Senescent Cells and Damage Accumulation in Aging

This open access review of cellular senescence in aging is perhaps noteworthy for being authored in part by Vadim Gladyshev, one of the more pessimistic researchers in our community. Simplified a little, his opinion is that aging and metabolism are too complex and poorly understood to hope for rapid progress towards rejuvenation and life extension in our lifetimes. He is not in agreement with the proposition that one can bypass the requirement for greater understanding of aging by targeting the root causes of aging - one of which is the accumulation of senescent cells - as I don't think he considers the SENS portfolio of causes of aging sufficiently proven. It is thus interesting to see him engage in detail with the topic of cellular senescence, particularly given the past few years of promising results in mice due to senolytic therapies capable of selectively destroying these cells.

Some animals are characterized by the so-called negligible senescence, such as a species within the genus of Cnidaria - Hydra, although it is known that their individual cells do age. This apparent nonaging phenotype can be achieved by replacing cells that accumulated damage over time with new cells generated from abundant stem cells that can give rise to any cell type in the body. However, this nonaging strategy is not applicable to the great majority of organisms with specialized, nonreplaceable cells and structures. When organisms are unable to replace cells at will or dilute damage, intracellular damage accumulates, exerting its deleterious effect on the host cell as well as other cells, impairing their function and ultimately contributing to age-related diseases and to aging itself.

The macroscopic age-associated changes in organisms are so obvious and severe that identifying their molecular bases would seem to be an easy task. Yet, all the research conducted so far has not led to the unambiguous identification of the causal factors orchestrating aging.

With recently published evidence, the role of cellular senescence in organismal aging has become increasingly clear. The phenomenon of cellular senescence has a special meaning in the context of damage accumulation in aging. Cells triggered to senesce by damaging insults exhibit higher basal levels of damaged macromolecules than healthy cells and also generate damage at a higher rate. This notion posits senescent cells as organismal carriers of damage. It is especially relevant for the irreparable forms of damage such as telomere-associated breaks and lipid-protein aggregates of lipofuscin.

Kinetics of senescent cell accumulation in response to lifespan-modulating interventions differs from the kinetics of irreparable and reparable types of damage. This is due to yet another layer of complexity in the regulation of senescent cell population in vivo that is mediated by the immune system. Subjected to a life-extending intervention, an organism can remove senescence-related damage, in contrast to other types of irreparable damage. A change from life-extending to life-shortening conditions does not, however, abolish the beneficial effects of the former. As shown for calorie restriction, animals on short-term calorie restriction maintain the status of low senescent cell abundance after the end of the treatment.

Accumulation of senescent cells is an integral part of the damage accumulation process. Senescent cells then emerge as causal to age-related diseases. This model explains the recently published evidence that elimination of senescent cells can alleviate multiple age-related diseases and increase health span but does not greatly affect the rate of aging/maximum lifespan. As senescent cells contain high levels of irreparable damage, we do not imply that a certain effect on the rate of aging is impossible. However, we argue that elimination of senescent cells is unlikely to be the intervention that would very significantly prolong human maximum lifespan.

Link: https://doi.org/10.1111/acel.12841

Comments

>... elimination of senescent cells can alleviate multiple age-related diseases and increase health span but does not greatly affect the rate of aging/maximum lifespan. ..., we do not imply that a certain effect on the rate of aging is impossible. However, we argue that elimination of senescent cells is unlikely to be the intervention that would very significantly prolong human maximum lifespan.

So or seems that the general expectation is to have an increased healthpsan and a slightly sliding down the aging process and, even probably, extending the Max human lifespan a bit.

Posted by: Cuberat at October 26th, 2018 8:34 AM

"Cells triggered to senesce by damaging insults exhibit higher basal levels of damaged macromolecules than healthy cells and also generate damage at a higher rate. This notion posits senescent cells as organismal carriers of damage. It is especially relevant for the irreparable forms of damage such as telomere-associated breaks and lipid-protein aggregates of lipofuscin."

Since he presents this as the main problem with senescent cells, instead of the SASP, it's not strange that he doesn't view senolytics as much useful.

Posted by: Antonio at October 26th, 2018 8:52 AM

The only important point is will there be relevant pharamcotherapeutic outcomes from senescent cell ablation - that's all that matters

This is really the core issue that stand alone senolytic strategies will need to keep their fingers crossed on

In the recent Samumed Phase 2b (not a senolytic, but hoping for the same type of outcomes), they fell short as it pertained to joint damage

https://endpts.com/mixed-data-doesnt-stop-this-biotech-unicorn-from-plotting-a-looming-phiii-showdown/

Cartilage regeneration is not a "given", and pain / function improvement is not enough to win in this market - Chondrogenesis is an extremely complex form of bio-morphologic regeneration in humans, and the hope that new, pristine cartilage will just miraculously start churning out is a bit of a leap of faith

To date, there has never been a "disease-modifying osteoarthritis drug" (DMOAD) success and pharma has been trying many things over the years

Samumed saw no DMOAD activity seen at 24 weeks - now they will try for 52 weeks

Will be interesting how this will compare to whatever happens with the Unity Biotechnology senolytic approach

Posted by: Ira S. Pastor at October 26th, 2018 10:44 AM

> Since he presents this as the main problem with senescent cells, instead of the SASP, it's not strange that he doesn't view senolytics as much useful.

In terms of actually extending the maximum human lifespan, I think that's probably correct; the SASP is likely a major factor in some age related diseases, but senescent cells are not the sole manifestation of age related damage; you also have things like ECM crosslinking, the formation of problematic protein aggregates, damage and mutation in nuclear and mitochondrial DNA, and declining immune functionality associated with persistent viral infection.

