Uncovering the Cellular Mechanisms of Brain Aging

Not all brain cell types age in the same way, according to new brain mapping research supported by the National Institutes of Health (NIH). Researchers discovered that certain cells may experience more age-related changes in genetic activity than others, such as a tiny subset of hormone-controlling cells.

The findings, which were published in Nature, lend credence to the notion that certain cells are more susceptible than others to the aging process and aging-related brain disorders.

Aging is the most important risk factor for Alzheimer’s disease and many other devastating brain disorders. These results provide a highly detailed map for which brain cells may be most affected by aging. This new map may fundamentally alter the way scientists think about how aging affects the brain and also provide a guide for developing new treatments for aging-related brain diseases.”

Richard J. Hodes, M.D., Director, National Institutes of Health

Researchers examined individual cells in the brains of 2-month-old “young” and 18-month-old “aged” mice using sophisticated genetic analysis tools. Researchers examined the genetic activity of several cell types spread across 16 broad regions, which make up 35% of the mouse brain's total volume, for each age.

Similar to earlier research, the preliminary findings indicated a decline in the activity of genes linked to neural circuits.

The main circuitry cells, neurons, as well as “glial” cells known as astrocytes and oligodendrocytes, which can support neural signaling by regulating neurotransmitter levels and electrically insulating nerve fibers, were observed to have decreased. On the other hand, genes linked to the brain's inflammatory and immune systems, as well as brain blood vessel cells, became more active with age.

The cell types that might be most susceptible to aging were identified through additional analysis. According to the findings, aging slows the growth of new neurons in at least three distinct brain regions. Some of these newborn neurons may be involved in the circuitry that governs certain types of learning and memory, while others may aid mice in identifying various scents, according to earlier research.

The third ventricle, a significant conduit that allows cerebrospinal fluid to flow through the hypothalamus, is surrounded by the cells that seem to be most susceptible to aging. The hypothalamus, which is situated at the base of the mouse brain, generates hormones that regulate the body's basic requirements, such as hunger, thirst, sleep, heart rate, and temperature.

The results revealed that cells lining the third ventricle, along with neighboring neurons in the hypothalamus, exhibited the most significant age-related changes in genetic activity. These included increased expression of immunity-related genes and decreased expression of genes associated with neuronal circuitry.

These findings, according to the authors, are consistent with earlier research on several different animals that demonstrated connections between aging and bodily metabolism, such as the ability of intermittent fasting and other calorie-restricting diets to lengthen life span.

In particular, the ventricle-lining cells regulate the flow of hormones and nutrients between the brain and the body, while the age-sensitive neurons in the hypothalamus are known to generate hormones that regulate feeding and energy. To investigate the biological processes behind the results and look for any potential connections to human health, more investigation is required.

Kelly Jin, Ph.D., Bosiljka Tasic, Ph.D., and Hongkui Zeng, Ph.D., from the Allen Institute for Brain Science in Seattle, spearheaded the project. The researchers examined over 1.2 million brain cells, or roughly 1% of all brain cells, from young and old mice using brain mapping tools created as part of the NIH's Brain Research Through Advancing Innovative Neurotechnologies^® (BRAIN) Initiative-Cell Census Network (BICCN).

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 BRAIN Initiative – researchers can study how aging affects much of the whole brain. 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.”

John Ngai, Ph.D., Director, The BRAIN Initiative^®