Improvements in public health have allowed humankind to survive to older ages than ever before, but for many, these added golden years are not spent in good health. Aging, a natural part of life, is closely tied to a heightened incidence of chronic diseases, including various cancers, diabetes, and Alzheimer’s disease.
The laboratory of Kris Burkewitz, an assistant professor of cell and developmental biology, is exploring ways to decouple aging from disease, aiming to extend the healthy years of life. The Burkewitz lab is particularly focused on how cells organize their internal compartments, known as organelles, and how these structures influence cellular function, metabolism, and disease risk.
Unveiling Cellular Adaptations
In a groundbreaking paper published in Nature Cell Biology, Burkewitz describes a novel mechanism by which cells adapt to aging: by remodeling the endoplasmic reticulum (ER), one of the cell’s largest and most complex organelles. His team discovered that aging cells undergo a process called ER-phagy, which selectively breaks down specific ER subdomains. This finding positions ER-phagy as a potential drug target for age-related conditions such as neurodegenerative diseases and metabolic disorders.
“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.
The efficiency of a cell’s function and metabolism relies heavily on the organization and distribution of these cellular machineries. Burkewitz likens this to a factory that must reorganize its layout to produce efficiently when space is limited or production demands change. If organization falters, inefficiencies arise.
New Insights into Aging
Eric Donahue, PhD’25, the first author of the paper, emphasized the significance of their discovery, stating, “We didn’t just add a piece to the aging puzzle—we found a whole section that hasn’t even been touched.” Donahue, a medical student in the Medical Scientist Training Program, focused his research on ER-phagy, ER remodeling, and aging.
Using advanced genetic tools and microscopy, Donahue, Burkewitz, and their team visualized the ER’s shape and organization in living Caenorhabditis elegans worms, a model organism for aging research. These worms are ideal due to their transparency and rapid aging, allowing researchers to observe cellular changes in real-time.
The team observed that as animals age, they significantly reduce the amount of “rough” ER, which is crucial for protein production. In contrast, the tubular ER, associated with lipid production, is less affected. This change aligns with broader aging themes, such as declining protein maintenance and metabolic shifts leading to fat accumulation. Further research is needed to establish causal links.
“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.”
Future Directions
The Burkewitz lab plans to continue exploring ER structures and their influence on metabolic outputs at both cellular and organismal levels. Given the ER’s role as a master organizer of cellular compartments, understanding its remodeling during aging is crucial to deciphering its impact on other cellular components.
If scientists can identify the precise triggers of aging-related dysfunction, they may be able to develop interventions to prevent these triggers from activating, potentially paving the way for healthier aging.
Collaborative Efforts and Funding
The research, “ER remodeling is a feature of aging and depends on ER-phagy,” was published in Nature Cell Biology in February 2026. The study was a collaborative effort involving the Vanderbilt University labs of Jason MacGurn, Andrew Folkmann, Rafael Arrojo e Drigo, and Lauren Jackson, along with 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.
As the scientific community continues to unravel the complexities of aging, these findings offer a promising avenue for enhancing the quality of life in our later years. Here’s to a long, healthy life for us all, thanks to the relentless pursuit of knowledge and innovation.
