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Review
. 2016 Jun 14;23(6):1013-1021.
doi: 10.1016/j.cmet.2016.05.010.

From Ancient Pathways to Aging Cells-Connecting Metabolism and Cellular Senescence

Christopher D Wiley  1 , Judith Campisi  2
Affiliations
Review

From Ancient Pathways to Aging Cells-Connecting Metabolism and Cellular Senescence

Christopher D Wiley et al. Cell Metab. .

Abstract

Cellular senescence is a complex stress response that permanently arrests the proliferation of cells at risk for oncogenic transformation. However, senescent cells can also drive phenotypes associated with aging. Although the senescence-associated growth arrest prevents the development of cancer, and the metabolism of cancer cells has been studied in depth, the metabolic causes and consequences of cellular senescence were largely unexplored until recently. New findings reveal key roles for several aspects of cellular metabolism in the establishment and control of senescent phenotypes. These discoveries have important implications for both cancer and aging. In this review, we highlight some of the recent links between metabolism and phenotypes that are commonly associated with senescent cells.

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Figures

Figure 1
Figure 1. Energy status regulates the senescence growth arrest
Senescent cells have increased AMP:ATP and ADP:ATP ratios, which activate AMP-activated protein kinase (AMPK). AMP kinase in turn activates p53, which increases p21 transcription. AMPK also inactivates HuR, which increases the stability of the p21 and p16INK4a mRNAs. p21 and p16INK4a are cyclin-dependent kinase inhibitors that impose the senescence proliferative arrest by increasing activity of the pRB tumor suppressor. p53 and pRB might counterbalance each other in regulating glycolysis in senescent cells.
Figure 2
Figure 2. The electron transport chain (ETC) and malate-aspartate shuttle antagonize senescence
Inhibition of glutamic-qxaloacetic transaminase 1 (GOT1) by aminooxyacetate (AOA) or ETC deficits decrease the cytosolic NAD+/NADH ratio, leading to AMPK activation. AMPK in turn phosphorylates and activated p53, which promotes senescence but suppresses the IL1R signaling arm of the SASP. Malate dehydrogenase (MDH1) and GOT1 are required for the synthesis of aspartate following ETC inhibition, and loss of either enzyme prevents pyruvate from rescuing cellular proliferation.
Figure 3
Figure 3. The senescence response entails a complex series of metabolic changes (metabolic reprogramming)
See text for details.
See this image and copyright information in PMC

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