The metabolic roots of senescence: mechanisms and opportunities for intervention

Abstract

Cellular senescence entails a permanent proliferative arrest, coupled to multiple phenotypic changes. Among these changes is the release of numerous biologically active molecules collectively known as the senescence-associated secretory phenotype, or SASP. 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. Additionally, we consider how interventions that target either metabolism or senescent cells might influence each other and mitigate some of the pro-aging effects of cellular senescence. 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.

The Mitochondrial Antioxidant Sirtuin3 Cooperates with Lipid Metabolism to Safeguard Neurogenesis in Aging and Depression

“…In age-related diseases, cell senescence has been shown to be modulated by both redox and metabolic shifts [ 55 , 56 ]. Here, we also revealed that SIRT3-inhibited NSC senescence really depends on SIRT3’s role in mediating both LCAD activation and oxidative protection.…”

Microbiome and Human Aging: Probiotic and Prebiotic Potentials in Longevity, Skin Health and Cellular Senescence

“…Metabolic stress acts as both a driver and consequence of cellular senescence. Mitochondrial dysfunction such as a disrupted nicotinamide adenine dinucleotide (NAD + )/ nicotinamide adenine dinucleotide hydride (NADH) cytosolic ratio can result in adenosine triphosphate (ATP) depletion and ultimately cell cycle arrest [29]. Damage caused by mitochondrial ROS such as the release of chromatin fragments may also drive senescence and promote SASP factors.…”

“…Damage caused by mitochondrial ROS such as the release of chromatin fragments may also drive senescence and promote SASP factors. A disrupted NAD + metabolism can activate the nuclear factor kappa-light-chain-enhancer of the activated B cells (NF)-κB pathway which has a casual role in promoting senescence and the SASP [29,30]. Moreover, the SASP activates CD38 + macrophages which further depletes NAD + , as seen in senescence-induced dermal fibroblasts and aged mice models.…”

“…Moreover, a decrease in cytosolic NAD + /NADH can induce senescence within human diploid fibroblasts. Once senescent, cells are shown to alter the lipid metabolism, exhibiting high activity of the sphingomyelin-ceramide pathway in fibroblast and endothelial cells, further promoting inflammation [29,33]. Additionally, free polyunsaturated fatty acids (PUFAs) are increased in the membrane of senescent cells and may accumulate as triglycerides in lipid droplets or convert into oxylipins, thereby contributing to the inflammatory arm of the SASP [34].…”

“…Additionally, free polyunsaturated fatty acids (PUFAs) are increased in the membrane of senescent cells and may accumulate as triglycerides in lipid droplets or convert into oxylipins, thereby contributing to the inflammatory arm of the SASP [34]. Hyperglycemia can also promote senescence and subsequent metabolic dysfunction (e.g., decreased sirtuin expression, accumulation of cystolic NADH, activated mitochondrial dysfunction-associated senescence) [29].…”