A Newly Found Cellular Shift May Explain Why Aging Leads to Disease

Scientists found that aging may begin with a hidden cellular remodel that could help drive disease later in life.

Thanks to advances in public health, people are living longer than ever before. However, many of those extra years are accompanied by chronic illnesses rather than good health. Aging is a normal part of life, but it is also linked to a higher risk of conditions such as cancer, diabetes, and Alzheimer’s disease.

Kris Burkewitz, an assistant professor of cell and developmental biology, is working to understand whether it is possible to separate aging from disease so people can remain healthier later in life. His lab studies how cells arrange their internal structures, known as organelles, and how the organization of those structures influences cellular function, metabolism, and disease risk.

In a recent study published in Nature Cell Biology, Burkewitz and his colleagues identified a previously unrecognized way that cells respond to aging. They found that cells actively reshape the endoplasmic reticulum (ER), one of the largest and most complex structures inside a cell. This remodeling occurs through a process known as ER-phagy, which selectively breaks down specific regions of the ER. Because ER-phagy appears to play a role in aging, it may represent a potential target for future treatments aimed at age-related conditions, including neurodegenerative and metabolic diseases.

The discovery that ER-phagy is involved in aging highlights this process as a possible drug target for age-related chronic conditions such as neurodegenerative diseases and various metabolic disease contexts. Credit: Burkewitz et. al.

Why Cellular Organization Matters

“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,” Burkewitz said.

A cell’s performance depends not only on the machinery it contains but also on how that machinery is arranged. Burkewitz compares this to a factory that produces a wide range of complex products. Even if all the necessary equipment is available, production will only run efficiently if everything is positioned in the proper order and location.

“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 is one of the cell’s most important structures. It consists of an extensive network of interconnected sheets and tubes that serves as a major center for producing proteins and lipids. The ER also helps organize other cellular components. Despite its central role, scientists previously knew very little about how the ER changes as animals grow older.

New Insights Into ER Remodeling and Aging

“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 recently completed the Ph.D. portion of his training in the Burkewitz lab, where he studied ER-phagy, ER remodeling, and aging.

To investigate the aging process, Donahue, Burkewitz, and their team used advanced genetic techniques along with light and electron microscopy to examine the ER inside living Caenorhabditis elegans worms, a widely used model organism in aging research. These worms are especially valuable because they are transparent and have short lifespans, allowing scientists to directly observe changes occurring inside aging animals.

The researchers discovered that aging animals experience a substantial decline in “rough” ER, the portion of the structure involved in protein production. In contrast, tubular ER, which is more closely linked to lipid and fat production, changes only modestly. These findings align with broader patterns seen during aging, including reduced ability to maintain healthy proteins and metabolic changes that can lead to fat accumulating in different parts of the body. Additional studies will be needed to determine whether these connections are directly responsible for those age-related changes.

The team also showed that cells rely on ER-phagy to remodel the ER during aging. Their findings further indicate that ER-phagy is connected to lifespan and plays an active role in supporting healthy aging.

Could ER Changes Trigger Age-Related Disease?

The Burkewitz lab plans to continue studying the various structures of the ER and how they influence metabolism at both the cellular and whole-animal levels. Because the ER helps organize many other compartments inside the cell, researchers are also interested in understanding how age-related ER remodeling affects the broader cellular landscape.

“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.”

If scientists can identify exactly what initiates these changes, they may eventually be able to prevent the chain of events that leads to declining cellular function and disease.

Reference: “ER remodelling is a feature of ageing and depends on ER-phagy” by Eric K. F. Donahue, Nathaniel L. Hepowit, Elizabeth M. Ruark, Alexandra G. Mulligan, Brennen Keuchel, Nicholas D. Urban, Li Peng, Stedman Stephens, Derek J. Johnson, Natalie S. Wallace, Lauren P. Jackson, Mark H. Ellisman, Rafael Arrojo e Drigo, Andrew W. Folkmann, Matthias C. Truttmann, Jason A. MacGurn and Kristopher Burkewitz, 2 February 2026, Nature Cell Biology.
DOI: 10.1038/s41556-025-01860-1

The research involved collaborations with several Vanderbilt University laboratories, including those led by Jason MacGurn, associate professor of cell and developmental biology; Andrew Folkmann, assistant professor of biochemistry; Rafael Arrojo e Drigo, assistant professor of molecular physiology and biophysics; and Lauren Jackson, associate professor of biological sciences. Additional collaborators came from the University of Michigan and the University of California, San Diego.

The work was supported by the National Institute on Aging, the National Institute of General Medical Sciences, and the Glenn Foundation for Medical Research/American Federation for Aging Research.

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