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A Broadening of Efforts to Clear Senescent Cells

The accumulation of senescent cells over time is one of the causes of aging. It is one of the limited number of root cause mechanisms that collectively distinguish old tissue from young tissue. Cells become senescent constantly, most because they have reached the Hayflick limit on replication, but senescence also occurs in response to cell damage, tissue injury, or a harmful tissue environment. Near all of these cells are destroyed shortly after becoming senescent, either through the programmed cell death process of apoptosis, or by the immune system. A tiny fraction linger, however. These cells generate a mix of signals and other proteins that promote inflammation, destructively remodel the nearby extracellular matrix, and change the behavior of normal cells for the worse, among other things. This all makes sense in the context of their presence in embryonic development, wound healing, and cancer suppression - and when there are comparatively few such senescent cells. When there are many senescent cells, however, and when they are not destroyed as they should be, this behavior adds up to cause significant harm. Destructive processes such as fibrosis, arterial calcification, development of atherosclerotic plaques in blood vessels, loss of tissue elasticity, chronic inflammation in joints, and many more can all be directly tied to the presence of senescent cells, and can be improved by removing those cells.

Targeted removal of senescent cells to at least some degree is in fact now fairly easy to accomplish in a laboratory setting through the methodology of targeting known suppressors of apoptosis. As a consequence a whole range of drug candidates of varying quality are emerging. The senescent cells that linger in old tissue are remain primed for the fate of apoptosis, but are held back by a few mechanisms that are increasingly well characterized. Near any established medical research group with experience in cellular biochemistry can jump in and try their hand. Clearly a growing number of researchers are doing just this, managing to raise funding and join the field. There is plenty of room for them. Clearance of senescent cells - as a rejuvenation therapy capable of turning back some of the consequences of aging - has a target market of every human much over the age of 40, for treatments undertaken once every few years. This is such an enormous potential industry that no one company or methodology will win it all. In the next few years, we'll probably see sizable and successful companies emerge in many different countries, all of which have different regulatory regimes, and thus there will be comparatively little direct competition between these ventures.

The publicity materials below are really just banging the drum for work published last year, in which researchers used ABT-737 to inhibit BCL-W and BCL-XL. These two members of the Bcl-2 family suppress the process of apoptosis. Targeting them thus selectively destroys senescent cells by removing one of the blocks to undergoing apoptosis - a manipulation that should have comparatively little effect in normal cells. Many of the apoptosis inducing drug candidates at this time have significant side-effects, however, and so it is likely that success in the market will only be achieved by those lacking that problem. At this point, the researchers here are somewhere in the early stages of commercializing their approach, and hence the emergence of extra publicity from their supporting institution. There will be a lot more of this sort of thing going on in the next few years.

Understanding why cells refuse to die may lead to treatments for age-related disease

One of the things that happens to our bodies as we age is that certain cells start to accumulate. So-called senescent cells - cells that "retire" and stop dividing but refuse to undergo cellular death - are always present, and they even serve some important functions, in wound repair, for example. But in aging organs, these cells don't get cleared away as they should, and they can clutter up the place. Researchers are revealing just how these cells are tied to disorders of aging and why they refuse to go away. The work is not only opening new windows onto the aging process, but is pointing to new directions in treatments for many of these disorders and diseases.

Research into cellular senescence has taken off in recent years, due to findings that clearing these cells from various parts of the body can reverse certain aspects of aging and disease processes. Pharmaceutical industries have taken note, as well, of research that could lead to the development of drugs that might target senescent cells in specific organs or tissues. In basic research conducted on human cell culture and on mice, researchers have asked exactly what ties senescent cells to aging. Are they, for example, a primary cause of age-related disease, or a side effect? And why don't these cells die, despite being damaged, so that the "clean-up crews" of the immune system have to clear them away?

The researchers hypothesized that the answer to the second question might lie in a family of cellular proteins that regulate a type of cell suicide known as apoptosis. They identified two proteins in this family that prevent apoptosis and which were overproduced in the senescent cells, BCL-W and BCL-XL. When they injected mice that had an extra supply of senescent cells with ABT-737 molecules that inhibit these two proteins, the cells underwent apoptosis and were then eliminated, and there were signs of improvement in the tissue. "In small amounts, these cells can prevent tumors from growing, help wounds clot and start the healing process. But as they amass, they trigger inflammation and even cancer."

