Against Senolytics

There is no consensus in science that is so strong as to have no heretics. So here we have an interview with a naysayer on the matter of senolytic treatments, who argues that the loss of senescent cells in aged tissues will cause more harm to long-term health than the damage they will do by remaining. To be clear, I think this to be a ridiculous argument given the present evidence. To make it one has to declare the existing results showing extension of healthy life span in mice to be something other than credible data, which just isn't the case. Further, it seems shaky on theoretical grounds to suggest that removal of something like 1% of cells will put onerous stress on the remaining 99%, particularly given that the 1% were contributing to declining stem cell activity via inflammatory signaling. All told, it is hard to take seriously the idea that loss of senescent cells can possibly produce greater degrees of dysfunction in tissue than is caused by the inflammatory signaling of senescent cells.

Your new review on senolytics suggests that senolytics may cause more harm than good. Can you summarize your objections and concerns?

Here is the argument: 1) theoretically, senolytics should make things worse and 2) the available data support this theoretical concern. To use an analogy, imagine that you have a factory in which 10 of the 100 factory workers are feeling overworked and tired. Furthermore, their complaints are disrupting the other workers. You have two possible interventions. You can: (a) Fire the 10 workers, thereby removing the complainers. The result is that the remaining 90 workers are now overworked, and they, too, begin to complain. You end up with 30 workers who are now complaining and disrupting your factory. This is the senolytic approach. (b) Improve the health and conditions of the 10 workers who are overworked and complaining. You now have 100 workers who are doing an excellent job. This is the telomerase therapy approach.

In the first case, your factory has a problem and you make it worse. In the second case, your factory has a problem and you solve the problem. This figure from my new paper illustrates the same point in terms of nine cells subjected to senolytics, with the result being temporary short-term improvement followed by decline and a worse situation than we started with.

This does not take into account the idea of replacing that pool of "workers" by bringing in fresh stem cells.

You have to keep a few points in mind. 1) Will the stem cells populate as desired? 2) If you do get a stem cell population, that requires cell division, which shortens telomeres, which accelerates cell senescence, and once again you have accelerated pathology. 3) Why would you bother recruiting stem cells when you can much more easily reset cell senescence in the resident cells of the tissue? 4) The long-term data (what there is of it) supports the failure of senolytics. Again: remember where those "new cells" come from: you are accelerating senescence in the stem cell pool. The only way to "replace them with healthy working cells" is to simply and effectively reset gene expression, taking senescing cells and turning them into functionally young cells.

It seems that we can only speculate on these issues, as these long-term follow-ups have not yet been done. However, senolytics have been shown to increase median lifespan and healthspan in murine models.

I don't see any credible data that supports the contention that "senolytics have been shown to increase median lifespan and healthspan in murine models".



The whole point of cellular senescence is to protect against cancer-causing mutations by preventing these potential cancer cells from dividing. So it's a really brilliant idea to deal with it by finding ways of turning it off - turning all the failed cancer cells into successful cancer cells. That'll make things better.

As for his factory analogy, the more accurate description of those ten workers is that they've gone mad and are actively sabotaging the machinery. His solution is to make those workers stronger so they can do even more damage.

Posted by: Arcanyn at November 19th, 2019 7:52 AM

Logically speaking, if you do many rounds of senolitics you could deplete the stem cells at the end, in the very long term. But in the mean time you are reducing the inflammation and improving short and medium term health. You have to love long enough to be affected by the potential downsides of senolitics. Without them you have good chances to be sick and die well before that. Now, there might be some seno modulating procedures to boost cells' solf repair. And turn a senecent cell into a good citizen. One therapy doesn't exclude the other, though. Either the cells recover or they get killed.

On a somehow unrelated note I started seeing a lot of titles about senolitics and senecent cells in the mainstream media. I think we have reached the critical mass, at least for senescent cells research.

Posted by: Cuberat at November 19th, 2019 8:06 AM

I guess I should start firing my complaining workers before they accumulate to a critical mass.

Posted by: JohnD at November 19th, 2019 8:19 AM

This is hallucinatory. I think it arises from the idea that all of the problems of aging
are caused by telomere shortening. When you only have a hammer everything looks like a nail.

Posted by: Antonio at November 19th, 2019 9:25 AM

Ah, I knew this one was sure to ruffle some feathers ;)

Posted by: Steve Hill at November 19th, 2019 10:17 AM

You'll only prove Fossel wrong by extending MAXIMUM as well as MEDIAN lifespan through senolytics. So far I'm not seeing that in the mice trials. Even in the Oisin trial (from what the founder said in a previous post) we only have data for a boost in median life expectancy.

Posted by: Mark at November 19th, 2019 11:31 AM

Seems it would be advantageous to have telomerase therapy, following senolytic therapy.

Posted by: bmack500 at November 19th, 2019 11:42 AM


Or the other way around. This way you boost only the better cells that already have survived the senolitics

Posted by: Cuberat at November 19th, 2019 12:22 PM

To me, he sounds desperate for financing.

Posted by: NY2LA at November 19th, 2019 1:47 PM

First, I addressed several of these arguments here; at the time, I was unaware of Fossel's paper.

Second, re: Fossel's bizzare claim that he "do[es]n't see any credible data that supports the contention that "senolytics have been shown to increase median lifespan and healthspan in murine models": as he almost immediately seems to concede in the full interview, "the Baker paper" shows exactly that.

