Chapter 2 - The Role of Autophagy in Aging: Molecular Mechanisms

Abstract

Autophagy is a conserved, subtly regulated process responsible for the lysosomal degradation of cytoplasmic components, such as long-lived proteins and unnecessary or dysfunctional organelles. It has a well-established housekeeping role under physiological conditions, and a cytoprotective and adaptive role under stress. The aging process is associated with marked decrease of autophagic activity and deregulated autophagy often correlates with accelerated aging and age-related pathologies. Conversely, genetic or pharmacological interventions that extend lifespan, such as reduced insulin/insulin-like growth factor-1 (IGF-1) signaling, target of rapamycin inhibition, deacetylation of histones and nonhistone cytoplasmic proteins, caloric restriction (CR), rapamycin, resveratrol, or spermidine supplementation, have been associated with autophagy and in some cases their beneficial effects on health and longevity require autophagy. Interestingly, the recently gained knowledge about autophagy regulation has revealed that several transcription factors required for lifespan extension have an important role in the upregulation of autophagy-related genes. Moreover, acetylation of histones and autophagy proteins has emerged as an essential regulatory mechanism of both autophagy and longevity, at least in yeast and mammals. Further studies are needed to clarify the antiaging role of autophagy and the conditions under which autophagy upregulation can sufficiently improve health and longevity. However, the existence of a large arsenal of drugs that induce autophagy, sometimes by mimicking the effects of long-term CR or short-term starvation, is a valuable tool for the development of future antiaging treatments.