Certain common age-related diseases have been shown to be associated with this build-up of senescent cells, for example, chronic obstructive pulmonary disease (COPD), and researchers hope to apply these findings to research into treatments for such diseases. The trick will be to target the offensive cells without causing undue side effects. Researchers have been developing mouse models of COPD and asking whether clearing senescent cells just from the lungs can prevent or ease the disease. They are now working to patent and license these discoveries.

Comments

While we're waiting for these to hit the market, are there any known lifestyle interventions that can aid in the clearance of senescent cells?

Posted by: Brandon Berg at May 20th, 2017 6:42 AM

Fasting for 48 hours, or protein restriction, as these trigger autophagy where the body starts to eat itself. It is worth looking online as there are many different ideas on the best way to do this.

Posted by: Tj Green at May 20th, 2017 7:28 AM

You can increase autophagy with spermidine supplements too. Increases autophagy but not via mtor or sirtuin pathways.

Posted by: Steve h at May 20th, 2017 10:06 AM

That's a good point Steve. There are known senescent cell types which are not affected by the mTOR pathway.
I'm not sure if fasting is necessarily going to be absolutely effective as well considering it does seem to mostly hit on the mTOR pathway, but it might activate or inhibit other pathways so who knows.

Most of our info is to this day murine based which is not ideal, there is quite the chance our senescent cells are more survivable, just like our cancers - mice are really not the best model to study cytotoxicity.

Posted by: Anonymoose at May 20th, 2017 10:29 AM

@bardu: None of the citations referenced in that article indicate that tocotrienols induce apoptosis in senescent cells - only that they slow the rate at which cells in culture become senescent. There are three problems with this.

The first is that things that are shown in vitro don't always pan out in vivo.

The second (which is actually closely related to the first) is that the usual way for cells in culture to go senescent is because their telomeres are massively bombarded by free radicals caused by exposure to the "artificially" high levels of oxygen in the atmosphere (20%). In the body, oxygen levels are <5% everywhere, and usually only 2-3%. So it's unsurprising when an antioxidant forestalls senescence under conditions of artificially high free radical generation. You can avoid such artifacts by culturing cells under physiologic O2, but none of the cited studies indicate that they did this, despite specifying keeping them at 5% CO2 (which is standard procedure because it's needed to help buffer the medium against changes in pH resulting from the cell's exchange of gasses, nutrients, and metabolites with the medium). So they presumably kept them under atmospheric O2 as is the unfortunately usual practice. There is therefore no reason to believe that this effect has a meaningful impact in vivo.

And the third is that even if it works, inhibiting the senescence process itself is a risky thing to do: cellular senescence is a program, which is induced when cells acquire alterations that put them at risk for becoming cancerous. Interfering with the senescence process potentially puts the cell at risk of turning cancerous instead of senescent. This is one of the many reasons why it's far better to ablate senescent cells once they're already formed than to try to prevent them from forming.

As to quercetin: I totally respect the work of the Mayo group that reported the senolytic effects of quercetin. However, I'm aware of two labs that have tried to replicate the effect, and neither has been able to do so: one group got inconclusive results and is trying a second round on different cell types, while the other got a mild inhibition of one component of the SASP but no selective killing. And, the only lifespan study that has ever been done with quercetin found that it shortened life rather than lengthening it.

Posted by: Michael at May 21st, 2017 12:12 PM

Yes I can confirm that we are testing a second round currently as the results are inconclusive thus far. I am leaning towards what Sinclair reported in 2013 and that quercetin inhibits elements of SASP such as CD38 rather than induces apoptosis.

Posted by: Steve Hill at May 21st, 2017 2:56 PM

Hi all !

I hope this pants out and senescent cell clearance ends up being something with potential; I have now set the bar to the lowest possible; I think it will not pan out like planned and we should just concentrate on improving health. THe quest for living over 150 is not going to happen anytime soon nor in our lifetime, the odds seem to improve but with every new stumbling block study my hope shrinkens. I think we are just a bit too late (For those over 40-50 years old). Those under Might have a chance at making it over a 100 years old, still the number of centenarians is so small, life expectancy still hovers 70-80ish, nothing more - and to go above that you need to Start Earlier - your therapies like 40 years before. All the people over 60 can aim for a 100 but my breath is not held.
I think the last element that needs solving is mTOR, it's been solved to death but is it really? Not really, it governs everything in our body and is the num1 cause of senescence and conversion to senescence after cell cycle arrest. If only we could stop it. We could affect the entire epigenetics and aging. Still, it is a two-face and we need it just as much as we don't (needed for growth). I think selective inhibition is the only option. I'm not talking about senescent agents like Quercetin and Sirtuin-activating Resveratrol, Rapamycin, CR or Metformin; but better than that, something that alters mTOR's program. 2 cent.

