Scientists at Vanderbilt University School of Medicine say they have uncovered a surprisingly active, organized cellular process that shows up early in aging, and may help explain why older bodies become more vulnerable to disease. The work focuses on how cells reshape the endoplasmic reticulum, one of the largest and most important structures inside a cell, and how that reshaping may influence lifespan.
Kris Burkewitz, an assistant professor of cell and developmental biology, led the research team. The findings were published in Nature Cell Biology in February 2026, with Eric Donahue, a medical student and PhD trainee, as the first author.
Burkewitz’s lab is trying to answer a central problem in aging research: people are living longer, but many of those added years are not healthy ones. Chronic diseases rise sharply with age, including cancers, diabetes, and Alzheimer’s disease. The lab’s big goal is to understand whether it is possible to loosen the connection between getting older and getting sicker.
Instead of looking only at whether cells have the right “parts” as they age, the team is studying how those parts are arranged inside the cell. Burkewitz explained the difference like this: “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.”
The Worms Who Gave Their Lives for Science
The researchers studied Caenorhabditis elegans, a tiny nematode worm widely used in aging research. These worms are especially useful because they are transparent and age quickly, which makes it possible to watch cellular structures change in living animals over a short period of time.
Donahue and the team used new genetic tools along with advanced light microscopy and electron microscopy to visualize the endoplasmic reticulum in both young and old worms.
What They Found Inside Aging Cells
The key discovery is that aging cells are not just slowly “wearing down.” They are actively remodeling the endoplasmic reticulum, or ER, in a way that looks purposeful.
As the worms grew older, the team saw a dramatic decline in rough ER, the portion closely tied to making and handling proteins. In contrast, the smooth or tubular ER, which is more associated with lipid and fat-related functions, changed only slightly.
The researchers note that this pattern might connect to big-picture themes of aging, like a weakening ability to maintain functional proteins and metabolic shifts that can change how fat is stored in the body. They also emphasize that more research is needed to prove cause and effect.
What the Endoplasmic Reticulum Does
The ER is a labyrinth of connected sheets and tubes inside the cell. It works like a major production and transport network.
- Rough ER helps synthesize, fold, sort, and transport proteins.
- Smooth ER helps synthesize and store lipids, among other roles.
The ER also acts as a scaffold that helps organize other parts of the cell. In other words, it is not just a factory floor. It is also part of the building’s framework that keeps the whole operation running smoothly.
Burkewitz used a factory analogy to explain why this matters. Having the right machinery is not enough if it is not arranged correctly. “When space is limited or production demands change, the factory has to reorganize its layout to make the right products,” he said. “If organization breaks down, production becomes very inefficient.”
What is ER Phagy?
ER phagy is a specific type of autophagy. Autophagy is the cell’s natural recycling system, where digestive enzymes break down and reuse damaged or unneeded components.
In ER phagy, the cell selectively targets certain subdomains of the endoplasmic reticulum, including damaged or excess regions that could threaten cellular health, and sends them for breakdown. This mechanism has only been discovered in recent years.
What is new here is the idea that ER phagy is not only a cleanup response to damage. It may also be part of normal, healthy aging, and possibly tied to lifespan itself.
How ER Phagy Might Affect Aging
Based on what the researchers observed, the mechanism looks like this:
- Aging begins to change cellular demands. The cell’s production goals and space constraints shift as the organism gets older.
- The ER restructures early in aging. The team reports that ER changes happen “relatively early in the aging process,” according to Burkewitz.
- ER phagy helps remodel the ER. The cell uses ER phagy to reduce specific ER structures, especially rough ER.
- That remodeling may be protective at first. The findings describe ER remodeling as a “proactive and protective response” during aging.
- But early remodeling may also set the stage for later problems. Burkewitz pointed to a possible chain reaction: “One of the most exciting implications of this is that it may be one of the triggers for what comes later: dysfunction and disease.”
In plain terms, the researchers are saying the ER may be one of the first dominoes to tip. If the ER’s structure changes, it could affect how well proteins are made and maintained, how metabolism is managed, and how other organelles are organized. That combination could help explain why aging raises the risk of so many different diseases.
The team’s language makes clear they think this is more than a small detail.
“We didn’t just add a piece to the aging puzzle, we found a whole section that hasn’t even been touched,” Donahue said.
Burkewitz also emphasized their approach is about cellular architecture, not just cellular inventory. Cells can have the same components, but if they are arranged poorly, performance drops, much like a factory with a bad layout.
The work was done in worms, so it does not prove the same process drives human aging. Still, the researchers believe the basic logic could translate because the ER is a core organelle in eukaryotic cells, including human cells.
The potential payoff is big: if ER phagy is part of the early aging program, then influencing it might help prevent or delay downstream breakdowns that contribute to chronic disease. The Vanderbilt summary notes that the discovery “highlights this process as a possible drug target for age-related chronic conditions such as neurodegenerative diseases and various metabolic disease contexts.”
That does not mean a pill is around the corner. It means scientists may have found a process that is specific enough to target, and early enough in aging to matter.