He then retreats to the position that ablating senescent cells "may increase median (but not maximum) lifespan in murine models, but the acceleration of the curve shows that pathology increases after an initial "honeymoon period". But there is no such acceleration (see Figure 1, (b) and (c): the only hint of such is the male mice in Fig 1(c), and that's after an exceptionally strong early protective effect, where you can only expect a steep fall-off if maximum lifespan is not to be increased.

And there's a perfectly reasonable counterexplanation for this, which was entirely predictable. As I said at the time, "This is as you'd predict, based on the principle of the "weakest link in the chain": to move the needle on maximum lifespan, you have to push back on all of the cellular and molecular damage of aging, not just one form."

It should also be noted that in separate reports, both fisetin and D+Q were shown to continue to extend mean lifespan even when administered late in life, and with some suggestion of an increase in maximum lifespan (albeit unconvincingly, for different reasons, in both reports).

Even more strangely, Fossel says "There is much better data for telomerase therapy than the questionable data on senolytics (see, e.g., Muñoz-Lorente, et al. 2018, and Jaskelioff, et al. 2011)." "Jaskelioff, et al. 2011" is a study in telomerase-deficient mice, who of course benefit from being given telomerase therapy by having their remaining lifespan normalized: that's hardly equivalent to increasing median lifespan in mice undergoing intrinsic, biological aging.

Muñoz-Lorente, et al. 2018 is so clearly off the mark that I don't think it bears comment.

Posted by: Michael at November 19th, 2019 5:44 PM

I'd like to suggest a "Latest Comments" section on the side column because users often are not aware of current disussions in older articles.

Posted by: Christian at November 20th, 2019 2:25 AM

Michael says, "This is as you'd predict, based on the principle of the "weakest link in the chain": to move the needle on maximum lifespan, you have to push back on all of the cellular and molecular damage of aging, not just one form."

And yet telomerase AAV gene therapy has extended both mean and max lifespan.

Posted by: Mark at November 20th, 2019 3:29 AM

@Christian: There is a RSS feed for comments.

@Mark: Reference?

Posted by: Antonio at November 20th, 2019 3:46 AM

MAXIMUM. You mix maximum for a control group or for individual, with a MAXIMUM for a species. Both D+Q and fisetin increased mean lifespan and maximum lifespan compared to a control untreated group. Which mean they increased maximum lifespan for a sizeable count of 'individuals' too. For a species like mice or human known maximum lifespan most probably already includes extensions like combating SASP that can be achived by natural substances found in food or herbs. At least two of so called "longevity island" has high consumption of SASP lowering wogonin, the others have the same for apigenin and/or kaempferol. To reach new lifespan maximum record for a species you would have to find something that will extend individual lifespan more than known life extenders. Or find a strain reaching maximum without treating it with any extenders, and then treat it with suspected ones.

Posted by: SilverSeeker at November 20th, 2019 4:57 AM

For sufficiently large control and treatment arms, the difference between max lifespan for the species and max lifespan in the trial, should become negligible. That's certainly a better approach than finding really old people, and cherry picking the reason for their longevity from your favourite current theory.

Posted by: Mark at November 20th, 2019 5:55 AM

Yeah, SilverSeeker got it right: the paper doesn't claim any maximum lifespan increase for the mice, only for an individual mouse in each group.

Posted by: Antonio at November 20th, 2019 7:34 AM

Only median lifespan increase is mentioned in the abstract, for a good reason. And in the text of the paper, only this is said, much weaker than Mark's claim:

"We also found a significant increase in the median survival of the longest-lived mice (90th percentile; Fig 3B) in the AAV9-mTERT group compared to the AAV9-eGFP group or the non-injected controls, suggesting that TERT may affect maximum longevity."

" Indeed, the longest-lived AAV9-mTERT treated mice from the 1 and 2 year old groups surpassed by 13 and 20%, respectively, the maximum longevity of the corresponding longest-lived AAV9-eGFP treated controls"

Posted by: Antonio at November 20th, 2019 7:37 AM

The curves suggest (Fig 3a) that medium and maximum lifespan were improved by a similar amount. Of course, the maximal span increase is much less significant statistically. The causes of death for the telomerase treated mice seemed to be the same as the untreated controls (only later). It would be interesting to see if another telomerase treatment would have extended life further, or whether Michael is right that other, unaddressed causes of aging would have prevented this. We know further treatments of fisetin would not extend life further because the mice were treated with it constantly after a certain age.

Posted by: Mark at November 20th, 2019 9:13 AM

I would focus more on foods and supplements accelerating aging. People eat them massively and so we can significantly decrease the population.

Posted by: Omasta at November 24th, 2019 2:59 PM

@omasta conspiracy theories don't belong on here

Posted by: Scott at November 29th, 2019 8:49 AM

And what about TGF-β blocking hTERT, and thus switching off telomerase?? TGF-β is greatly elevated by Senescence-Associated Secretory Phenotype. How would it be ever possible to lengthen telomeres in old people without lowering TGF-β? Senolytics are one of the more efficient ways to do it. Even Bill Andrews with TAM818 which probably attained actuarial escape velocity already didn't achieved it. You have to switch off machinery switching hTERT off too... Leaving senescent cells in place is like sabotaging factory and killing the host... And for sure, senolytics (or SASP lowering substances like apigenin, kaempferol, wogonin, fisetin in doses lower than senolytic) are most effective taken together with telomere lenghtening substances like baikalin, sylibinin, TA65, TAM-818 (and the list is growing). They have both great synergy to extend life span.

Posted by: SilverSeeker at January 15th, 2020 6:32 PM
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