Scientists Discover Link Between Loss of Endoplasmic Reticulum and Aging

Every cell in our body contains a branched network of membranes – the endoplasmic reticulum (ER). This organelle has long been considered an untiring workhorse: proteins are synthesized and acquire their correct shape on its surface, lipids and hormones are produced, and the very framework of the ER supports the cell's architecture. However, new research conducted by a scientific group from Vanderbilt University (USA) overturns the understanding of this structure's role in the aging process. Scientists have proven that the cell consciously and extensively dismantles its own ER as it ages, and this process, called ER-phagy, may be the key to healthier aging.

To track the fate of the ER, researchers chose a classic object of gerontology – the microscopic worm C. elegans. Its transparent body and short lifespan (the first signs of aging appear as early as the seventh day) allowed for detailed observation of changes in real time. Using genetic markers and high-precision microscopy, scientists compared the picture in worms with data from yeast and laboratory mice. The result was the same: cell aging in such different organisms is accompanied by a significant decrease in the volume of the endoplasmic reticulum.

It turned out that the cell does not just passively lose parts of the ER. It actively recycles it through a mechanism similar to autophagy – the process of disposing of intracellular "waste." The membranes of the "garbage-collecting" organelles themselves, autophagosomes, originate from the ER, after which they, ironically, begin to engulf and destroy their own "parent." The authors termed this closed cycle ER-phagy.

The most interesting part is that destruction does not occur chaotically, but according to a clear plan. First and foremost, the volumes of the so-called rough ER are reduced – extensive flat membranes studded with ribosomes, whose main function is protein synthesis. In contrast, the system of tubules, responsible to a greater extent for lipid metabolism, remains relatively untouched. This fits perfectly with known age-related physiology: with age, the body reduces the intensity of protein synthesis but often faces the problem of lipid accumulation in tissues. Thus, ER-phagy appears to be a programmed restructuring of metabolism.

"Imagine the ER as a huge factory," explains the head of the study, Christopher Burketwitz. "When external conditions or internal needs change, management has to optimize production. Sometimes the best strategy is not to increase capacity, but to intelligently reduce and reorganize workshops to avoid inefficiency and defective products."

Initially, scientists assumed that ER-phagy was a consequence of age-related accumulation of cellular stress, particularly due to chronic problems with protein folding. Indeed, key proteins involved in the process are associated with the response to such stress (e.g., IRE-1–XBP-1) and the core factors of autophagy (Atg8, ULK1). However, further experiments revealed an unexpected twist: ER-phagy not only accompanies aging but may be a condition for healthy longevity.

It turned out that life-extending interventions – reducing the activity of insulin and mTOR signaling pathways – also lead to a decrease and reorganization of the ER. Moreover, in long-lived individuals, this process had a special, orderly character. Furthermore, blocking ER-phagy in worms and yeast deprived them of the ability to live longer in response to mTOR suppression. This means that the strategic reduction of protein production may be a protective adaptation that prevents the accumulation of damage.

The discovery of a fundamentally new cellular program associated with aging opens new therapeutic horizons. Understanding the regulation of ER-phagy could lead to the development of methods for managing this process. Targeted stimulation of "correct" ER remodeling could potentially slow the development of neurodegenerative diseases (such as Alzheimer's and Parkinson's) or metabolic disorders, where proteostasis and lipid metabolism play a key role.

"We didn't just find another piece of the aging puzzle," concludes the first author of the work, Eric Donahue. "We discovered an entire new segment of the picture, the existence of which we hadn't even suspected. Now we have to figure out how to manage it for the benefit of health." Thus, a process that outwardly resembles regression – the large-scale self-destruction of the main cellular factory – may turn out to be a hidden tool for extending high-quality, healthy life.

Publication date: 2026.02.13

Source:
Donahue E.K.F. et al. ER remodelling is a feature of ageing and depends on ER-phagy. Nat Cell Biol. 2026 Feb 2. doi: 10.1038/s41556-025-01860-1. Epub ahead of print. PMID: 41629400.
https://www.nature.com/articles/s41556-025-01860-1