Posted by: CANanonymity at May 21st, 2017 3:18 PM

PS: MEtabolic tinkering seems counterintuitive and we barely get any results - but the truth is, it's all about the metabolism and speed of it. The damages are the consequences, but we can't stop (enough) all those damages (not even CR is capable, we still die anyways). I definitely hope that, stopping and repairing the damages (enough of them) would be enough to slow aging and repeat ad vitam eternam for near immortality; but I have great reservations when even a simple CR can't do it (of course CR does not stop everything, we understood that). I think we need to get back to 'growth and metabolism' control of old days, howeever hopeless it seems. Growth and metabolism are what allows a mice to live 2 years old and a greenland shark to live 500 years.

Posted by: CANanonymity at May 21st, 2017 3:40 PM

@CANanonymity It's definitely not going to be easy but I'm still optimistic.

I think between the paradigms of stem cell reprogramming and senescent cell clearance we'll build the first viable therapies. I don't know if they'll give us 30 years like Aubrey thinks. They might give some people 30 years - but others won't be so lucky.
You have to remember, these therapies don't exist in isolation, they will enhance the outcomes of the medicine we already have.

We'll see.

Posted by: Anonymoose at May 21st, 2017 4:04 PM

@CANanonymity I think you have been drinking from that defeastist fountain again.

"I hope this pants out and senescent cell clearance ends up being something with potential; I have now set the bar to the lowest possible; I think it will not pan out like planned and we should just concentrate on improving health."

You cannot possibly know that so you "think" means you are operating from feelings. Feelings are absolutely awful and are not indication whatsoever. Remember, a number of us here are seeing the data for senolytics and so your assesment could not be further from the situation. I think you need to ignore your feelings and look at facts.

"The quest for living over 150 is not going to happen anytime soon nor in our lifetime"

Based on what? Your feelings again? Next!

"I think the last element that needs solving is mTOR, it's been solved to death but is it really?"

Its all part of deregulated nutrient sensing and mTOR, SIRT1 and AMPK are all a part of that puzzle. However the data strongly suggests that this is an atagonistic damage caused by primary hallmarks higher up the chain eg, DNA damage, Epigenetic changes, loss of proteostasis and telomere attrition.

"MEtabolic tinkering seems counterintuitive and we barely get any results - but the truth is, it's all about the metabolism and speed of it. The damages are the consequences, but we can't stop (enough) all those damages"

Tinkering with metabolism as an approach is completely pointless beyond personal supplementing. The damages are the consequences of entropy and the damage the body does during normal metabolic operation as well as exeternal stressors. We havent even really got started trying to stop the damages yet we are still testing in mice so give us a chance will you! When we deploy a repair approach that addresses multiple hallmarks of aging, then and only then can you see if it will or will not work. Until that point its pure conjecture.

So just wait and see and enough with the negative nelly already :P

Posted by: Steve Hill at May 21st, 2017 5:50 PM

Michael, the study that quercetin shortens lifespan - was that in mice or man? Can you give us some more info that one? The only thing I'm finding is a 1982 0.1% quercetin supplement study done in mice, which seems like a terribly awful lot of quercetin if I'm reading that correctly.

Posted by: Slicer at May 21st, 2017 6:18 PM

Hes talking about the Spindler experiment:

https://www.ncbi.nlm.nih.gov/pubmed/23432089

However spindler used a tiny amount of quercetin on a daily basis instead of a larger dose on an infrequent basis. We already know that quercetin scales in a dose-dependent manner for anti-inflammatory action as well as a against cancer proliferation/growth. My issue with Spindler here is the dosage and frequency and I dont think we can draw any solid conclusions from a single albeit well designed study.

