Concerns About Harms Caused by Senolytics are Not Supported by the Mouse Studies

Senescent cells accumulate with age to cause harm via their pro-inflammatory secretions. Senolytic therapies can selectively destroy these cells, to benefit the patient quite rapidly. Hypothesized harms that might be caused by senolytics generally revolve around the idea that some senescent cells might be structurally useful and hard to replace, so while having those senescent cells is bad, getting rid of them could be worse. The response to these concerns is to point to the mouse studies, in which no such problems appear to occur. The article here is a lengthy examination of this sort of argument of hypothetical concern versus actual mouse data in the specific case of muscle tissue.

Skeletal muscles are organized into long fibers composed of many nuclei, and when a fiber is damaged, the entire fiber is often lost. It seems that if any one of these nuclei were in a senescent state and were hit by a senolytic therapy, it might result in a fiber break and pull down the entire muscle fiber with it. And muscle fibers aren't easily replaced, and loss of muscle mass and function is already a major problem in aging, so the drug-induced destruction of muscle fibers could accelerate an aging person's slide into disability. Is this a real risk, and if so, does it make senolytic therapies a non-starter?

That's a worrying scenario for those of us who are excited by the promise of senolytic therapies. Fortunately, all the animal data refute it. When we get to the bottom-line question of what senolytic treatment did to the mass and function of muscle in old mice, we see good news all around. Not only did the senolytic-treated old mice not lose muscle, the treated animals actually sustained or restored the distribution of their muscle fiber sizes to the same distribution seen in young mice. Senolytic-treated mice also either gained more strength or suffered less age-related loss of strength than the untreated aging animals, leaving their muscle power partway between that of old and young untreated mice. And senolytic treatment also reduced the amount of dysfunctional repair activity in their muscles.



For sure, senolytics have some negative effects. 1) off-site damage 2) higher rate of depletion of stem cells due to ablation ; 3) and loss of useful ScC .

Some of them might be evident after long-term use. However, it is all about tradeoffs. If I can feel 10 years younger as a quality of life now, I will be less worried about potential long-term effects sine i have to live long enough to really be affected. Murine studies are terrible model for long-term effects, so there we cannot tell anything. However we can reduce off-site damage with second (are there third?) generation of senolytics like betagalactocease conjugation, micro rna, and such.

I am a bit disappointed that the bulk of the research is focused on D+Q

Posted by: Cuberat at October 23rd, 2023 7:54 AM

Sort of a moot point right now in that the dasatinib quercetin study in humans didn't really show an indication of senescent cell removal after treatment.

Maybe future senolytics will work better but first they need to be found or created.

Posted by: Lee at October 23rd, 2023 7:55 AM


The TruDiagnostic preprint states that several epigenetic clocks cannot measure the expected effect of Dasatinib and Quercetin (and Fisetin) as dosed in their trial on 'biological age' using their respective methylation markers. Examining what TruDiagnostic intends to sell might provide some insights into this outcome.

Also, small sample size, curious P-Values and conflict of interest: NC, VBD, RS, HW, AL, LT, and TLM are employees of TruDiagnostic.

'...epigenetic aging markers were not supplemented with classical blood measurements or classical phenotypic markers of aging and thus, it is possible that some unmeasured confounders biased our results'

Posted by: Jones at October 23rd, 2023 11:47 AM

@Jones: Good find. I think it draws attention to the point that we really need someone to run a few-hundred person study with biopsies. There is a lack of data, given the potential - it is ridiculous that there is only the one published study with biopsy data. It could be done at much lower cost than a formal trial.

Posted by: Reason at October 23rd, 2023 12:28 PM

A lab in Cambridge run by Daniel Munoz-Espin has developed a senoprobe with photoacustic Tomography Properties to detect and monitor senescent cell burden. It is being presented at the ICSA conference in Minnesota next week.

Posted by: Helga Sands at October 23rd, 2023 1:18 PM

But in defense of the dastinib trial that didn't show obvious benefit: the dose of dasatinib was pretty low at only 50mg for 3 days each month. Also seemed too often to me.

My favorite mouse study, for what that's worth, showed they stopped spine degeneration with weekly doses when started at a relatively young mouse age, something like 8 months IIRC. So if humans live 30-40x longer than mice that would be a dose every 30-40 weeks.

I have taken d+q 4 times in 4 years, 100mg for 2 days, 100mg 2 days, 150mg2 days, 50mg 7 days. Should have done some bloodwork but didn't. Can't say I really noticed anything better or worse but after recently seeing a paper on a bunch of leukemia patients taking 50mg daily for multiple years straight and there was something like 96% survival I decided to not worry about any negative health effects from a small handful of doses

Posted by: Lee at October 23rd, 2023 3:18 PM

'Can't say I really noticed anything better or worse'

I can leave this anecdotal remark.

The 13 self-experimenters (52-83yo) that I know report the same.
Four had bloodwork (4 pro-inflammatory markers) done before/after treatments.
Effect size, if of any significance at all, about the same as treatment with low dose NSAIDs .
Disruption by SASP is more complex than inflammation, though. But so far the noticable benefits outside of labs seem elusive.

Posted by: Jones at October 24th, 2023 3:54 AM
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