Cellular Senescence in the Context of Aging, Metabolism, and Epigenetics

The accumulation of senescent cells is clearly an important contribution to the progression of degenerative aging. This was firmly established to be the case not by the careful examination of mechanisms, because it is very challenging to assign relative significance to the many different processes involved in aging, but rather by the selective removal of senescent cells in mice. The best way, and possibly the only practical way at the present time, to establish the relevance of a mechanism to aging and disease is to very selectively block just that mechanism and then observe the results.

In the case of senescent cell removal, the outcome is a rapid rejuvenation of many aspects of aging. Senescent cells clearly actively maintain a disrupted state of metabolism and tissue function via the signals that they secrete. Remove that signaling, and tissues begin to return to a more youthful function. This can produce quite profound reversals. In mice, for example, ventricular hypertrophy, the distortion and weakening of heart muscle, is reversed by treatment with therapies capable of removing senescent cells. That is a surprising result, and one that might make us all more optimistic as to the degree to which rejuvenation therapies will be able to help people in later life.

A great deal of effort is presently going into understanding the biochemistry of cellular senescence, particularly regarding how it arises, meaning the various contributing factors that tip the balance of cell fate towards senescence. Many researchers are interested in preventing senescence, which may or may not prove to be a better way forward than periodic selective destruction of senescent cells. At least some cells become senescent for a good reason, in that they are damaged in ways that can raise the risk of cancer. Further, approaches based on minimizing the onset of senescence in cell populations have yet to produce animal studies anywhere near as impressive as the rejuvenation that results from clearance of senescent cells. But time will tell.

Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention

Accumulating studies have proven the relationship between senescent cells and organismal ageing. Meanwhile, the concept of eliminating senescent cells to counteract ageing-related conditions has emerged and succeeded in rodent models. Researchers have found a large number of p16INK4a-positive senescent cells in various tissues that cause a range of ageing symptoms, including sarcopenia, cataracts, and lipodystrophy. Accordingly, targeted clearance of p16INK4a senescent cells alleviates the adverse symptoms and successfully extend the health span in many diseased models.

The field began to look for traces of senescent cells in common ageing diseases in humans, and successfully established a causal relationship between pathogenesis of ageing-related diseases and cell senescence. Take atherosclerosis as an example, we have known that plaques composed of fat and protein gradually accumulate on the inner arterial wall, which is prone to cause coronary atherosclerotic disease, stroke, or other ischemic severe diseases. Next, senescence-associated macrophages were recruited to the arterial wall, where the plaque initially formed. As time elapsed, other senescent cell types appeared near these sites. Compared with other control cells, these senescent cells expressed abundant secretory factors and metabolites that promoted the pathogenesis of atherosclerosis, concurrent with significant alterations in epigenetic imprints. Using a variety of approaches to remove these senescent cells attenuated the lesions, and thus alleviating the progress of atherosclerosis.

Consequently, focusing on the epigenetic and immunometabolic regulation of cell senescence may shed light on managing ageing-related diseases and therapeutic interventions. In this review, we highlight the recent advances in the understanding of the inflammatory, epigenetic, and metabolic basis of cell senescence, a comprehensive overview of relevant molecules and signaling pathways associated with cell senescence and organismal ageing are discussed. Finally, novel techniques and strategies intervening in the ageing process are briefly summarized.

Comments

A very nice paper, well worth reading. Thanks.

Posted by: Jones at July 8th, 2021 1:58 AM

https://medicalxpress.com/news/2021-07-immune-response.html

We discovered that Tpex cells were exposed to increased amounts of an immunosuppressive molecule, TGF-β early on in an infection. This molecule essentially acts as a brake, reducing the activity of mTOR and thereby dampening the immune response."

Excitingly, the researchers were able to use this discovery to improve the immune response to severe viral infection.

"When we treated mice with an mTOR inhibitor early, this resulted in a better immune response later during the infection," Dr. Gabriel said.

I wonder if this is (one of) the mechanism(s) by which Rapamycin works?

Posted by: Robert Read at July 8th, 2021 3:36 AM

@Bob Read
mTOR is over activated in aged tissue/cells (probably due to mitochondrial stress) and prevents proper tissue/cellular maintenance due to inhibition of autophagy and promotion of 'endless' growth. Rapamycin somewhat remedies mTORs over activation and its disruption of tissue/cell homeostasis. Having a 'better' working immune system is just one of the downstream effects.

Posted by: Jones at July 8th, 2021 4:02 AM
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