Researchers Report on More New Senolytic Drug Candidates
Now that clearing senescent cells as a therapy for aging finally has meaningful support in the research community, there is far more funding available to turn the wheels of the standard drug discovery and evaluation process. Researchers are in search of senolytic drugs, those that can kill senescent cells without harming normal cells. The process starts at first with an evaluation of the performance of each molecule in the standard compound libraries in cell cultures, in search of molecules that preferentially kill senescent cells. This can be automated to a fair degree, especially when the desired result is as black and white as destroying one distinctive class of cell. It is very similar to the sort of cancer drug screening that the research community has a great deal of experience in carrying out. At scale, this might cost a few dollars per molecule screened these days. In fact, the existing candidates for senolytic drugs have largely emerged from the cancer drug candidate databases, and were tested for their effects on cancer for some years without noticing their strong effects on senescent cells - it wasn't in the list of items to evaluate at the time.
Given the starting point of a few promising compounds, preferably already tried in animals and humans, and thus with decent pharmacology data, researchers then branch out to examine other chemically similar compounds. It is usually the case that a better version with greater primary effects and lesser side-effects can be established one way or another. The level of work to achieve that end varies greatly, however, ranging from finding another well-characterized small molecule drug candidate in the archives to the researchers having to carry out all of the work to model and synthesize a novel molecule and prove it to be effective. It is usually the case that researchers and developers are far more willing to push ahead with a suboptimal compound that is already fairly well tested than to work with a less well explored but potentially better compound. Nonetheless, in theory the competition in the system weeds out worse drugs in favor of better drugs, though that process may never seem as efficient in practice or as fast as we'd like it to be. Personally, I'd like to see more funding going towards the sort of programmable gene therapy pioneered by Oisin Biotechnologies, a better approach than mining cancer chemotherapy drugs in search of those with side-effects that are minimal enough for patients to accept.
Then it is on to animal studies, starting companies, and human trials, the standard process for moving forward with the development of new medicine. Many candidates will turn out to be not so useful in human medicine, others will pass all the way through. Insofar as senolytic drug discovery goes, all of the groundwork has already taken place for a number of cancer drug candidates that can promote apoptosis in senescent cells, such as navitoclax and dasatinib, some of which are being carried forward into clinical trials by UNITY Biotechnology. In animal studies, these appear to remove on the order of 10-50% of senescent cells in a single course of treatment, varying widely by tissue type. The research community isn't resting on its laurels, however, and is turning up new candidates on a fairly regular basis at the moment, such as piperlongumine. The paper below offers another few candidates for consideration, though I would say that they are less interesting in and of themselves at this stage, but rather as an indication that we should expect the list of potential drugs to expand quite rapidly in the next few years, and hopefully the quality of the best candidates along with it.
Senescent cells accumulate in numerous tissues with aging and at sites of pathogenesis of multiple chronic diseases. Small numbers of senescent cells can cause extensive local and systemic dysfunction due to their pro-inflammatory senescence-associated secretory phenotype (SASP). For example, transplanting only 200,000 senescent ear chondroblasts or preadipocytes around knee joints induces osteoarthritis in mice, while injecting similar numbers of non-senescent cells does not. Clearing senescent cells by activating a drug-inducible "suicide" gene in progeroid or naturally-aged mice alleviates a range of age- and disease-related phenotypes, including sarcopenia, frailty, cataracts, adipose tissue dysfunction, insulin resistance, and vascular hyporeactivity.
To decrease the burden of senescent cells in non-genetically-modified individuals, we used a hypothesis-driven approach to identify senolytic compounds, which preferentially induce apoptosis in senescent rather than normal cells. Our approach was based on the observation that senescent cells are resistant to apoptosis. This suggested that senescent cells either have reduced engagement of pro-apoptotic pathways that serve to protect them from their own pro-apoptotic SASP or they have up-regulated pro-survival pathways. We demonstrated the latter to be the case and identified senescence-associated pro-survival pathways based on expression profiling of senescent vs. non-senescent cells. We confirmed the requirement of these pathways for survival of senescent but not non-senescent cells by RNA interference. These pathways included pro-survival networks related to PI3K / AKT, p53 / p21 / serpins, dependence receptor / tyrosine kinases, and BCL-2 / BCL-XL, among others.
