Improvements in public health have allowed humans to live longer than ever before, but these additional years are not always spent in good health. Aging, a natural part of life, is often accompanied by a higher incidence of chronic diseases such as cancer, diabetes, and Alzheimer’s disease. The laboratory of Kris Burkewitz, an assistant professor of cell and developmental biology, is investigating whether it is possible to decouple the aging process from disease, potentially extending the period of healthy living in our later years.
Burkewitz’s team focuses on how cells organize their internal compartments, or organelles, and how these structures influence cellular function, metabolism, and disease risk. In a recent paper published in Nature Cell Biology, Burkewitz describes a novel cellular adaptation to aging: the active remodeling of the endoplasmic reticulum (ER), one of the cell’s largest and most complex organelles. This process, known as ER-phagy, selectively targets specific ER subdomains for breakdown, highlighting a potential drug target for age-related conditions like neurodegenerative diseases.
Understanding Cellular Architecture and Aging
“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 explained.
The efficiency of a cell’s function and metabolism depends on the organization and distribution of its internal machineries. Burkewitz likens this to a factory that requires specialized machinery to run smoothly. “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.”
The ER is a critical structure within cells, acting as a production hub for proteins and lipids and serving as a scaffold for organizing other cellular components. Despite its importance, scientists have known surprisingly little about how the ER’s structure changes in aging animals.
Breakthrough in Aging Research
“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, a medical student in the Medical Scientist Training Program, completed his Ph.D. in the Burkewitz lab, focusing on ER-phagy, ER remodeling, and aging.
Using new genetic tools and advanced microscopy, Donahue, Burkewitz, and their team visualized the ER’s shape and organization in the cells of living Caenorhabditis elegans worms, a model organism for aging research. These worms are ideal for such studies due to their transparency and rapid aging, allowing researchers to observe cellular changes in real time.
The team discovered that as animals age, they significantly reduce the amount of “rough” ER, involved in protein production, while the “tubular” ER, associated with lipid production, is less affected. This change aligns with broader aging themes, such as declining protein maintenance and shifts in metabolism leading to fat accumulation. More research is needed to establish these links causally.
“Cells use the process of ER-phagy to remodel their ER during aging, and this is linked to lifespan, actively contributing to healthy aging.”
Future Directions in Aging Research
The Burkewitz lab plans to continue exploring the ER’s structures and their impact on metabolism at both cellular and organismal levels. Since the ER organizes all other cellular compartments, understanding its remodeling during aging could reveal how it affects other cellular components. “Changes in the ER occur relatively early in the aging process,” Burkewitz noted. “One of the most exciting implications of this is that it may be one of the triggers for what comes later: dysfunction and disease.”
By identifying the triggers of cellular aging, scientists hope to prevent them from initiating disease processes, potentially paving the way for longer, healthier lives.
Collaborative Efforts and Support
The paper “ER remodeling is a feature of aging and depends on ER-phagy” was published in Nature Cell Biology in February 2026. This research was conducted in collaboration with Vanderbilt University labs and partners from the University of Michigan and the University of California, San Diego.
Funding for this research was provided 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.
The findings from the Burkewitz lab offer a promising avenue for understanding and potentially mitigating the impacts of aging, contributing to the broader goal of enhancing human healthspan.
