Autophagy reshapes the aging ER

Apr 28, 2026Autophagy

How cell cleanup changes the aging protein-making system

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

The endoplasmic reticulum (ER) shows a reduction in volume and a shift from rough sheets to tubular networks as organisms age.

Age-onset remodeling of the ER is actively driven by a process called ER-phagy.
Changes in ER structure are accompanied by compositional shifts, including declines in proteostasis components and preservation of lipid-associated enzymes.
ER-phagy is identified as a conserved aspect of the aging process across multiple cell types and organisms.
This remodeling is associated with longevity paradigms and requires ER-phagy for lifespan extension during mTOR impairment.
ER-phagy is proposed to play a critical role in regulating organelle architecture and age-related metabolic shifts.

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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.: ER: endoplasmic reticulum; TMEM-131: transmembrane protein 131; UPR: unfolded protein response; IRE-1: inositol-requiring enzyme 1; XBP-1: X-box binding protein 1; mTOR: mechanistic target of rapamycin. Abbreviations

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Autophagy reshapes the aging ER

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