Does Immune System Decline Determine the Contribution of Senescent Cells to Aging?

The self-experimentation rumor mill has it that presently available senolytic pharmaceuticals, repurposed chemotherapeutics that can selectively destroy some fraction of senescent cells, can show results for inflammatory conditions in elderly individuals. Equally, they don't appear to produce evident benefits in basically healthy 40-somethings. While senescent cells are indeed a source of chronic inflammation, one should never act on whispers: wait until data from the present or near future clinical studies is published and ratified. We can certainly debate and hypothesize, however, where anecdotes overlap with existing animal data and supporting evidence from other lines of research.

My thinking runs much as follows: the immune system is responsible for destroying cancerous cells and those senescent cells that fail to self-destruct. Immune cells are very efficient when it comes to this task, and thus the risk posed by both of these classes of harmful cell remains low for much of life. This is the case until immune function has declined significantly with age; one can look at the models that correlate cancer risk with atrophy of the thymus, and therefore reduction in T cell generation, for example. It fits well. Peak cancer risk lies between 60 and 80, which is also, more or less, where one starts to see incidence of inflammatory age-related conditions linked to cellular senescence increase greatly.

No-one has yet run the studies needed to build a decent picture of senescent cell burden by age. I will go out on a limb and wager that when this is accomplished, the numbers will closely mirror both cancer risk and loss of immune function. Some researchers have been thinking along these lines for a while now, and I noticed this commentary in the middle of a recent interview conducted by the Life Extension Advocacy Foundation volunteers:

Research suggests that "inflammaging" plays a key role in aging; many publications also suggest that of the various sources of this chronic age-related inflammation, senescent cell accumulation and the senescence-associated secretory phenotype it produces is the primary culprit. What might we expect to see if therapies to remove these problem cells are used in people?

I have a different view from the majority. I was one of the big fans of senescent cells, and I was 100% inspired by the idea of finding them, eradicating them, and using that for rejuvenation. However, after we spent several years very focused on an extensive study of senescent cells in vivo, we realized that for a major portion of the mouse lifespan, we simply cannot find these cells. This is not because they don't exist; I think they appear pretty frequently during our lives and mice's lives, but they are being very efficiently eradicated by the immune system.

Whether the changes in inflammation in vivo with age are due to the activity of senescent cells is a big question, because when we tried to find these cells in, for example, an irradiated organism, most of the cells that people thought were senescent before the existence of conventional biomarkers appeared to be just parts of the immune system, which is malfunctioning in aging and created the appearance of senescent cells. Macrophages frequently become positive for biomarkers of senescent cells, and people using these biomarkers without looking carefully call them senescent. You might say that does not matter because the whole concept did not change that much; who cares what you name these cells? If certain cells with certain properties accumulate with life and if they secrete something bad, the concept is still intact, and I agree with that.

However, knowing the nature of these cells, we can choose the right weapon against them, and as long as we try to kill the cells that we can make senescent in culture and think we are killing the same cells in vivo, I think that we are on the wrong path. This is my first problem; my second problem is that the accumulation of senescent cells means a malfunction of the immune system because the normal immune system gets rid of them very efficiently. If you kill a cell that cannot be removed by the immune system, you are not getting rid of this potential garbage; you turn it into a different type of garbage. Because to eradicate a senescent cell, something needs to find it and eat it, swallow it, such as a macrophage.

If this function is not working very well and you simply help the immune system by killing these cells, they still remain in the same place where they were; they're just dead. Maybe this is good or not; maybe this will indeed help another branch of the immune system to clean up. I think, in general, that this is not obvious; first, it's not obvious to me that senescent cells are unique in creating the "smell" of garbage that leads to inflammation or if it's only one of many types of cells that become damaged and accumulate with age. I'm not sure that killing them physically really helps to improve the situation, because you are creating a wave of remains that has to be taken care of, too.

I personally chose an approach to invest in the immune system and repair its function so that it can do its job better, instead of us thinking that we can substitute it. So far, in medicine, substitution of lost function has only worked well in orthopedics but not in other areas. Therefore, I think that we need to either invest in a mechanism that blocks the appearance of senescent cells or invest into the mechanism of natural eradication to make the immune system work better. For example, if the part of the immune system that is responsible for clearing senescent cells gets exhausted, you can always try to redirect adaptive immunity against them by vaccination; I would see that as a more appealing thing.



Probably the right answer is 'all of the above'.
However one can stop an expriment to get this hypothesis. Culture/produce various types of senescent cells and inject/transplant them to young mice. Then try young immunocompromised mice. Then in old mice. Create a culture with some kill antigen or chemical kill switch and inject them in old mice. Compare immune cleanup vs senolitics.

Posted by: Cuberat at April 27th, 2018 7:12 AM

Interesting alternative approach. But I accustomed to Russian researchers making extraordinary claims that never crystallize.

Posted by: JohnD at April 28th, 2018 10:36 AM
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