Cellular Senescence Promotes Metabolic Dysfunction, in Turn Promoting Cellular Senescence

Aging is built on feedback loops, interactions between damage and dysfunction in which both sides accelerate the other. This is a feature of all complex systems, not just biological ones. The existence of feedback loops in which damage accumulation causes dysfunction that accelerates damage accumulation is the fundamental reason as to why aging is an accelerating process. It starts slowly, and moves ever more rapidly with time. Aging in one's 30s is a very different beast to aging in one's 70s, and the downhill slide is much faster in later life.

The way to break this cycle is to repair the damage. This is true whether we are talking about a manufactured machine or a living being: repair is the only viable road to rejuvenation. All other options perform poorly. If you want to engage in a costly struggle, try to keep a damaged machine running without repairing the causes of its dysfunction. That is the story of most present day medicine for age-related disease, unfortunately. It is compensatory in nature and fails to address the causes of disease, the processes of aging itself.

Yet times are changing, and there is a far greater acceptance now for scientific and medical development initiatives that seek to address the damage that causes aging, such as the accumulation of senescent cells that actively disrupt tissue function and promote chronic inflammation. To the degree that these initiatives succeed, we will all have the opportunity to live significantly longer, better lives, spending a greater number of years in vigorous, youthful health.

The metabolic roots of senescence: mechanisms and opportunities for intervention

The senescence response can be beneficial or deleterious, depending on the physiological context. This dualism is consistent with the evolutionary theory of antagonistic pleiotropy. Antagonistic pleiotropy postulates that traits selected to ensure the survival of young organisms in natural environments, in which life spans are short, can become deleterious in modern protected environments, in which life spans are significantly longer. Thus, aging is likely a consequence of the declining force of natural selection with age.

With regard to the beneficial effects of cellular senescence, the senescence growth arrest protects young organisms from developing cancer. In addition, senescence-associated secretory phenotype (SASP) factors can optimize the morphogenesis of certain structures in the embryo, and initiate parturition in the placenta. Finally, senescent cells occur transiently at sites of tissue damage where they contribute to wound healing, tissue repair and regeneration, most likely through specific SASP factors.

In contrast, senescent cells increase with age in most mammalian tissues, where they appear to persist. Whether this increase is due to increased production or decreased clearance, for example by the immune system, is unclear. More importantly, experiments using human cells and tissues, transgenic mouse models, and pharmacological interventions in cells and mice strongly implicate senescent cells in a large number of age-related pathologies, ranging from neurodegeneration to, ironically, age-related cancer. Most of the detrimental effects of senescent cells can be attributed to the SASP, which is rich in pro-inflammatory molecules.

A growing body of literature indicates that both senescence and the SASP are sensitive to cellular and organismal metabolic states, which in turn can drive phenotypes associated with metabolic dysfunction. Here, we review the current literature linking senescence and metabolism, with an eye toward findings at the cellular level, including both metabolic inducers of senescence and alterations in cellular metabolism associated with senescence.

There are three types of interventions that target senescent cells and their degenerative pathologies. First, we can slow the formation of senescent cells, as observed during dietary restriction and similar interventions. Second, we can allow senescent cells to accumulate, but prevent them from causing harm, as observed during metformin-mediated SASP suppression or after CD38 inhibition. Finally, we can use senolysis to remove senescent cells. Unlike the first two interventions, senolysis can be used intermittently - allowing for a 'hit and run' approach that might be easier to implement in humans - whereas dietary and suppressive drug regimens require regular adherence to maintain benefits. We conclude that the most effective interventions will likely break a degenerative feedback cycle by which cellular senescence promotes metabolic diseases, which in turn promote senescence.


This is a robust article which process that senolytics are close to mainstream acceptance

Posted by: Cuberat at October 27th, 2021 9:31 PM

Yeah, well...

Ethics declarations
Competing interests
J.C. is a scientific founder of Unity Biotechnology, which develops senolytic therapies. C.D.W. and J.C. hold patents for induction and detection of senolysis using metabolic targets.

Some of the cited papers are flagged as problematic on pubpeer and/or cite such papers. Some of the cited papers have competing interests.

Feels a bit like Big Tobacco telling me that smoking is healthy and Google telling me my private data is safe with them.

Posted by: Jones at October 28th, 2021 2:59 AM

Some highlights:


186. Martin-Montalvo, A. et al. Metformin improves healthspan and lifespan in mice. Nat. Commun. 4, 2192 (2013).


141. Han, L. et al. Senescent stromal cells promote cancer resistance through SIRT1 loss-potentiated overproduction of small extracellular vesicles. Cancer Res. 80, 3383-3398 (2020).


129. Catalano, A., Rodilossi, S., Caprari, P., Coppola, V. & Procopio, A. 5-Lipoxygenase regulates senescence-like growth arrest by promoting ROS-dependent p53 activation. EMBO J. 24, 170-179 (2005).


90. Xu, C. et al. SIRT1 is downregulated by autophagy in senescence and ageing. Nat. Cell Biol. 22, 1170-1179 (2020).


83. Zhang, H. et al. NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352, 1436-1443 (2016).


81. Gomes, A. P. et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624-1638 (2013).


75. Hachmo, Y. et al. Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells: a prospective trial. Aging 12, 22445-22456 (2020).


72. Parikh, P. et al. Hyperoxia-induced Cellular Senescence in Fetal Airway Smooth Muscle Cells. Am. J. Respir. Cell Mol. Biol. 61, 51-60 (2019).


65. Leontieva, O. V. et al. Hypoxia suppresses conversion from proliferative arrest to cellular senescence. Proc. Natl Acad. Sci. USA 109, 13314-13318 (2012).


44. Miwa, S. et al. Low abundance of the matrix arm of complex I in mitochondria predicts longevity in mice. Nat. Commun. 5, 3837 (2014).


Posted by: Jones at October 28th, 2021 3:49 AM

Sorry but senolytics have a very long way to go

Unity is flailing, down $900 million in market cap and down to its last 12 months of cash, all while spinning its wheels in Phase 1 with a ophthalmic indication that has so much competition, it will most likely never see the light of day

Campisi is another example of a great researcher who should have stayed in the lab, optimized things there first, instead of dumping this dog on investors...

Posted by: Greg Kellman at October 28th, 2021 8:56 AM
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