Senolytics have been in the news a great deal ever since van Deursen and his team conducted a landmark 2011 study showing that removing senescent cells could delay age-related ill health in mice . Since then, interest in what was once a niche topic has continued to grow at an ever-increasing pace. Now, there are many researchers engaged in exploring senescent cells and their role in aging and disease.
Lately, there has been enthusiastic interest in developing therapies to remove these problematic senescent cells, but are there potentially better ways to deal with senescent cells beyond periodically purging them with senolytic drugs and therapies?
The immune system
We recently interviewed Dr. Andrei Gudkov and discussed with him the potential of senolytic therapies. He holds the somewhat different view that nature has already provided us with the solution to senescent cells, the one which works perfectly well during the majority of our lives: the immune system.
Gudkov and his team have studied senescent cells and they have found that for a major portion of the lifespan of mice, these cells simply cannot be found. Now, this is not because they do not exist but simply that they do not exist for very long before being detected and destroyed by the immune system.
For the majority of our lives, the immune system is highly efficient and rapidly removes these problematic cells. For Gudkov, the accumulation of senescent cells means a malfunction of the immune system because the normal immune system gets rid of them very efficiently.
It is clear from the literature that the secreted pro-inflammatory signals secreted by senescent cells are harmful, but could the solution in the long term be to rejuvenate the immune system so that it works as it did in youth?
One possible therapeutic target are the macrophages. These garbage-gobbling immune cells clear away senescent cells while the immune system works, but with age, they become increasingly dysfunctional and begin to favor behavior that supports inflammation. Gudkov and his team have described these dysfunctional macrophages as senescence-associated macrophages.
A number of studies have manipulated the behavior of macrophages to make them work better, and this is one potential approach that we might use to get the immune system back on track [2-3].
Macrophages have a kind of behavioral pattern known as polarization, which places them into two broad categories, M1 and M2. This is a simplification, and the details are only now being explored.
M1-type macrophages aggressively destroy problematic cells while sending signals that promote inflammation and recruit other types of immune cells to the site. However, when there are too many M1-type macrophages present, that inflammation becomes excessive, and this hinders the repair and regeneration of tissues.
M2-type macrophages can be considered “healing” cells, as they facilitate the suppression of inflammation and promote tissue regeneration.
Manipulating the ratios of M1 and M2 macrophages to those typically observed in youth may be one possible route to improving the aging immune system. Gudkov and his team published a paper showing that macrophages and their behavior are reversible and inducible .
A second option could potentially be to develop senolytic therapies that specifically seek out dysfunctional macrophages and target them for destruction. The problem with this idea is that macrophages are some of the most robust cells in our body; because they process toxins and garbage, they would be highly resistant to being destroyed. It may also create an additional problem: destroying them could add to the cellular garbage that an already struggling immune system is unable to cope with.
Of the possible solutions here, reprogramming macrophage behavior seems to be the preferable approach. Modulating the behavior of immune cells is a very new area of research, but it holds a great deal of promise for managing immune cell dysfunction.
The current focus on removing senescent cells with senolytic therapies is certainly a very welcome development, although this approach may only be a short-term solution compared to rejuvenating the immune system and restoring it to a more youthful level of function.
There are two overall schools of thought in this field: one is that we should periodically repair the damage that aging does, and the other is that we should engineer resilience into our cells and organs so that they better resist the damage of aging. Some people argue as if these two positions are absolutes, however, why don’t we do both?
If we can develop the tools to periodically repair age-related damage, then surely it makes sense to also develop ways to make our biology more robust and resistant to that damage in the first place. The less often we need to repair ourselves, the better, so the two approaches go hand in hand.
We are excited about the potential for senolytic therapies in the near future, but we are also open to the possibility of engineering resilience in the longer term so that many decades down the road, senolytic therapies may be infrequent or even unnecessary, as the immune system would work properly.
 Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., … & van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236
 Subramaniam, S. R., & Federoff, H. J. (2017). Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson’s Disease. Frontiers in Aging Neuroscience, 9, 176.
 Karishma Rahman, Yuliya Vengrenyuk, Stephen A. Ramsey, Noemi Rotllan Vila, Natasha M. Girgis, Jianhua Liu, Viktoria Gusarova, Jesper Gromada, Ada Weinstock, Kathryn J. Moore, P’ng Loke, and Edward A. Fisher (2017). Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression. J Clin Invest. doi:10.1172/JCI75005.
 Hall, B. M., Balan, V., Gleiberman, A. S., Strom, E., Krasnov, P., Virtuoso, L. P., … & Leonova, K. I. (2017). p16 (Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging (Albany NY), 9(8), 1867.
Akshay Atomic Bliss
July 2, 2018
Great article Steve. I am glad I followed you on LinkedIn. The Lab I am associated with also believes that just clearing senescent cells can be dangerous. As some senescent cells are needed for wound healing and as raw material for biogenesis of new cells. I agree with Gudkov lab we have a lot of similar thinking. I too realized that macrophage dysfunction (mainly the ratio of m2 to m1 goes askew as we age) is at the core of almost ALL age related diseases. In fact my colleague and me are considering writing a review article on how macrophage dysfunction is a precursor to everything that goes wrong with aging. Our Lab is going after another path to tackle senescent cells. Augmenting Nature’s own technology autophagy which involves the above but also involves other tools. Kudos to Gudkov. Wish them great success. My only suggestion will be to add clearance of other waste products that accumulate if he wants to fully resolve the macrophage dysfunction.
July 2, 2018
Thank you very much. I believe that inflammaging plays a key role in the immune system becoming dysfunctional and that the origin point for that initial inflammation may be the gut and changes to the gut microbiome which then sets of inflammation and a constantly activated immune system. We already know thanks to studies that macrophage polarization is influenced by inflammation so management of inflammation should allow us to control the M1 to M2 ratio.
So I think a big part of restoring immune function is going to be managing “inflammaging” Ironically a source of inflammaging is senescent cells but the data I am seeing supports that the origin point could be changes to the microbiome, a drop in production of SCFAs and the resulting loss of gut membrane integrity sending microbial products into the deeper body and triggering that initial spark of chronic inflammation.
July 11, 2021
Excellent article Steve. (Btw, I found this article following a link you put in comment on a FA article.) I agree, if a rejuvenated immune system clears out the senescent cells, this is a better long-term approach. Anything that gets our bodies to efficiently heal themselves is preferable. I also agree with your point on the FA article that I am hopeful the Conboy’s approach to resetting the blood “milieu” may partly achieve this goal. I was extremely impressed by the success at clearing senescent cells in their NBE experiment. It did better at clearing the senescent cells than the senolytic Navitoclax. Perhaps this is because of the rejuvenation of the immune system caused by NBE. In any case, these are some of the reasons I favor a TPE experiment over a senolytic experiment, although both would be terrific.
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