ER-phagy Drives Conserved, Age-Related Remodeling of the Endoplasmic Reticulum and Promotes Longevity

Abstract

Public health advances have significantly reduced early life mortality, enabling humans to live longer than ever before. As we age, however, a progressive accumulation of molecular damage drives homeostatic failure and chronic disease, thus increasing the disease burden in our rapidly aging society. Targeting the underlying mechanisms of aging itself can mitigate disease progression, reduce late-life morbidity, and promote longer, healthier lives. Evidence increasingly highlights endoplasmic reticulum (ER) dysfunction as a key factor in aging. Because ER function is determined by its specialized morphologic subdomains, this dissertation investigates the central hypothesis that remodeling of ER structure-function is an upstream event in the aging process, which may serve as a target for healthspan and lifespan interventions. The first part of this dissertation reviews the fundamental roles for inter-organelle communication in aging. The ER has long been recognized as a central regulator of cellular homeostasis, and the recent identification of its myriad organelle contact sites enhances its relevance to the aging process. The second part of this dissertation demonstrates that selective degradation of the ER, or ER-phagy, drives ER remodeling in early aging. Across eukaryotes, aging is associated with a significant loss of ER mass, shifting ER function from proteostasis to lipid metabolism. We identify TMEM-131 as a novel ER-phagy receptor and demonstrate that aging tissues utilize specific pathways to regulate ER-phagy, which likely serves a proactive, protective response in younger animals. Finally, we show that ER-phagy is required for lifespan extension in yeast and C. elegans. These findings establish declines in ER structure-function as a critical factor in aging and longevity, suggesting that manipulating ER morphology via ER-phagy could provide new longevity paradigms