The endoplasmic reticulum is a cell structure associated with ribosomes that aids in protein folding and protein transport, but also has a range of other purposes. It is an important component of the machinery that builds proteins and other molecules in the cell. Like other organelles, the endoplasmic reticulum is subject to the cell maintenance processes of autophagy, in which structures or their component parts are identified as worn, damaged, or excess to requirements, and then broken down and recycled. Preventing this autophagy is known to have negative consequences for other organelles, and researchers here show that this is also true for the endoplasmic reticulum. Much of what is noted in this paper parallels what is known of the relationship between autophagy, aging, and mitochondria, another complex organelle essential to cell function: structural changes with age; shifts in autophagy; changes in function; and the protective role of autophagy.
The endoplasmic reticulum (ER) comprises an array of structurally distinct subdomains, each with characteristic functions. While altered ER-associated processes are linked to age-onset pathogenesis, whether shifts in ER morphology underlie these functional changes is unclear. We report that ER remodeling is a conserved feature of the aging process in models ranging from yeast to C. elegans and mammals. Focusing on C. elegans as an exemplar of metazoan aging, we find that as animals age, ER mass declines in virtually all tissues and ER morphology shifts from rough sheets to tubular ER. The accompanying large-scale shifts in proteomic composition correspond to the ER turning from protein synthesis to lipid metabolism. To drive this substantial remodeling, ER-phagy is activated early in adulthood, promoting turnover of rough ER in response to rises in luminal protein-folding burden and reduced global protein synthesis. Surprisingly, ER remodeling is a pro-active and protective response during aging, as ER-phagy impairment limits lifespan in yeast and diverse lifespan-extending paradigms promote profound remodeling of ER morphology even in young animals. Altogether our results reveal ER-phagy and ER morphological dynamics as pronounced, underappreciated mechanisms of both normal aging and enhanced longevity.
Link: https://doi.org/10.1101/2024.08.07.607085