We tested drugs that target these pro-survival pathways. We initially reported that the dependence receptor/ tyrosine kinase inhibitor, dasatinib (D) and the flavonoid, quercetin (Q), are senolytic in vitro and in vivo. D and Q induced apoptosis in senescent primary human preadipocytes and HUVECs, respectively. Combining D+Q broadened the range of senescent cells targeted, and, in some instances, proved synergistic in some types of senescent cells. D+Q alleviated cardiovascular, frailty-related, osteoporotic, neurological, radiation-induced, and other phenotypes and disorders in chronologically aged, progeroid, and high fat-fed atherosclerosis-prone mice, consistent with our observations in mice from which senescent cells had been removed by inducing the suicide gene in transgenic INK-ATTAC mice. Expanding upon our findings with Q, we tested if the related flavonoid fisetin is senolytic. Fisetin is widely available as a nutritional supplement and has a highly favorable side-effect profile.
Based on our earlier hypothesis-driven identification of senolytic drugs and identification of the BCL-2 pro-survival pathway as one of the "Achilles' heels" of senescent cells, we and others simultaneously reported that the BCL-2 / BCL-W / BCL-XL inhibitor, navitoclax (ABT263; N), is senolytic. Like D and Q, N is senescent cell type-specific, being effective in inducing apoptosis in HUVECs but not human preadipocytes. We also found that the related BCL-2 family inhibitor, TW-37, is not senolytic. TW-37, unlike N, does not target BCL-XL. Others confirmed that N targets senescent cells, but Bcl-2 family inhibitors that do not target BCL-XL are not senolytic. We therefore tested if the relatively specific BCL-XL inhibitors, A1331852 and A1155463, are senolytic. Unlike N, these agents do not target BCL-2. Consequently, A1331852 or A1155463 may cause less BCL-2-induced neutrophil toxicity, a serious side-effect of N.
We found that fisetin and the BCL-XL inhibitors, A1331852 and A1155463, are senolytic in vitro, inducing apoptosis in senescent, but not non-senescent HUVECs. This adds three new agents to the emerging repertoire of senolytics reported since early 2015, which currently includes D, Q, N, and piperlongumine. Fisetin has a plasma terminal half-life of just over 3 hours in mice. It alleviates dysfunction in animal models of chronic disease, including diabetic kidney disease and acute kidney injury, attributes consistent with those expected from a senolytic agent. Here we demonstrate that fisetin is indeed senolytic in senescent HUVECs, but not in senescent IMR-90 cells or human preadipocytes. A1331852 and A1155463 are senolytic in HUVECs and IMR-90 cells but not primary human preadipocytes. We noted that these drugs increased cellular ATP levels significantly in senescent human preadipocytes, but not HUVECs, through an as yet unknown mechanism.
We predict many more senolytic drugs will appear at an accelerating pace over the next few years. Initially, most are likely to be based on re-purposed drugs or natural products. Increasingly, new senolytics will likely be derived using medicinal chemical approaches based on optimizing properties of the repurposed agents. Consistent with this, it appears that small changes in the senolytic drugs already discovered can interfere with senolytic activity, such as in the case of D vs. imatinib, with the latter not being senolytic, or N vs. the closely-related agent, TW-37. Conversely, we speculate that small structural changes to repurposed senolytic drugs could enhance senolytic activity, with increases in the percent and range of types of senescent cells eliminated, as well as better stability, bioavailability, and side-effect profiles.
"The existing candidates for senolytic drugs have largely emerged from the cancer drug candidate databases, and were tested for their effects on cancer for some years without noticing their strong effects on senescent cells - it wasn't in the list of items to evaluate at the time". But doesn't this imply that their effect on health and perhaps lifespan (I am assuming that some old people were cured of cancer) are negligible? Or there should be at least some anecdotal evidence of the contrary....
