Claiming Cellular Senescence for the Hyperfunction Theory of Aging

This mildly infuriating commentary well illustrates just why it is that theories of aging are so very diverse. Even a mechanism as well understood as cellular senescence can be fairly convincingly argued into one camp or another. For those who see aging as damage accumulation, lingering senescent cells are clearly a form of damage, a byproduct of normal metabolism that grows slowly over time and produces tissue dysfunction in proportion to the number of such cells. For those who consider the hyperfunction theory of aging, in which aging is the result of developmental programs failing to shut down in adult life, it is fairly easy to argue that the prevalence of cellular senescence in old people is an embryonic development mechanism or wound healing mechanism run wild. Cellular senescence does indeed play important roles in those circumstances.

Senolytics are drugs that extend lifespan and delay some age-related diseases by killing senescent cells. I want to draw your attention to the paradoxes associated with senolytics, which argue against the dogma that says aging is a functional decline caused by molecular damage. This dogma predicts that senolytics should accelerate aging. If aging is caused by loss of function, then killing senescent cells would be expected to accelerate aging, given that dead cells have no functionality at all. Instead, however, senolytics slow aging, which highlights a contradiction in the prevailing dogma.

The theory of hyperfunctional aging addresses this paradox. Killing senescent cells is beneficial because senescent cells are hyperfunctional. The hypersecretory phenotype or Senescence-Associated Secretory Phenotype (SASP) is the best-known example of universal hyperfunction. Most such hyperfunctions are tissue-specific. For example, senescent beta cells overproduce insulin and thus activate mTOR in hepatocytes, adipocytes, and other cells, causing their hyperfunction, which in turn leads to metabolic syndrome and is also a risk factor for cancer. SASP, hyperinsulinemia and obesity, hypertension, hyperlipidemia and hyperglycemia are all examples of absolute hyperfunction (an increase in functionality).

In comparison, relative hyperfunction is an insufficient decrease of unneeded function. For example, protein synthesis decreases with aging, but that decrease is not sufficient. In analogy, a car moving on the highway at 65 mph is not "hyperfunctional." But if the car were to exit the highway and enter a residential driveway at only 60 mph it would be "hyperfunctional," and stopping that car would likely prevent damage to other objects. Similarly, killing hyperfunctional cells can prevent organismal damage. Senolytics eliminate hyperfunctional cells, which otherwise damage organs.



> If aging is caused by loss of function, then killing senescent cells
> would be expected to accelerate aging, given that dead cells have no
> functionality at all

This line makes no sense at all. It's equivocating on 'functionality' vs. 'having any behavior' and it is premised on the straw man that the position of those he criticises is "aging is caused by loss of function" for an absurdly simplistic value of 'function'. Of course clearing misbehaving cells is not 'loss of function' and thus not something that accelerates aging.

This seems intended to pick a bone with 'aging as damage' proponents. A good faith exposition of this view would not need the first paragraph at all. The presented view isn't even at odds with the 'aging as damage' view: one cells functionality is the others damage-causing-hyperfunctionality.

Posted by: Ivo at January 8th, 2019 11:06 AM

I fail to see what's the added value of all those discussions. Aging is a complicated process, and having damage, hyper-function, or programmed aging is too simplistic. It certainly has elements of all of the above but they are not nearly close of encompassing the whole story.

I agree, that paragraph is mildly incoherent :)

Posted by: cuberat at January 8th, 2019 11:50 AM

"It certainly has elements of all of the above"

I don't see the certainty anywhere.

Posted by: Antonio at January 8th, 2019 2:48 PM

do you object against one of the topics or all of them wholesale ? Extensive damage does accelerate aging, some hyperfunction does too. And some tissues and cells have programmed death... Why it has to make the whole body age is another story...

Posted by: cuberat at January 8th, 2019 7:13 PM

I simply say that I don't see anything pointing to your said certainty that the 3 are elements of aging.

Posted by: Antonio at January 9th, 2019 12:01 AM

That first paragraph would only make sense if all cells were essential and, if even minimally functional, their removal would be detrimental. One can simply point at fat cells in this respect - their removal does not reduce function. The presence of malfunctioning cells causing decline and their removal doing the opposite is precisely what cancer is all about too. I rather suspect the writer's use of the word 'dogma' indicates that he or she is the one with the problem.

Posted by: Neal Asher at January 9th, 2019 2:02 AM

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