One hallmark of aging is the accumulation of various forms of molecular damage, embodied in malfunctioning organelles, defective enzymes, proteinaceous aggregates, or DNA mutations. At the same time, the incidence of chronic diseases such as neurodegeneration, type II diabetes, or cancer rises with age concomitantly with accumulating cellular damage. Therefore, one of the main challenges for future medicine is the development of strategies to prolong health span (i.e., maintaining a healthy state without necessarily extending the maximum life span) by subverting the etiology of age-related disorders rather than solely providing symptomatic treatments. One of the most promising toeholds in the ascension toward a causal treatment of aging is autophagy, a cellular program for the removal of damaged cellular components and the digestion of cell-intrinsic macromolecules in the context of dwindling nutritional resources. Since lysosomes were first described in the 1950s, a spectrum of different lysosome-mediated degradation pathways has been discovered. Macroautophagy (hereafter referred to as autophagy) constitutes a mechanism through which cytoplasmic organelles or cytosolic molecules are sequestered in double-membrane vesicles, so-called autophagosomes, that subsequently fuse with lysosomes for bulk digestion of the autophagic cargo. Besides its role in mobilizing endogenous macromolecules for meeting the cell’s energetic demands when extracellular nutrients are scarce, autophagy contributes to the maintenance of organelle homeostasis and the avoidance of proteotoxic stress, thereby attenuating or avoiding age-associated processes and mediating cytoprotection.
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Caloric restriction (CR) is the most effective strategy to induce autophagy, as it activates multiple regulatory pathways. For example, CR results in the inhibition of TOR complex 1 (TORC1) and activation of AMPK, which in turn activates the autophagy-promoting Unc-51 like autophagy activating kinase 1 (ULK1) complex , as well as the acetyltransferase MEC-17, which stimulates the cellular microtubule transport machinery that is indispensable for autophagy. Furthermore, CR stimulates SIRT1, which deacetylates and thereby activates essential autophagic proteins. This interplay between acetylation and deacetylation seems to be a leitmotif of autophagy control