@Barbara T.: Not really; these cancer studies are short-term and very focused on effects on the cancer and immediate side-effects. Further, the dosages are high in comparison to what would be used in a senolytic role and side-effects quite significant, the standard level of damage caused by chemotherapeutics, possibly outweighing any potential benefits.
"Or there should be at least some anecdotal evidence of the contrary...."
Haha, you think so? It took as about 100 years to notice metformin and aspirin make us live longer and those drugs are in wide use and healthy people take them all the time. Cancer drugs on the other hand are used sparingly and mostly by people who don't survive their disease. They also stop taking the cancer drugs after they achieve remission. So the answer is no - there wouldn't be any evidence.
The argument about rejuvenation being negated by the toxicity of high dosages makes sense, but I should hope that senolytics will give us more than the couple of years (at best) that people get from metformin or aspirin. Were it no so, the excitement about this whole enterprise would be pretty unjustified.
Senolytics to eliminate senescent cells are also not meant to be taken continuously.
I noticed that two of these chemicals (quercetin and fisetin) are available over the counter as supplements. Have there been any studies of people taking these supplements? If not, this seems to be an inexpensive way to get some feedback, or do some human trials.
@Rick Davis
On quercetin there have been lots of studies. For a quick overview you can read Steve Hill's article on leafscience.org:
http://www.leafscience.org/quercetin/
@Rick Davis: Definitely worth thinking about. Quercetin I wouldn't expect much of; in the studies in mice it didn't do much on its own, only made the chemotherapeutic more effective. But a viable approach for citizen science is to try a mix of these various compounds - preferably the non-chemotherapeutics - that is unlikely to be trialed by the big players like UNITY any time soon.
This is pointless without a good assay before and after, however. This is something to look into; what is the best approach to assays in humans, something that is accessible to the average fellow, and can be done on a sample with a fair degree of reliability. E.g. one concern is that if you biopsy tissue, is the wound healing response immediately going to mess up the result by generating senescent cells in a way unrelated to your normal metabolism?
Actually they very much are meant to be taken continuously. Just not daily or weekly. A small monthly dose maybe.
As for how much they extend the lifespan... on their own I doubt it's significantly longer than aspirin. Not with a single cancer course anyway. Maybe if they are taken for a very long period starting from around your mid 30s the effect might be significant - but there's no way for us to know besides being the first people to try it on ourselves.
Senescent cells at the end of the day are just one aspect of aging and removing them can protect you against only some of the diseases which kill in old age.
No, that senolytics should be taken once a month and started in one's mid-30s is your speculation and your speculation only, since experiments in elderly mice showed extended lifespans of up to 35% with a single dose or a time-limited intervention.
http://joshmitteldorf.scienceblog.com/2015/03/13/kill-senescent-cells-before-they-kill-you/
https://www.sciencedaily.com/releases/2016/02/160203145723.htm
In fact, continuous administration of these compounds could interfere with wound healing and cancer suppression. Periodic clearance of senescent cells - just like intermittent promotion of telomerase activity - seems to be the best way to create a degree of "rejuvenation" while suppressing tumorogenesis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494070/
http://onlinelibrary.wiley.com/doi/10.1002/emmm.201200245/full
https://www.fightaging.org/archives/2013/05/how-senescent-cells-can-promote-cancer-formation/
And whether it's very doubtful that the same magnitude of results could be expected in humans, no one in the SENS / radical life extension community would even glance in that direction if they thought that senolytics were as useful as aspirin. While aspirin can prevent death in middle age, its life extension potential is still not quantified and in fact debated.
https://news.usc.edu/111659/an-aspirin-a-day-extends-life-prevents-heart-attacks-for-certain-older-americans-usc-study-finds/
http://healthland.time.com/2012/01/11/will-an-aspirin-prolong-your-life-it-depends/
http://www.acsh.org/news/2016/12/20/it-time-abandon-your-baby-aspirin-10620
The mouse experiment is not conferable to humans for many reasons not least of which is the fact you'd probably drop dead if you killed 60% of your senescent cells in a single go - they reach around 15 to 20% in aged primate tissue and I suspect even more in humans which are longer lived.