All of these insults will continue to accumulate even without the burden of chronically senescent cells, and while some of them will likely accumulate at a slower rate without SASP signaling, the lack of an abnormally large senescent cell burden in supercentenarians suggests it's not a limiting factor on maximum human lifespan.

The potential impact on "healthspan" and median lifespan is something else entirely however, and that has huge implications for the long term prospects of people alive today.

Unlike some of the more shall we say "idealistic" people in the life extension community, I'm highly skeptical that there'll be a "cure" for aging before the mid 22nd century, and am very skeptical of any tipping point of "Longevity Escape Velocity" occurring before the end of the 21st century. Treatments that increase healthspan (and consequently median lifespan) without actually extending maximum lifespan would have a huge impact on how many people alive today would live to see LEV and a genuine cure for aging.

Posted by: Dylan at October 26th, 2018 11:09 AM

@Dylan and your predictions based on what?
At the rate discoveries are being made you can't rule out anything!

Posted by: Moses at October 26th, 2018 12:12 PM

@Moses , his "predictions" based on nothing. When you have no idea what to say, just say -- "aging and metabolism are too complex and poorly understood to hope for rapid progress towards rejuvenation and life extension in our lifetimes." or "I'm highly skeptical that there'll be a "cure" for aging before the mid 22nd century". People will think that you are very clever and wise guy! ;-)

Posted by: Ariel at October 26th, 2018 3:58 PM

As for Gladyshev, he cannot be pessimistic or optimistic in regenerative medicine, just because he is not bioengineer! He does not work on any rejuvenation therapy in any sense! How may he make any predictions? He just wish to have more money for his lab, and if he says that we can make rejuvenation therapy without fully understanding of ageing, yeah, guys -- he will receive less money! If you wish to fix a car you will go to mechanic, not basic researcher. What does real bioengineer say on regenerative medicine ?

"I think one of the most exciting areas is 3D bio-printers that enable people to print patches for transplantation. We can already grow tissues from single cells and bio-materials, and with certain organs like cartilage and bone this is already in the clinic, but in the future people will print whole organs for replacement. I believe we will see this with organs like livers, kidneys and maybe hearts within the next 10 years. A lot of the technology for that is already here we just need to perfect the process, but we will one day be able to print organs directly in a hospital for transplantation."

Dr Tal Dvir, Israeli bioengineer

https://tmrwedition.com/2018/02/25/interview-with-tissue-engineering-and-regenerative-medicine-expert-prof-tal-dvir

Posted by: Ariel at October 26th, 2018 4:13 PM

i read the LEAF interview with vadim a few months ago and the only thing i agree with him on is when he says that we dont fully know what aging is, which is true. but as for saying this is nowhere near fruition, i think thats very ignorant seeing as senolytics and other things are entering human testing. and i know that no timeframe is guaranteed, but to say "LEV wont happen this century" is short sighted given the progress being made so far. on another note, i just ordered my first bottle of fisetin and i plan to self test given that it now has some very promisng data on senescent cells in mice.

Posted by: scott emptage at October 26th, 2018 5:55 PM

@Dylan
@Moses
Interestingly enough a "cure" for aging is easier to prove that it works than LEV and max life-span increases. We might not make it till LEV but we have a real, as non-imaginary, chance.

Posted by: cuberat at October 26th, 2018 5:59 PM

@cuberat remember that LEV is about buying time. If we get 20 extra years then that's 20 years for the therapies to improve

Posted by: Scott emptage at October 27th, 2018 4:02 AM

I think you should all listen to this video which features Aubrey and Vadim. Vadim actually states he thinks we can get 20-30% human lifespan now with what we know but more sophisticated approaches will take more time.

https://youtu.be/Mje_To9DB3c?t=96

Posted by: Steve Hill at October 27th, 2018 8:06 AM

If he think in this way, why he does not work on these new more powerful approach? Why does not he work on lipofuscin breaker therapy for example?

Posted by: Ariel at October 27th, 2018 11:47 AM

And what do you "think" he works on then Ariel?

Posted by: Steve Hill at October 27th, 2018 12:13 PM

Rejuvenation is basically impossible. Whether reprogramming the code, removing senescent cells.

Posted by: Jan Omasta at October 28th, 2018 11:15 AM

Since 1956, the production and eating of aging foods has increased tenfold. Whether reprogramming the code, removing senescent cells, everything is just a way to make people aged at an increased rate. If I can advise, simply skipping aging foods will extend your life to more than just the above-mentioned benefits.

Posted by: Jan Omasta at October 28th, 2018 11:16 AM

@jan omasta and your claim is based on what exactly ?

Posted by: Scott emptage at October 28th, 2018 2:26 PM

@Ariel: We have yet to actually fully address any major aspect of mammalian aging in animal models. Once we get to that point, there's going to be at least a 20+ year gap between the basic research and implementation in the clinic.

At this time, beyond the level of individual cells, we know enough to do some minor tweaks here or there to the aging process that will hopefully translate in humans push morbidity a bit further into the future. That's the current state of our cutting edge research.

Given sufficient time and research, I'm fairly confident that understanding will eventually be sufficient to completely address all aspects of aging, but any speculation about how long it will take whether its your's, mine, or Aubrey De Grey's is at best supposition.

Posted by: Dylan at October 29th, 2018 12:43 PM

"We have yet to actually fully address any major aspect of mammalian aging in animal models."

No! Moreover for some type like glucosepan there is no any animal model! Many rejuvenation therapies are already in II or III phase KT in humans. And some of them like immunotherapy -- which took 5 years from paper work to clinic, -- cell or gene therapy are approved in USA and Europe. What you refer to is the whole rejuvenation panel. Hovewer you are finally right -- people must not speculate -- people have to work on such a panel.

Posted by: Ariel at October 30th, 2018 5:44 PM

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