would explain the disappointing senolytic results you cite: killing the cells is bailing water while the leak is the clearance system itself.
Why did the senescent cell stop going to work?
Because it had reached retirement age… but refused to leave the tissue!
“I’m not dividing anymore,” it said. “I’m just going to sit here, complain, and send inflammatory messages to everyone around me.”