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Review
. 2021 Oct;3(10):1290-1301.
doi: 10.1038/s42255-021-00483-8. Epub 2021 Oct 18.

The metabolic roots of senescence: mechanisms and opportunities for intervention

Christopher D Wiley  1   2 , Judith Campisi  3   4
Affiliations
Review

The metabolic roots of senescence: mechanisms and opportunities for intervention

Christopher D Wiley et al. Nat Metab. 2021 Oct.

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.

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Conflict of interest statement

Conflict of interest

Dr. Campisi is a scientific founder of Unity Biotechnology, which develops senolytic therapies. Drs. Wiley and Campisi hold patents for induction and detection of senolysis using metabolic targets.

Figures

Figure 1.
Figure 1.. Relationships between metabolism and cellular senescence.
Left: Metabolic drivers of senescence. Mitochondrial dysfunction can drive senescence through disruption of cytosolic NAD+/NADH ratios, production of reactive oxygen species, and potentially other mechanisms. Accumulation of excess metals (especially transition metals) also promotes senescence. Loss of NAD+ results in senescence through loss of sirtuin or PARP activities and changes in cellular redox states. Hyperglycemia can drive senescence, though mechanistic detail is still needed. Disrupted autophagy can drive senescence in some contexts, but also prevent it in others. Non-physiological oxygen levels influence the development of senescent cells, with higher oxygen generally favoring senescence. Right: Senescent cells as drivers of metabolic disease. Senescent cells and/or the SASP can drive both formation of atherosclerotic plaques as well as plaque instability. In the liver, senescent cells can promote steatosis. The SASP also activates macrophages, which elevate CD38 and lower tissue NAD+ levels. In the pancreas, senescent beta cells promote hyperinsulinemia, but as beta cells are attacked by the immune system, this can become hypoinsulinemia. In peripheral tissues (e.g., fat) senescent cells can promote insulin resistance – so senescent cells can drive diabetes and metabolic disease in multiple ways. Finally, senescent cells promote sarcopenia in muscle tissue, which can influence basal metabolism, activity levels, and frailty.
Figure 2.
Figure 2.. NAD Metabolism and Cellular Senescence.
NAD+ levels and NAD+/NADH ratios are controlled by multiple pathways during senescence. The NAD+/NADH ratio is maintained by conversion of pyruvate to lactate in the cytosol, or by transfer of reducing equivalent of NADH to the mitochondrion by the malate-aspartate shuttle. NADH is then oxidized back to NAD+ in the mitochondrion by the activity of Complex I of the electron transport chain (ETC). Disruption of any of these processes leads to increased cytosolic NADH, AMPK activation, and senescence. NAD+ acts through PARPs and sirtuins to prevent genotoxic stress and p53 activation, which promotes senescence, but antagonizes the SASP. Once released by senescent cells, SASP factors can bind their cognate receptors on macrophages, which then elevate CD38. CD38 then lowers tissue levels of NAD+ in the surrounding tissue as part of cyclic ADP ribose (cADPR) synthesis.
Figure 3.
Figure 3.. Altered metabolic states of senescent cells.
Senescent cells have increased free cytosolic polyunsaturated fatty acids (PUFAs), which in turn can be converted into oxylipins as part of a lipid-based SASP. Fatty acids also accumulate in lipid droplets during senescence. Sterols preferentially accumulate in the ER of some senescent cells in a p53-dependent manner, inhibiting sterol-response element binding protein 2 (SREBP2) activation and lowering sterol synthesis in the cell as a whole. Senescent cells often have increased mitochondrial mass or mtDNA, but this is coupled to altered membrane potential and ROS production. Lysosomes of senescent cells can become permeable, acidifying the cytosol and disrupting some forms of autophagy. This can lead to accumulation of transition metals inside senescent cells. Finally, senescent cells can have lower dNTP levels due to loss of ribonucleotide reductase 2. *Note that senescence is a complex and varied phenomenon, and it is likely that individual metabolic alterations may be present in some, but not all, forms of senescence.
Figure 4.
Figure 4.. Lipid metabolism in senescent cells.
Activation of phospholipase A2 (PLA2) frees polyunsaturated fatty acids (PUFAs) from the plasma membrane, which then accumulate in the form of triglycerides in lipid droplets but are also used as substrates for oxylipin synthases such as arachidonate 5-lipoxygenase (ALOX5) and cyclooxygenase 2 (COX-2), resulting in release of an oxylipin SASP. Prostaglandin transporter (PGT) imports prostaglandins into the cytosol, where cyclopentenone prostaglandins activate RAS, leading to p53 activation, leading to both cell cycle arrest p21 and elevation of COX-2, reinforcing oxylipin biosynthesis.
Figure 5.
Figure 5.. Multiple roles for senescence in diabetes and its complications.
Senescent adipose cells can result in insulin resistance, which results in hyperglycemia, which can in turn promote additional adipose tissue senescence. Hyperglycemia also forces pancreatic beta cells to over-produce insulin. This stress results in beta cell senescence, leading to insulinemia, resulting in further hyperglycemia. Hyperglycemia also results in senescence in peripheral tissues such as the retina and the kidney, fueling diabetic complications.
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