Autophagy

Autophagy is a lysosome-based degradative process used to recycle obsolete cellular constituents and eliminate damaged organelles and aggregate-prone proteins. ^[1] It is a self-digestive process conserved in eukaryotic cells and responsible for maintaining cellular homeostasis through proteolysis, and it can be classified into three categories: macroautophagy, microautophagy, and chaperone-mediated autophagy. ^[2]

Macroautophagy is an essential, conserved self-eating process that degrades intracellular components including soluble proteins, aggregated proteins, organelles, macromolecular complexes, and foreign bodies. ^[3] The process requires formation of a double-membrane structure, the autophagosome, that sequesters the cytoplasmic material and ultimately fuses with the lysosome. ^[3] Newly formed autophagosomes then undergo maturation, fusing with vesicles from endolysosomal compartments to form amphisomes that eventually become degradative autolysosomes, a step requiring the concerted actions of SNAREs, tethering proteins and RAB GTPases. ^[4] Beyond bulk degradation, selective autophagy degrades specific targets such as damaged organelles through mitophagy, lysophagy, ER-phagy and ribophagy, aggregated proteins through aggrephagy, or invading bacteria through xenophagy, using ubiquitin-dependent receptors such as p62, NBR1, OPTN and NDP52. ^[5] The upstream signaling that regulates autophagy mainly involves an mTOR-dependent pathway and mTOR-independent pathways including AMPK, PI3K, Ras-MAPK, p53 and PTEN. ^[6]

Malfunctioning of autophagy with age contributes to the loss of proteostasis that characterizes all old organisms, placing autophagy at the center of the aging process. ^[7] The dependence on autophagy of many geroprotective interventions has motivated a search for direct modulators of autophagy that could be used to slow aging and extend healthspan. ^[7] Aging impairs autophagy while many neurodegeneration-associated proteins are autophagy substrates, and autophagy upregulation ameliorates disease in many animal models of neurodegeneration by enhancing the clearance of toxic proteins and dysfunctional organelles. ^[8]

Among the stress stimuli that induce autophagy, fasting and calorie restriction are the most potent non-genetic autophagy stimulators, and the evidence overwhelmingly suggests that autophagy is induced in a wide variety of tissues and organs in response to food deprivation. ^[9] Because autophagy inhibition attenuates the anti-aging effects of calorie restriction, autophagy is proposed to play a substantive role in calorie-restriction-mediated longevity. ^[9] The natural polyamine spermidine, a caloric restriction mimetic, has prominent cardioprotective and neuroprotective effects, shares the molecular pathways engaged by other caloric restriction mimetics, and depends on functional autophagy. ^[10] AMPK, activated under conditions of low energy, promotes autophagy directly by phosphorylating autophagy-related proteins in the mTORC1, ULK1, and PIK3C3/VPS34 complexes. ^[11] Exercise reduces age-related oxidative damage and chronic