That effect is probably not possible in a human anyway because you'd need to dose yourself quite aggressively with chemo drugs and that alone could shorten your lifespan rather than lengthen it.
Killing a small amount of senescent cells monthly will not impede wound healing.
As for cancer it has nothing to do with it, you're killing the senescent cells, you're not stopping your body from putting cells into a senescent state.
Hi,
Just a 2c.
I believe Aspirin is a very powerful healer and inflammation pain reliever, its acting constituant is Salicylic acid/Salicylates extracted from the Willow Tree's bark. Salicilic acid is like caffeine or rapamycin : a CR-mimetic, they activate AMPK pathway (Adenosine MonoPhosphate Kinase) just like calorie restriction does. By activating survival AMPK pathway (survival pathway in face of specie starvation during famine), this increases AMP:ATP ratio, which activates the starvation signal mechanisms akin to CR or full starvation with near 0 cal. In turn, this signal preps for a stress period (famine/starvation) by altering mTOR Target Of Rapamycin CR pathway - which then alters inflammation genes like TNF and IL-6; by reducing IGF signalling, thus reducing endocrine, carbs (insulin) and metabolism speed. All of this is epigenetically orchestrated at the nuclear chromosome level; with NRF2 translocating to nucleus upon stressful period (starvation) to increase oxidative stress enzymes (SOD, Cat,..), and increasing chromosomal histone-depedent SIR SIRTuins that are necessary for genetic protection against inflammation caused ROS excess by immune system TNF-a, NOX, Cox, oxidases, Interleukin-6, Interferon-g, mitochondrial ETC H202 -o2 ROS excess, and other immune system caused ROS overtproduction tipping the balance towards inflammatory oxidative DNA lesion/frag SSBs DSBs formation and macromolecular damage in the ECM.
As a heart attack survivor myself...
I can tell you aspirin, or should I say salicylic acid, is the most powerful thing there is, as it saved me from death.
Aspirin can stop a heart attack if taken soon enough after the deathly attack. It's only of 2 minutes between life and death.
Always keep aspirin handy and close-reach, it could save you from a incognito assured death; as it did for me caused by my deadly silent embolic atherosclerosis. Or better yet, buy willow tree bark (though it's raw, not purified)), keep an aspirin or a bark bit in your pockets/wallet.
By stabilizing Inflammatory TNF ROS excess and reducing thrombosis/fibrotic clot formation in cholesteric-plaque rupture, a heart attack is stopped/mitigated to survive and get a chance to heal the massive cardiac senescence due cardiac tissue dying from ischemia.
Salicilic acid (aspirin) itself increases health quality by inflammatory reduction, like CR, reducing TNF and ROS excess.
Health quality improvement translates as higher longevity and post-ponement of late-life diseases onset. Some
Centenarians have taken aspirin salicylic acid for Years, along with coffee...
It is tantamount to a form of daily CR mimesis because it activates the same pathways as CR-induced lifespan extension.
My take is that salicylic acid aspirin activates neuronal, neural, endocrinal sensing mechanisms and CR-like signals that end up altering the metabolism (speed, energy ATP AMP, caloric energy kJ cal, endocrine sexual growth to DNA repair resource translocation shift by famine need for energy conservation for somatic tissue maintenance/repair in front of starvation nutrient/cal elimination) and thus, lifespan extension.
This is visible in mice as 20-30% lifespan extension that does not translate into humans because of diverging specie evolutionary goals. Plus, CR in rhesus monkeys does not make them live a double lifespan; but only reduces early premature mortality and improves healthspan (thus allowing a longer lifespan yet no more than the specie's known MLSP).
