Autophagy reshapes the aging ER.

Abstract

Age-associated changes in organelle structure are often viewed as passive deterioration. Our recent work challenges this view by identifying an evolutionarily conserved, age-onset remodeling of the endoplasmic reticulum (ER) that is actively driven by ER-phagy. Across multiple cell types and organisms, the ER undergoes a reduction in volume and a shift from rough ER sheets to tubular networks. ER compositional shifts accompany these changes in morphology, with declines of the proteostasis machineries enriched within rough ER and preservation of lipid-associated enzymes tied to tubular subdomains. This remodeling occurs via autolysosomal targeting and degradation of the ER, establishing selective ER-phagy as a conserved aspect of the aging process. Notably, ER-phagy is also engaged by multiple longevity paradigms, resulting in precocious, spatial reorganization of the ER. Furthermore, ER-phagy is required for lifespan extension during mTOR impairment, indicating that ER turnover is adaptive and contributes to longevity. These findings reveal ER-phagy as a regulator of organelle architecture and age-dependent shifts in cell metabolism, thus illuminating important roles for selective autophagy in shaping organelle identity and function across the lifespan.