According to research recently published in Nature Cell Biology, as we age, our cells are not just wearing down; they are reorganizing, actively remodeling the endoplasmic reticulum, reducing protein-producing regions while preserving fat-related ones. ER-phagy is driving this process, and it is linked to both lifespan and healthy aging. The paper suggests that because these changes happen early, they may help trigger later diseases OR offer a chance to stop it.
Healthspan Shorter than Lifespan
Thanks to advances in medicine, technology, and public health, people are living longer than ever; however, those extra years are often affected by poor health rather than vigor. The process of aging is unstoppable, and with age, the risk of many chronic diseases such as dementia, cancer, and diabetes increases.
This study set out to understand why aging is most often linked with disease by investigating whether it is possible to separate the biological process of aging from the development of disease, with the goal of helping people remain healthier well into later life. To search for answers, the team studied how cells organized their organelles and how changes in these internal structures influenced cellular performance, metabolism, and the risk of disease.
New Ways that Cells Adapt to Aging
The paper describes a newly identified way that cells respond to aging, showing that cells actively respond to the endoplasmic reticulum, which is the largest and most complex structure inside cells. The endoplasmic reticulum was found to undergo controlled remodeling as organisms grow older, rather than remaining static.
The remodeling happens through ER-phagy, during which cells selectively break down specific regions of the endoplasmic reticulum. According to the researchers, identifying ER-phagy as part of the aging process could make it a target for therapeutics aimed at age-related conditions such as metabolic diseases and neurodegenerative disorders.
Beyond Cellular Parts to Organizing
“Where many prior studies have documented how the levels of different cellular machineries change with age, we are focusing instead on how aging affects the way that cells house and organize these machineries within their complex inner architectures,” said Kris Burkewitz, assistant professor of cell and developmental biology at Vanderbilt University.
How a cell functions depends on what molecular tools it contains and how those tools are arranged.
“When space is limited, or production demands change, the factory has to reorganize its layout to make the right products,” Burkewitz said. “If organization breaks down, production becomes very inefficient.”
The endoplasmic reticulum plays an important role in cellular organization. Essentially, it forms extensive networks of tubules and sheets that help to produce lipids and proteins while acting as a structural framework for the rest of the cell.
Shedding New Light on Aging Cells in Living Organisms
“We didn’t just add a piece to the aging puzzle — we found a whole section that hasn’t even been touched,” said Eric Donahue, PhD’25, the study’s first author. Donahue is a medical student in the Medical Scientist Training Program who completed his doctoral research in the Burkewitz lab, where he studied ER-phagy, ER remodeling, and aging.
Age-Related Endoplasmic Reticulum Changes
Aging cells significantly reduce the amount of rough endoplasmic reticulum associated with protein production, while, in contrast, the tubular form of endoplasmic reticulum associated with lipid and fat production only declines slightly. This pattern is in line with established features of aging, such as the reduced ability to maintain healthy proteins and metabolic changes that contribute to fat accumulation.
The paper also describes how ER-phagy plays an active role in shaping the endoplasmic reticulum during aging: linking ER-phagy to lifespan and suggesting that it directly contributes to healthier aging rather than reflecting cellular decline.
Next Steps
“Changes in the ER occur relatively early in the aging process,” Burkewitz said. “One of the most exciting implications of this is that it may be one of the triggers for what comes later: dysfunction and disease.”
The researchers plan to continue investigating how different endoplasmic reticulum structures influence metabolism at both the cellular and whole-organism levels. Understanding how the endoplasmic reticulum remodeling affects the broader cellular landscape will be a key next step in anti-aging research to slow and prevent the cascade of events that leads to age-related disease.
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