As our body ages, not only joints, bones and muscles wear out, but also our nervous system. Nerve cells die, are no longer fully replaced, and the brain shrinks. “Aging is the most important risk factor for Alzheimer’s disease and many other devastating brain diseases,” says Richard Hodes of the National Institutes of Health (NIH). But what exactly happens in our minds as we age, and which parts of the brain age the fastest?

A look into the brains of young and old mice

A team led by Kelly Jin from the Allen Institute for Brain Science in Seattle has now investigated this in more detail. To do this, the neuroscientists compared what happens in the brains of two-month-old “young” and 18-month-old “old” mice. The “old” mice correspond roughly to the brain age of people in older middle age.

The researchers sequenced the RNA of a total of 1.2 million brain cells from 16 brain regions and thus mapped which genes are active in which brain region and which cell types. The tests covered about 35 percent of the entire mouse brain.

Some cells age faster

This showed that some brain cells are more sensitive and age faster than others. In the older mice, these cells showed a significantly different pattern of gene activity than in the young animals, and the contrast was stronger than in other brain cells. In total, around 2,500 genes were more or less active than at a young age, but not equally in all cells.

Most of these sensitive cell types were glial cells, known as the supporting cells of the brain. They do not transmit signals themselves, but support the neurons in transmitting signals through neurotransmitters and support structures. The cells that changed particularly strongly with age included microglia and border-associated macrophages, oligodendrocytes, tanycytes and ependymal cells, as Jin and her colleagues found.

Does altered gene activity promote inflammation and dementia?

It was striking that in these cells in the aging brain, those genes that are associated with inflammation and the immune system as well as the blood vessel cells of the brain were more active. The age-related changes could therefore promote inflammation.

On the other hand, genes related to neuronal structure and function were less active than in young brain cells. This suggests that these cells no longer adequately protect and support neurons, making it easier for neurodegenerative diseases such as dementia to occur.

“Our hypothesis is that these cell types become less efficient at integrating signals,” says Jin. “And this loss of efficiency somehow contributes to what we know as aging in the rest of our bodies.”

Aging hotspot in the hypothalamus

At a certain point in the brain, adjacent to the third ventricle of the hypothalamus, these two effects even occurred together. The third ventricle is an important pipeline through which the cerebrospinal fluid flows, exchanging hormones and nutrients between the hypothalamus and the body. According to the study, there is an aging hotspot in the aging brain where the nerve cells wear out particularly quickly.

At this turntable, the researchers also found cell types with strongly altered gene activity – including tanycytes, ependymal cells and neurons – that are important for nutrient and energy metabolism. Jin and her colleagues conclude that brain aging may also be related to diet and other lifestyle factors such as sleep. Previous studies also suggest that a balanced diet, intermittent fasting or calorie restriction can slow down the aging process of the brain.

Hope for new therapies against aging

“These results provide a very detailed map of which brain cells may be most affected by aging,” Hodes says. “This new map could fundamentally change the way scientists think about how aging affects the brain, and also provides guidance for developing new treatments for age-related brain diseases.”

In particular, the aging hotspot in the hypothalamus is now to be researched in more detail in follow-up studies. Together with the knowledge of which cell types need to be specifically treated, this could lead to the development of new drugs and nutritional strategies that delay the aging process, maintain the function of nerve cells and prevent Alzheimer’s and Co. The knowledge could therefore help to maintain brain health into old age. (Nature, 2025; doi: 10.1038/s41586-024-08350-8)

Sources: Allen Institutes, NIH

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