Aging ‘hot spot’: Where the brain first starts showing signs of getting older

Scientists create cellular atlas for maturing minds in mouse model

SEATTLE — What if we could pinpoint exactly where aging begins in the brain? Scientists at the Allen Institute have done just that, creating the first detailed cellular atlas of brain aging by analyzing millions of individual cells and identifying key regions where age-related changes first emerge.

The brain is like a massive city with thousands of different neighborhoods, each populated by unique types of cells performing specific jobs. Until now, researchers haven’t had a detailed “census” showing how each neighborhood changes as the city ages. This study, published in Nature, provides exactly that, examining cells from young adult mice (2 months old) and aged mice (18 months old). While mice age differently than humans, this comparison roughly mirrors the differences between young adult and older adult human brains.

Researchers analyzed 16 different brain regions, covering about 35% of the mouse brain’s total volume. They identified 847 distinct types of cells and discovered that certain cell populations, particularly support cells called glia, were especially sensitive to aging. They found significant changes around the third ventricle in the hypothalamus, which is the brain’s master control center that regulates essential functions like hunger, body temperature, sleep, and hormone production.

As the brain ages, it shows increased immune activity across various cell types. The researchers observed this, particularly in microglia, which are specialized cells that act as the brain’s maintenance and immune defense system. They also found this in border-associated macrophages, another type of immune cell. These cells showed signs of increased inflammatory activity in aged mice, suggesting they were working harder to maintain brain health.

The research team discovered fascinating changes in specialized cells called tanycytes and ependymal cells that line fluid-filled chambers in the brain, particularly around the third ventricle.

“Our hypothesis is that those cell types are getting less efficient at integrating signals from our environment or from things that we’re consuming,” says lead author Kelly Jin, Ph.D., in a statement. This inefficiency might contribute to broader aging effects throughout the body.

The study revealed changes in cells that produce myelin, the crucial insulating material around nerve fibers. Like the protective coating around electrical wires, myelin helps neurons communicate effectively. The researchers found that aging affects these insulator-producing cells, which could impact how well brain circuits function.

Most intriguingly, the researchers identified specific groups of neurons in the hypothalamus that showed dramatic changes with age. These neurons, which help control appetite, metabolism, and energy use throughout the body, showed signs of both decreased function and increased immune activity. This finding aligns with previous research suggesting that dietary factors, like intermittent fasting or calorie restriction, might influence lifespan.

“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,” says Dr. Richard J. Hodes, director of NIH’s National Institute on Aging.

While this research was conducted in mice, the findings provide a crucial roadmap for understanding human brain aging. The identification of specific vulnerable cell types and regions gives scientists clear targets for future development of therapies to maintain brain health throughout life.