That certain centenarians lived a 100 years taking some aspirin quite frequently for many years, while other centenarians barely took any their whole life (they were healthy/not sick, did not need aspirins) demonstrates that lucky genetics, at birth, were the reason for their extreme longevity, not aspirin : many had sisters or brothers, even their (grand) parents, who All of them lived to 90 and above; a Clear and obvious genetic family inheritance Genetic Perk/Advantage : evolution selects these families' offsprings for Continued Extreme Longevity (because that's what evolution wants for sexless and low offspring species; Longevity = Long lifespan inscribed in the few offsprings = specie survival).
Just a 2c.
Aspirin is not a dietary restriction mimetic. It is a geroprotector and as such is superiour.
Metformin - as well as fasting or CR go together with physiological changes, whereas the benefits of aspirin are more or less acquired for free.
One mechanism is a trade off, the other is simply activating what is already present but not working optimally.
Senescent cell clearance is unrelated to these two in any way. If anything it should work better the higher and longer lived the organism.
Hi Anonymoose,
Some studies seem to show that AMPK energy sensing pathway is CR pathway (depending on nutrient/cal intake) that shifts the metabolism to using fatty lipids reserves as fuel rather than carbs, basically just like CR does and ketotic ketones burning activation (CR shifts energy production to lipid and ketones usage). CR activates AMPK, and AMPK is needed for CR longevity by fatty acid/fat usage/burning switch.
Salicylic acid/salicylates (Aspirin), just like Metformin, Caffeine or Rapamycin, activates AMPK pathway fatty burning and fat energy usage switch. That's because AMPK is a mTOR regulator and autophagy regulator. Autophagy is needed for CR longevity; thus AMPK (by virtue of its autophagic and lipid burning activation) is essential to CR-induced lifespan extension.
AMPK -> ULK1 -> Autophagy -> CR longevity extension
"Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777."
Anacardic acid (6-nonadecyl salicylic acid, a salicylic-based aspirin homologue from cashew tree nut) activates AMPK,
"The extract of the seed as well as anacardic acid activated AMPK in the myotubules after 6 h of incubation, (Tedong et al. 2010)."
"Activation of AMPK is likely to increase the number of plasma membrane glucose transporters resulting in elevated glucose uptake (Tedong et al. 2010)". Just like Metformin in type 2 diabetes, my father has T2D (..'lucky' for me...) and takes Metformin to control his blood glucose, insulin spikes, sugar cravings pangs (glucose spikes and dips) and HbA1c glycated hemoglobin.
All of this demonstrates or seems to suggest that Aspirin salicylic acid acts in a CR mimesis fashion, and its benefits are CR same acting pathways, same as caffeine, metformin or rapamycin CR mimetics.
The ancient drug salicylate [aspirin] directly activates AMP-activated protein kinase.
1. https://www.ncbi.nlm.nih.gov/pubmed/22517326
AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network.
2. http://www.sciencedirect.com/science/article/pii/51568163711000778
AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.
3. http://www.nature.com/ncb/journal/v13/n2/full/ncb2152.html
AMPK -> ULK1 -> Autophagy.
4. http://mcb.asm.org/content/31/15/3082.full
Role of AMPK-mTOR-Ulk1/2 in the Regulation of Autophagy: Cross Talk, Shortcuts, and Feedbacks.
5. http://mcb.asm.org/content/32/1/2.full
Aspirin Induces Body Fat to Burn, Study Says [salicylate AMPK pathway activation, same as CR, same as CR fat weight loss; news based off of 2012 study "The ancient drug salicylate directly activates AMP-activated kinase"}
6. http://www.emaxhealth.com/8782/aspirin-induces-body-fat-burn-study-says
Hydro-ethanolic extract of cashew tree (Anacardium occidentale) nut and its principal compound, anacardic acid, stimulate glucose uptake in C2C12 muscle cells.
