Improvements in public health and medicine have enabled people to live to older ages than at any other point in human history. However, these added years are often accompanied by declining health rather than prolonged vitality. Ageing itself is unavoidable, but it is closely linked to a sharp rise in chronic illnesses, including cancer, diabetes, and Alzheimer’s disease. As a result, many individuals spend their later years managing disease rather than enjoying the benefits of a longer lifespan. This growing gap between lifespan and healthspan has become one of the central challenges of modern biomedical research.
The laboratory led by Kris Burkewitz, an assistant professor of cell and developmental biology, is working to address this challenge by asking whether the biological links between ageing and disease can be weakened or even broken. The goal is not to stop ageing altogether, but to preserve health for as long as possible, allowing people to remain active and independent later in life. To pursue this aim, the Burkewitz lab studies how cells organise their internal compartments, known as organelles, and how the structure and arrangement of these compartments shape cellular function, metabolism, and vulnerability to disease.
In a recent paper published in Nature Cell Biology, Burkewitz and his colleagues describe a previously unrecognised way in which cells adapt to ageing. Their work shows that cells actively remodel the endoplasmic reticulum, or ER, one of the largest and most complex organelles in the cell. This remodelling occurs through a process called ER-phagy, in which specific regions of the ER are selectively broken down and recycled. The discovery that ER-phagy plays a role in ageing suggests that this process is a promising target for future therapies aimed at age-related conditions, including neurodegenerative and metabolic diseases.
Previous studies of ageing have largely focused on how the levels of different cellular components change over time. In contrast, the Burkewitz lab is interested in how ageing alters the spatial organisation of these components within the crowded interior of the cell. The efficiency of cellular metabolism depends not only on which molecular machines are present, but also on where they are located and how they interact. Burkewitz compares this to a factory filled with specialised equipment: even if all the machines are available, production only runs smoothly when they are arranged in the correct order and position. When space is limited, or demands change, reorganisation becomes essential, and when organisation fails, efficiency rapidly declines.
The ER plays a central role in this internal organisation. It is a sprawling network of sheets and tubules that functions as a major site for protein and lipid production while also acting as a structural scaffold for other organelles. Despite its importance, little was previously known about how the ER changes as organisms age. Using advanced genetic tools and high-resolution light and electron microscopy, the research team was able to observe the ER inside living cells of ageing Caenorhabditis elegans worms, a powerful model organism for ageing research due to its transparency and short lifespan.
These observations revealed that ageing cells undergo striking changes in ER structure. As animals grow older, the amount of rough ER, which is involved in protein production, decreases substantially, while the tubular ER associated with lipid metabolism is far less affected. The team also demonstrated that ER-phagy actively drives this remodelling and is linked to lifespan and healthy ageing. Looking ahead, the Burkewitz lab aims to understand how early changes in ER structure influence the organisation of other cellular compartments and whether these alterations act as triggers for later dysfunction and disease. Identifying such triggers could open the door to interventions that preserve health deep into old age, offering the prospect of longer lives that are not only extended, but truly lived well.
More information: Eric Donahue et al, ER remodelling is a feature of ageing and depends on ER-phagy, Nature Cell Biology. DOI: 10.1038/s41556-025-01860-1
Journal information: Nature Cell Biology Provided by Vanderbilt University
