Essential role for autophagy in life span extension
Frank Madeo, … , Maria Chiara Maiuri, Guido Kroemer
Frank Madeo, … , Maria Chiara Maiuri, Guido Kroemer
Published January 2, 2015
Citation Information: J Clin Invest. 2015;125(1):85-93. https://doi.org/10.1172/JCI73946.
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Essential role for autophagy in life span extension

Abstract

Life and health span can be prolonged by calorie limitation or by pharmacologic agents that mimic the effects of caloric restriction. Both starvation and the genetic inactivation of nutrient signaling converge on the induction of autophagy, a cytoplasmic recycling process that counteracts the age-associated accumulation of damaged organelles and proteins as it improves the metabolic fitness of cells. Here we review experimental findings indicating that inhibition of the major nutrient and growth-related signaling pathways as well as the upregulation of anti-aging pathways mediate life span extension via the induction of autophagy. Furthermore, we discuss mounting evidence suggesting that autophagy is not only necessary but, at least in some cases, also sufficient for increasing longevity.

Authors

Frank Madeo, Andreas Zimmermann, Maria Chiara Maiuri, Guido Kroemer

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Figure 2

Nutrient and growth factor signaling regulates autophagy induction.

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Nutrient and growth factor signaling regulates autophagy induction. Grow...
Growth factor binding to IGFR and/or nutrient availability stimulates the TORC1 pathway, which in turn deactivates the pro-autophagic ULK1 complex and activates the autophagy inhibitory kinase S6K. Cellular energy resources are also detected by AMPK, which initiates pro-autophagic signaling when the AMP/ATP ratio rises. Recent data have underscored the importance of post-translational protein acetylation (Ac), which is controlled by HATs such as EP300, HDACs such as SIRT1, and levels of acetyl-CoA. In addition to epigenetic regulation via histone acetylation and methylation, transcription factors such as FOXO3A or TFEB also influence transcription of pro-autophagic genes (e.g., ATGs).