Posted by: Steve Hill at May 21st, 2017 7:13 PM

That said I am still leaning towards what Sinclair found about quercetin, that it inhibits CD38 as well as some other cytokines including the NF-kB complex. However I am not convinced it is a true senolytic and it really just masks the problem. It has a lot going for it in terms of anti-inflammatory action and its influence over SIRT1 but I think the claims it is a senolytic have been somewhat overstated.

Posted by: Steve Hill at May 21st, 2017 7:17 PM

I remember reading that Unity had documented something like 22 beneficial effects of senescent cell clearance, but they had only published 9. Have they since published all effects? I'm very curious as to what they were keeping secret....

Posted by: mborbely at May 21st, 2017 8:02 PM

@Michael, @Steve Hill Thanks for sharing your insides.

I'm wondering about what would be the noticeable difference one could recognize after a successful senescent cell clearance?

If I would post a body image of myself without my head, you might think I'm in my 30ties. However, if I would reveal my face, it becomes clear that I'm in my 60ties.

For me, it is evidence that my lifestyle and diet ( paleo diet ) as well as my level of exercise ( mostly resistance exercise 3 - 5 times a week for 90 - 120 minutes ) combined with CR, did a lot of good for me. And according to my annual blood test, I should be in excellent health conditions too.

That said, I want to get to the next level that allows me to reach my goal - living forever - ( I know, I know ..., Richard Branson once said: "If your dreams don't scare you, they are not big enough ).

That's why I'm on this forum and financially support the SENS Research Foundation, and I'm hungry for the first SENS-style rejuvenation therapies.

Posted by: bardu at May 21st, 2017 9:50 PM

@Slicer, @Steve: Ah, thank you Steve: while I read Spindler's Rejuvenation Research lifespan study on quercetin and other supplementes at the time, I had actually never connected the dots back to it from the original Mayo senolytic report.

I agree with Steve that, to properly test the anti-aging effect of a putatively senolytic compound (or indeed any SENS-style therapy targeting celluar and molecular aging damage), one would want periodic cycles of administration rather than chronic dosing. However, I can't agree that he used a low dose: they administered 62 mg/kg mouse/d, which is actually somewhat higher than the weekly gavage of 50 mg/kg mouse in the Mayo senolytic report.

Equally, Slicer: you were right that I was referring to the 1982 Jones & Hughes quercetin lifespan study. I suppose that whether this was an awful lot depends on your scale of reference: it's certainly quite a bit compared to normal dietary intake, but it's again only modestly higher than the Kirkland senolytic study: their mice weighed 22-36 g over the course of the study, which is on the light side for mice, but assuming that they ate as much food per kg as Spindler's mice, 0.1% of chow is "only" a bit under twice as much as in the Kirkland senolytic trial.

So we have one lifespan study at a more moderate dose close to what's in widely-available dietary supplements, showing no effect on lifespan, and another at half again that dose, again doubtless similar to what many supplement users take, showing that it shortens life - and, indeed, only begins killing mice early in "old age" (88 weeks - roughly similar to a 60-year-old human), suggesting that it's not simple toxicity, but an effect on age-related disease.

(And, I meant a mouse lifespan study: no one does human lifespan studies because they take too long and would be logistical nightmares, even if they're late-onset).

Posted by: Michael at May 21st, 2017 10:42 PM

@ bardu - how do we know if a senescent cell treatment is actually removing senescent cells? Cellage are developing a marker, which could probably be used on a skin biopsy before and after treatment. There is also the option of looking at DNA methylation pre and post treatment to see if methylation changes correltated with canological age have 'reversed' to any degree.

Posted by: Jim at May 21st, 2017 11:08 PM

We will need a combination of therapies to end aging, but I agree with George Church that we will end aging within ten years.

Posted by: Tj Green at May 22nd, 2017 3:15 AM

@Tj Green I did read the article in which George said that, but I'm still unclear on exactly why he thinks so. Why do you agree with him?

Posted by: Sadi Khan at May 22nd, 2017 2:31 PM

@Michael yes true about the dosage I was thinking of another study, possibly Miller for the small dose. But chronic dosing is indeed a bad choice.

Posted by: Steve Hill at May 22nd, 2017 2:56 PM

@Tj Green & Sadi Khan: I think that George Church used the verb "reverse" rather than "end". The first implies that by the late 2020s we will have some degree of age reversal (very likely), the second that we will be able to totally control aging (very unlikely).

Posted by: Barbara T. at May 22nd, 2017 5:43 PM

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