"Aging hotspot" found in the brain may hold the key to longevity

Researchers at the Allen Institute have identified a specific brain region in mice where aging triggers significant changes in numerous cell types. The study also pinpointed which cell types undergo the most profound transformations

This new information, published in the journal Nature, points toward potential approaches for slowing or controlling the aging process in the brain.

The research was focused on numerous glial cell types – the brain’s “support cells” – that demonstrated considerable shifts in gene activity with age. Among the cells most affected were microglia, border-associated macrophages, oligodendrocytes, tanycytes, and ependymal cells. 

The study showed that, in aging brains, the activity of genes linked to inflammation rose, while the activity of genes important for neurons decreased.

Aging hotspot identified in the brain

The researchers discovered a concentration of these changes in an “aging hotspot,” located in the hypothalamus. 

The most significant gene expression changes were discovered in cell types located near the third ventricle of the hypothalamus.

The cells include tanycytes, ependymal cells, and neurons with an important role in food intake, energy homeostasis, metabolism, and how our bodies use nutrients. 

This observation hints at a connection between diet, lifestyle factors, brain aging, and changes that influence susceptibility to age-related brain disorders.

“Our hypothesis is that those cell types are getting less efficient at integrating signals from our environment or from things that we’re consuming,” said study lead author Kelly Jin, a scientist at the Allen Institute for Brain Science. 

“And that loss of efficiency somehow contributes to what we know as aging in the rest of our body. I think that’s pretty amazing, and I think it’s remarkable that we’re able to find those very specific changes with the methods that we’re using.”

Analyzing millions of brain cells

The experts employed advanced single-cell RNA sequencing and high-resolution mapping methods created through The BRAIN Initiative®. 

The team analyzed over 1.2 million brain cells taken from mice at two months of age (classified as “young”) and 18 months of age (considered by researchers to be “late middle-aged”). 

Mice share critical structural, functional, and genetic features with humans, making them useful for studying how the brain evolves over time.

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

“This new map may fundamentally alter the way scientists think about how aging affects the brain and also provides a guide for developing new treatments for aging-related brain diseases.”

How will this study help?

The researchers found that particular clusters of cell types in the hypothalamus had a meaningful drop in the genes essential for neuron functioning, while the genes involved in inflammation rose in activity. 

The experts reasoned that examining this hotspot and these cell types more closely could lead to targeted interventions.

“We want to develop tools that can target those cell types,” said Hongkui Zeng, the executive vice president and director of the Allen Institute for Brain Science. “If we improve the function of those cells, will we be able to delay the aging process?”

Lifestyle factors in brain aging

These data support earlier links between aging and metabolic changes, along with evidence suggesting that intermittent fasting or a balanced diet might influence longevity. 

While the study did not test dietary patterns directly, it highlights the importance of understanding which brain cells may be “players” in the aging process.

“It’s not something we directly tested in this study,” said Jin. “But to me, it points to the potential players involved in the process, which I think is a huge deal because this is a very specific, rare population of neurons that express very specific genes that people can develop tools for to target and further study.”

Preventing age-related brain decline

The study provides a starting point for deeper inquiries into how diet, lifestyle, or pharmaceuticals might alleviate or slow age-related declines in brain health.

By tracking the most vulnerable cell types, researchers hope to devise strategies – whether dietary or pharmaceutical – that help maintain healthy brain function well into old age.

“The important thing about our study is that we found the key players – the real key players – and the biological substrates for this process,” Zeng said. 

“Putting the pieces of this puzzle together, you have to find the right players. It’s a beautiful example of why you need to study the brain and the body at this kind of cell type-specific level.” 

“Otherwise, changes happening in specific cell types could be averaged out and undetected if you mix different types of cells together.”

As scientists probe further into the link between these specific cells and the hypothalamic region, this line of research sets the stage for developing new methods aimed at preserving cognitive abilities and forestalling age-related diseases. 

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