A new study published in Nature offers the most detailed map to date of how individual cell types in the brain change with age. Scientists analyzed over 1.2 million brain cells from young and aged mice and found that many specific cells undergo significant gene expression changes as animals grow older. These changes were not spread evenly throughout the brain. Instead, they clustered in a particular region: the hypothalamus, a part of the brain that helps regulate hunger, hormones, and energy balance.
While past research has identified general signs of aging—such as increased inflammation or reduced capacity for repair—it has been difficult to pinpoint which specific cell types are most affected and where in the brain these changes take place. The brain is an incredibly diverse and structured organ, with thousands of cell types performing different functions across various regions. Understanding how these cells change over time could offer clues into not only normal aging but also conditions like Alzheimer’s and Parkinson’s disease.
“Our brain consists of thousands of types of cells which carry out different functions. We study the molecular basis of the diversity of brain cell types and how the different cell types change with time (in development and aging),” said study author Hongkui Zeng, the executive vice president and director of the Allen Institute for Brain Science.
To investigate aging in the brain, the research team used an advanced technique called single-cell transcriptomics to profile the gene activity of individual cells. They examined brains from young adult mice (around two months old) and older mice (18 months old), which is roughly equivalent to middle age in humans. In total, they profiled 16 major regions across the brain, covering about 35% of its total volume. This produced a dataset of over a million high-quality brain cell transcriptomes—the most extensive single-cell brain aging dataset ever produced in mice.
By comparing gene activity in young and aged brains, the researchers identified 2,449 genes that changed with age. Many of these changes were specific to individual cell types. For example, the gene Ccnd2, which is involved in cell cycle regulation, was found to decrease in several types of neurons and glial cells. Other genes, like Oasl2 and Ifit1, which are linked to immune responses, increased in activity, especially in cells like microglia, the brain’s resident immune cells.
“Changes in these genes point to deteriorated neuronal structure and function in many neuronal and glial cell types, as well as increased immune response and inflammation in the brain’s immune and vascular (blood vessel) cell types,” Zeng told PsyPost.
One of the key takeaways was that aging does not affect all brain cells equally. Certain types of glial cells—support cells that are not neurons—were especially sensitive. These included microglia, border-associated macrophages, oligodendrocytes (which help insulate nerve fibers), ependymal cells (which help circulate cerebrospinal fluid), and tanycytes (which line the walls of the brain’s third ventricle and interact with circulating hormones and nutrients). Many of these cells showed signs of increased inflammation, altered nutrient processing, and changes in their ability to support neurons.
But perhaps the most striking finding was the discovery of a specific “hotspot” for aging-related changes in the hypothalamus. This region sits near the base of the brain and plays a central role in energy homeostasis, hormone regulation, and feeding behavior.
“A major new finding is that cell types concentrated around the third ventricle in the hypothalamus, a major interface between brain and blood for hormone and chemical exchange, exhibit especially pronounced changes in both decreased neuronal function and increased immune response,” Zeng said. “These cell types are well-known regulators of food intake and energy homeostasis. Thus, our finding suggests that the brain’s controlling center for metabolism and energy homeostasis is a hotspot for aging.”
The researchers were particularly intrigued by the role of tanycytes. These cells not only help regulate the blood-brain barrier in key regions but may also retain some ability to generate new neurons. With age, tanycytes showed reduced expression of genes involved in neurogenesis and increased expression of immune-related genes, hinting at a possible decline in the brain’s ability to regenerate itself over time.
“The most surprising finding to us is the hypothalamic cell types showing pronounced changes in genes related to both neuronal function and immune response,” Zeng explained. “These cell types are tiny populations located at the bottom of the brain and sitting at the juncture between brain and blood. These are tantalizing cell types with unique structure and function. They include the special glia cell types called tanycytes and ependymal cells lining the wall of the brain’s third ventricle and mediating the hormone and nutrient exchange with the blood.”
“They also include the adjacent special neuron types that express well-known ‘feeding neuropeptides’ AGRP and NPY, or express leptin and GLP-1 receptors that are known to be important regulators of food intake and energy homeostasis. Thus, our finding suggests a hotspot of neuroinflammation in the aging brain at the interface of brain and blood, and reveals a connection between diet, metabolism, immunity, and aging.”
In addition to these broad trends, the scientists also identified specific clusters of cells that were either more common or less common in older brains. For example, they found certain clusters of microglia that were enriched in older brains and displayed a pro-inflammatory gene activity profile, further supporting the idea of increased inflammation in the aging brain.
“Aging is the most important risk factor for many brain diseases,” Zeng told PsyPost. “Our study provides a highly detailed genetic map for which brain cell types may be most affected by aging and suggests new gene and cell targets for developing new treatments for aging-related brain diseases.”
But while the dataset provides an unprecedented view into the aging brain, the authors acknowledge some limitations. Most importantly, the study is correlational. It shows which genes change in which cell types, but it does not prove that these changes are the cause of aging or cognitive decline. Future research will be needed to test whether reversing some of these gene changes can actually alter the course of brain aging or protect against neurodegenerative diseases.
“Our study lays the groundwork by providing a detailed genetic map and potential new gene and cell targets for future studies that investigate their roles in aging and test if the reversal of the changes could delay the aging process,” Zeng explained.
The researchers also plan to extend this work to human brains. While mice share many brain features with humans, they do not develop age-related brain diseases in the same way. Nonetheless, the mouse data provides a valuable reference point for identifying vulnerable cell types and potential therapeutic targets.
“We want to understand how different types of cells in the brain change in their molecular, structural and functional properties in healthy aging and diseased conditions, in both mouse and human,” Zeng said.
“For years scientists studied the effects of aging on the brain mostly one cell at a time. Now, with innovative brain mapping tools – made possible by the NIH’s BRAIN Initiative – researchers can study how aging affects much of the whole brain,” added John Ngai, the director of The BRAIN Initiative. “This study shows that examining the brain more globally can provide scientists with fresh insights on how the brain ages and how neurodegenerative diseases may disrupt normal aging activity.”
The study, “Brain-wide cell-type-specific transcriptomic signatures of healthy ageing in mice,” was authored by Kelly Jin, Zizhen Yao, Cindy T. J. van Velthoven, Eitan S. Kaplan, Katie Glattfelder, Samuel T. Barlow, Gabriella Boyer, Daniel Carey, Tamara Casper, Anish Bhaswanth Chakka, Rushil Chakrabarty, Michael Clark, Max Departee, Marie Desierto, Amanda Gary, Jessica Gloe, Jeff Goldy, Nathan Guilford, Junitta Guzman, Daniel Hirschstein, Changkyu Lee, Elizabeth Liang, Trangthanh Pham, Melissa Reding, Kara Ronellenfitch, Augustin Ruiz, Josh Sevigny, Nadiya Shapovalova, Lyudmila Shulga, Josef Sulc, Amy Torkelson, Herman Tung, Boaz Levi, Susan M. Sunkin, Nick Dee, Luke Esposito, Kimberly A. Smith, Bosiljka Tasic, and Hongkui Zeng.