Advances in public health and medicine have contributed to people living longer than ever before. However, these extra years of life are often characterized by poor health rather than vitality. While aging is inevitable, it significantly increases the risk of many chronic diseases, including cancer, diabetes and Alzheimer’s disease.
Understanding why aging is so often associated with disease is the focus of the lab led by Kris Burkewitz, assistant professor of cell and developmental biology. His team is investigating whether it is possible to separate the biological process of ageing from the development of disease, with the aim of helping people stay healthy into old age. To this end, the laboratory is investigating how cells organize their internal structures, known as organelles, and how changes in these structures influence cell performance, metabolism and the risk of disease.
A New Way for Cells to Adapt to Ageing
In a recent study published in Nature Cell Biology, Burkewitz and his colleagues describe a newly discovered way in which cells respond to aging. Their research shows that cells actively remodel the endoplasmic reticulum (ER), one of the largest and most complex structures within the cell. Instead of remaining static, the ER undergoes a controlled remodeling process as the organism ages.
The team discovered that this remodeling occurs through a process called ER phagy. During ER phagy, cells selectively degrade certain areas of the ER. The identification of ER phagy as part of the ageing process suggests that it could one day become a target for drugs against age-related diseases, including neurodegenerative disorders and metabolic diseases.
Beyond Cell Components to Cell Organization
“While many previous studies have documented how the concentrations of various cellular machineries change with age, we are instead focusing on how aging affects the way cells house and organize these machineries within their complex internal architecture,” Burkewitz said.
How well a cell functions depends not only on what molecular tools it contains, but also on how these tools are arranged. Burkewitz compares the cell to a factory that produces many complicated products. Even if all the machines required for production are present, efficiency depends on these machines being in the right places and in the right order. “If space is limited or production requirements change, the factory has to reorganize its layout to make the right products,” Burkewitz says. “If the organization breaks down, production becomes very inefficient.”
The ER plays a central role in this cellular organization. It forms an extensive network of sheets and tubules that helps in the production of proteins and lipids while serving as a structural scaffold for the rest of the cell. Despite its importance, scientists have had limited understanding of how the structure of the ER changes as animals age.
Visualization of Aging Cells in Living Organisms
“We didn’t just add a piece to the puzzle of aging – we found an entire section that hadn’t even been touched before,” said Eric Donahue, PhD’25, the study’s first author. Donahue is a medical student in the Medical Scientist Training Program and completed his PhD in the Burkewitz lab, where he studied ER phagy, ER remodeling and aging.
To observe how the ER changes over time, the research team used new genetic tools as well as advanced light and electron microscopy. They studied living Caenorhabditis elegans worms, an established model organism for aging research. These worms are transparent and have a short lifespan, allowing scientists to directly observe cellular changes inside intact animals during the ageing process.
What Changes in the ER With Increasing Age
The researchers found that ageing cells significantly reduce the amount of “rough” ER, the form associated with protein production. In contrast, the tubular form of ER, which is more closely associated with lipid or fat production, decreases only slightly. This pattern is consistent with known features of aging, such as a reduced ability to maintain healthy proteins and metabolic changes that contribute to fat accumulation in new tissues. However, further research is needed to confirm direct cause-and-effect relationships.
The study also showed that ER phagy plays an active role in ER remodeling during the aging process. Importantly, ER phagy was associated with lifespan, suggesting that it directly contributes to healthier aging rather than simply reflecting cellular decline.
What’s Next in Aging Research?
The Burkewitz lab plans to continue investigating how different ER structures affect metabolism at both the cellular and organismal levels. Since the ER contributes to the organization of many other components within the cell, understanding how its remodeling affects the overall cellular landscape will be an important next step. “Changes in the ER occur relatively early in the aging process. One of the most exciting implications of this is that it could be one of the triggers for what comes later: dysfunction and disease. If researchers can identify exactly what triggers these early changes in the ER, they could potentially prevent the cascade of events that leads to age-related diseases.