7. https://www.ncbi.nlm.nih.gov/pubmed/20603833
Posted by: Barbara T. at March 11th, 2017 6:26 PM:No, that senolytics should be taken once a month and started in one's mid-30s is your speculation and your speculation only, since experiments in elderly mice showed extended lifespans of up to 35% with a single dose or a time-limited intervention.
You're confounding the results of two different studies in a way that exaggerates the results of both. The study on which the Mittledorf blogpost is based was a one-time administration, but it was only a short-term study, too: it showed rapid health benefits, but wasn't a lifespan study. The lifespan study behind the Sciencedaily story you link:
(a) didn't involve senolytics, but a genetic "suicide gene," which is more effective and less prone to side-effects (stem cell and neuron depletion) than the current senolytics (which are based on inhibiting cell survival pathways) can be, and also more effective than OisÃn's senescent-cell-clearing nonintegrating genetic technology is likely to be;
(b) "induce[d] apoptosis in p16Ink4a-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age" until death, which is indeed the equivalent of starting in one's mid-30s and dosing frequently over the course of the ensuing decades;
(c) didn't extend lifespans by 35%: it increased median lifespans by 24-27% under most conditions, with no effect on maximum lifespan; it only increased median LS by 35% in a subset of animals where the controls were exceptionally short-lived compared to all the other animals in the study (all of which, as we discussed at the time, were shorter-lived than healthy mice normally are, probably due to some combination of the stress of twice-weekly injections and possibly some effect of the transgenes, though the latter is probably minor); and
(d) again as we discussed at the time, you can't extrapolate even a 25% increase in median lifespan to humans, because we already have our survival curves squared up by access to modern medicine.
Posted by: Anonymoose at March 12th, 2017 7:28 AM: Aspirin is not a dietary restriction mimetic. It is a geroprotector and as such is superiour.
There's no real evidence that aspirin is a geroprotector. Yes, it reduces risk of heart attack and stroke, because it inhibits clot formation; yes, it probably reduces risk of cancer in most patients, due to the role of inflammation in progression of many cancers. But there's no evidence of a primary effect on aging. In the NIA ITP, eg., it had a teensy-tinesy effect on median survivorship only, in male mice only.
Posted by: Anonymoose at March 12th, 2017 7:28 AM : Metformin - as well as fasting or CR go together with physiological changes, whereas the benefits of aspirin are more or less acquired for free.
Metformin is an even poorer case than aspirin: there's no good reason to think it's of any benefit to aging but basically-healthy (non-glucose-intolerant) humans or mice, as discussed here.
I'm not arguing that all of the three are weak options.
If you go further up the thread the whole argument started when I pointed out exactly that.
Anyway, I imagine senescent cell clearance should at least have a measurable impact on healthspan. We seem to be more prone to age related conditions related to senescent cell accumulation than mice are.
Michael, my point is that if a SENS-based intervention like senescent cell clearing (achieved with whatever means) were expected to have the same effectiveness of metabolic tinkering with aspirin or metformin, no one would be remotely as excited as the scientific community happens to be.
Also, I never said that people will get a 35% extension of their maximum lifespan. As you pointed out, yes, the difficulties of translating results from mice to humans have already been enumerated in a previous thread. But this also means that extrapolating from a mice study - just one of many, which offers one option out of many - that drugs should be taken once a month starting from one's mid-30s is equally not very sound. It could be the best strategy, or it could be not.
My point is that to my knowledge aspirin has never been proven to extend median lifespan in mice by 24-27% (but please correct me if I am wrong - the best I found is 21-23% in nematodes), and hence that the comparison is moot to say the least.
My other point is that I was pretty satisfied with Reason's answer that side effects, patients with comorbidities non-amenable to mitigation by senolytics, and wrong dosages, are enough to mask any potential benefit of the 'accidentally senolytic' drugs that have been trialled in cancer studies so far.
However, everything seems to turn into a polemic on this site, with posters trying to show up other posters when they disagree about something on which there isn't even solid data, or - worse - when they are simply asking a question. And I am not being thin skinned here: I have seen a lot of people taunting others as of late, which has in fact deterred me from posting and at times even reading.
