Advances in public health and medicine have enabled people to live longer than ever before. However, these additional years are often marred by poor health rather than vitality. While aging is unavoidable, it significantly increases the risk of chronic illnesses such as cancer, diabetes, and Alzheimer’s disease. Understanding why aging frequently coincides with disease is the primary focus of research led by Kris Burkewitz, assistant professor of cell and developmental biology. His team is exploring whether it is possible to decouple the biological process of aging from disease development, with the ultimate goal of helping individuals maintain health well into old age.
To achieve this, Burkewitz’s lab investigates how cells organize their internal structures, known as organelles, and how changes in these structures affect cellular performance, metabolism, and disease risk. Their recent study, published in Nature Cell Biology, unveils a newly identified method by which cells respond to aging, potentially paving the way for novel treatments targeting age-related conditions.
A New Way Cells Adapt to Aging
The study reveals that cells actively reshape the endoplasmic reticulum (ER), one of the largest and most complex structures within the cell. Contrary to previous beliefs that the ER remains static, the research shows that it undergoes controlled remodeling as organisms age. This remodeling occurs through a process called ER-phagy, where cells selectively break down specific regions of the ER. Identifying ER-phagy as part of the aging process suggests it could become a target for drugs aimed at neurodegenerative disorders and metabolic diseases.
Looking Beyond Cellular Parts to Cellular Organization
“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 depends not only on the molecular tools it contains but also on their arrangement. Burkewitz likens the cell to a factory that produces complex products, emphasizing that even if all necessary machines are present, efficiency hinges on their proper placement and order.
The ER plays a central role in this cellular organization, forming an extensive network of sheets and tubules that aids in protein and lipid production while also providing a structural framework for the rest of the cell. Despite its importance, the scientific understanding of how the ER’s structure changes with age has been limited until now.
Visualizing Aging Cells in Living Organisms
“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 study’s first author. Donahue, a medical student in the Medical Scientist Training Program, completed his doctoral research in the Burkewitz lab, focusing on ER-phagy, ER remodeling, and aging. To observe how the ER changes over time, the research team employed new genetic tools alongside advanced light and electron microscopy, studying living Caenorhabditis elegans worms, a well-established model organism for aging research. These transparent worms, with short lifespans, allow scientists to directly observe cellular changes within intact animals as they age.
What Changes Inside the ER With Age
The researchers discovered that aging cells significantly reduce the amount of “rough” ER, which is associated with protein production. In contrast, the tubular form of the ER, more closely linked to lipid or fat production, declines only slightly. This pattern aligns with known features of aging, such as a decreased ability to maintain healthy proteins and metabolic changes leading to fat accumulation in new tissues. However, further research is needed to confirm direct cause-and-effect relationships.
“ER-phagy plays an active role in reshaping the ER during aging. Importantly, ER-phagy was linked to lifespan, suggesting it contributes directly to healthier aging rather than simply reflecting cellular decline.”
What Comes Next for Aging Research
The Burkewitz lab plans to continue examining how different ER structures influence metabolism at both the cellular and whole-organism levels. Given the ER’s role in organizing numerous other cellular components, understanding how its remodeling affects the broader cellular landscape will be a crucial next step. “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.”
If researchers can pinpoint what initiates these early ER changes, they may be able to prevent the cascade of events leading to age-related disease. This research, conducted in collaboration with Vanderbilt University labs and other institutions, was supported 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, detailed in the paper “ER remodelling is a feature of ageing and depends on ER-phagy,” published in Nature Cell Biology, represent a significant advancement in the field of aging research. As scientists continue to unravel the complexities of cellular aging, the potential for developing interventions that promote healthier, longer lives remains an exciting frontier.
