Advances in public health and medicine have extended lifespans, but these additional years are frequently accompanied by chronic illness rather than sustained vitality. While aging itself is inevitable, it significantly elevates the risk of conditions like cancer, diabetes, and Alzheimer’s disease. Understanding the link between aging and disease is a central focus of current research.
A New Understanding of Cellular Adaptation to Aging
Researchers are increasingly focused on how cells organize their internal structures, known as organelles, and how changes within these structures influence cellular function, metabolism, and disease risk. A recent study published in Nature Cell Biology details a newly identified way cells respond to aging: the active reshaping of the endoplasmic reticulum (ER), a large and complex structure within the cell. This remodeling isn’t a passive consequence of aging, but rather a controlled process that occurs as organisms grow older.
The key mechanism driving this reshaping is a process called ER-phagy, where cells selectively break down specific regions of the ER. Identifying ER-phagy as a component of the aging process raises the possibility of developing drugs targeting age-related conditions, including neurodegenerative and metabolic diseases.
Beyond Cellular Parts: The Importance of Cellular Organization
Kris Burkewitz, assistant professor of cell and developmental biology, emphasizes a shift in focus from simply documenting changes in cellular components to understanding how aging affects the organization of those components. “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.
Cellular function isn’t solely determined by the presence of molecular tools, but also by their arrangement. Burkewitz uses the analogy of a factory: even with all the necessary machines, efficiency depends on their strategic placement and order. “When space is limited or production demands change, the factory has to reorganize its layout to make the right products,” he explained. “If organization breaks down, production becomes very inefficient.”
The ER plays a crucial role in this cellular organization, forming a network of sheets and tubules that produce proteins and lipids while also providing structural support. Despite its importance, the structural changes within the ER during aging were previously poorly understood.
Visualizing Aging Cells in Living Organisms
Eric Donahue, PhD’25, the study’s first author and a medical student, described the research as uncovering “a whole section that hasn’t even been touched” in the aging puzzle. The research team utilized new genetic tools alongside advanced light and electron microscopy to observe these changes over time. Their work focused on the Caenorhabditis elegans worm, a commonly used model organism in aging research due to its transparency and short lifespan, allowing for direct observation of cellular changes in living animals.
Changes Within the ER During Aging
The researchers observed a significant reduction in “rough” ER, the form associated with protein production, in aging cells. Conversely, the tubular form of the ER, linked to lipid production, showed only a slight decline. This pattern aligns with known aspects of aging, such as a reduced capacity to maintain healthy proteins and metabolic shifts contributing to fat accumulation. However, the researchers note that further investigation is needed to establish direct cause-and-effect relationships.
The study also demonstrated that ER-phagy actively participates in reshaping the ER during aging. Importantly, ER-phagy was linked to lifespan, suggesting it contributes to healthier aging rather than simply being a byproduct of cellular decline.
Future Directions in Aging Research
The Burkewitz lab intends to continue investigating how different ER structures influence metabolism at both the cellular and organismal levels. Understanding how ER remodeling affects the broader cellular landscape will be a key focus. “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.”
Identifying the factors that initiate these early ER changes could potentially prevent the cascade of events leading to age-related diseases.
The research published in Nature Cell Biology in February 2026, was conducted in collaboration with researchers at Vanderbilt University and the University of Michigan and the University of California, San Diego. Funding for the study 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.