PS:
2c,
I think the realistic results of senescent cell clearance therapy will be at least equal or a bit better than senescent cells clearance nutraceuticals like quercertin, fisetin, hesperidin, pelargonidin or dasitinib. Some o f these are already present in our fruit/herb diets, as such it may end up not as impressive as hoped. It will be therapeutic and improve sick people's health by senescent cells-caused p16 TNF SASP inflammation reduction upon senescent cells clearance; this will cut some slack to the (still) healthy surrounding tissue/cells. My take is a possible if uncertain 7 to 8 years life extension by healthspan increase (just like biogerontologists predicted from CR and exercise combination), very worse case 1-2, Very Best case 10. I say this because centenarians' offsprings DNA methylation epigenetic age was 8-years younger on average than shorter-lived people who did not reach a 100 years (centenarians had higher global DNA methylation and they had higher immune leukocyte telomere/lost them slower by aging's oxidative stress caused redox loss vs short-lived people who became immunosenescent by faster shortening leukocyte telomere length or shorter telomeres right off the bat at birth since centenarian's and very old fathers' offspring had taller telomeres at birth vs offspring of short-lived parents (Telomeres which take part in aging-bound replicative senescence but can also be uncoupled from pathological stress-induced DDR premature senescence in diseases or oncogene-induced senescence (cancer is an accelerated epigenetic aging)). Telomeres are of course not reliable,
DNA methylation epigenetic clock age is.
Aspirin salicylic acid will not make humans reach 100, but it does help giving you health-boost chance of living perhaps 5 years or less more in adequate health - it does not stop replicative senescence because you eat willow bark salicylic acid or aspirin. As said, some centenarians took aspirin some did not, aspirin might have slightly improved their odds of making sure they reach a 100 as light CR mimetic : it's not aspirin, but luck of the draw long-lived-family-inherited birth genetic makeup and late life epigenetic trajectory on top of that fortuned birth genetic makeup that will make them reach a 100 years old.
Aspirin (methylsalicylate) can improve health in very low dose by AMPK CR pathways, but, as mentioned there are side effects like deadly hemorrhage since it inhibits platelet clotting/wound closure for internal arterial bleeding open wound. The lowest dose possible and the least frequently seems the best inbetween to minimize these high bleeding risks. Willow bark is better than aspirin surely, and less dangerous on hemorrhaging; even less dangerous but confering about equal benefits is Anacardic acid (6-pentadecyl salicylic acid) from cashews' shell liquid and eating the nuts (just be careful, cashews contribute to cholesterol LDL elevation and are atherosclerotic from their saturated/monounsaturated lipid fatty acids despite having some cardiac benefits, which are nullified in cardio-pathological condition).
As for taking senescent cells clearance therapy in your mid 30s or late life ? The motto is generally the younger the better, because of the total Irreversible permanent DNA lesions, fragmentations and nucleotide bp-deletions burden getting heavier with age. Younger allows more chance/odds of successful results in these therapies, although it's not assured.
Some studies required the animal to be in old age for the specific effect only happening for the older animal (kind of like the flawed idea that rejuvenation only works on old people because they damaged-enough - to be repaired (kind of like when AdG said wait till your middle age for rejuvenation 'to have accumulated enough damage by age' so we have 'something' (tangible, damage) to repair/rejuvenate) while very young people have little to no real consequential damage at this early point in life - thus, pointless rejuvenation in young people. When, in fact, some small permanent damage starts at very birth)).
As side point, I saw that Jim O'Neill is no longer in the running for FDA commissioner. I'm not surprised although it irritates me for the economics blogger Tyler Cohen to suggest that America is "not ready" for him.
It appears we are still on our own with regards to the regulatory and health care systems themselves.
Once we are born we start to age, accumulate damage. In teenagers this damage is well established. We need to seriously consider using senescent cell clearance therapies at a much earlier age than thirty.