Researchers uncover a new cellular process linked to healthy aging

The idea

Improvements in public health have allowed humankind to survive to older ages than ever before, but, for many people, these added golden years are not spent in good health. Aging is a natural part of life, but it is associated with a greatly increased incidence of most chronic diseases, including various cancers, diabetes, and Alzheimer's disease.

The laboratory of Kris Burkewitz, assistant professor of cell and developmental biology, wants to figure out if there is a way to break the links between the aging process and disease so that we can stay healthy longer, allowing us to better enjoy our later years. To accomplish this goal, the Burkewitz lab focuses on how cells organize their internal compartments, or organelles, and how organelle structures can influence cellular function, metabolism, and disease risk.

In his most recent paper, published in Nature Cell Biology, Burkewitz describes a new way by which cells adapt to the aging process: by actively remodeling the endoplasmic reticulum, one of the cell's largest and most complex organelles. His team found that aging cells remodel their ER through a process called ER-phagy, which selectively targets specific ER subdomains for breakdown. 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.

What we knew

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."

Kris Burkewitz, assistant professor of cell and developmental biology, Vanderbilt University

The efficiency of a cell's function and metabolism depends on how those collections of machineries are organized and distributed within a cell. A helpful way to envision how the inner architecture of a cell impacts its function is to imagine a factory that builds many complex products. According to Burkewitz, that factory needs a lot of specialized machineries, but even if all they are all present, the factory only runs smoothly if they are arranged in the right position and sequence. "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."

One of the largest and most important structures in a cell is the ER, a labyrinth of interconnected sheets and tubules that not only acts as a major production hub for proteins and lipids but serves as a scaffold for organizing other parts of the cell. Despite these critical roles, scientists knew surprisingly little about how the structure of the ER might change in aging animals.

What we found out

"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 first author of the paper. 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 focused on ER-phagy, ER remodeling, and aging.

Donahue, Burkewitz, and their team used new genetic tools and advanced light and electron microscopy to visualize how the ER is shaped and organized inside cells of living Caenorhabditis elegans worms, a widely used model for aging research. C. elegans worms possess a unique combination of characteristics that make them the ideal model to study aging: They are transparent and age rapidly, a combination that allows researchers to observe what happens inside the cells of intact, aging animals.

Burkewitz and his team found that, as animals age, they dramatically reduce the amount of "rough" ER in their cells, which is involved in creating more protein; the amount of tubular ER, which is more closely associated with lipid or fat production, is only slightly impacted. This change fits with broader themes of aging, including declines in our ability to maintain functional proteins and shifts in metabolism that lead us to accumulate fat in new places; more research is needed to establish these links causally.

The researchers also found that cells use the process of ER-phagy to remodel their ER during aging and that ER-phagy is linked to lifespan, actively contributing to healthy aging.

What's next?

The Burkewitz lab will continue to probe the different structures of the ER and how they can promote different metabolic outputs at the cell and whole-animal scales. As the ER is one of the master controllers for organizing all other compartments within the cell, it will be important to ask how its remodeling during aging impacts the organization of other cellular components. "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 figure out what, exactly, is the trigger, they may be able to stop it from firing.

Here's to a long, healthy life for us all! Thank you, science.

Go deeper

The paper "ER remodeling is a feature of aging and depends on ER-phagy" was published in Nature Cell Biology in February 2026.

This work was performed in collaboration with the Vanderbilt University labs of 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, plus collaborators from the University of Michigan and the University of California, San Diego.

Funding

This research was supported by funds from the National Institute on Aging, the National Institute of General Medical Sciences, and the Glenn Foundation for Medical Research/American Federation for Aging Research.