Autophagy

Autophagy (Greek: 'self-eating') is the conserved cellular pathway by which cytoplasmic contents — damaged mitochondria, misfolded proteins, intracellular pathogens, and surplus organelles — are sequestered within double-membrane autophagosomes and delivered to lysosomes for degradation and recycling. The three principal forms are macroautophagy (the most-studied, involving autophagosome formation), microautophagy (direct lysosomal engulfment of small cytoplasmic regions), and chaperone-mediated autophagy (selective unfolded-protein delivery via HSC70/LAMP-2A). Macroautophagy is initiated by the ULK1 complex in response to nutrient or growth-factor deprivation and is coordinated through the highly conserved ATG (autophagy-related) gene family. Autophagic activity is regulated by mTOR (negative — autophagy is suppressed under nutrient-replete, mTOR-active conditions) and by AMPK and sirtuins (positive — autophagy is activated under nutrient-restricted, AMPK/sirtuin-active conditions). Defective autophagy is implicated in neurodegenerative disease (impaired clearance of α-synuclein, β-amyloid, tau), cardiac and metabolic disease, and the cellular ageing phenotype generally. Autophagy is the primary mechanistic explanation for the longevity effects of caloric restriction and intermittent fasting. In peptide research, autophagy is a downstream readout for compounds proposed to act on cellular ageing — Humanin, MOTS-c, SS-31, and epitalon are all studied partly for autophagic-flux effects.