Unlocking the Secrets of Brain Aging: New Discoveries on Cellular Damage Behind the Years

Key Insights

• Vulnerable cells: Researchers uncovered various specific cell types, primarily glial cells, recognized as brain support cells, that experienced notable gene expression alterations with aging. The most affected included microglia and border-associated macrophages, oligodendrocytes, tanycytes, and ependymal cells.
• Inflammation and neuronal safeguarding: In aging brains, there was an increase in gene activity linked to inflammation, while those tied to neuronal structure and function showed a decline.
• Aging hot spot: Investigators identified a particular area combining both the decline in neuronal function and the rise in inflammation in the hypothalamus. Significant gene expression alterations were noted in cell types near the third ventricle of the hypothalamus, comprising tanycytes, ependymal cells, and neurons recognized for their involvement in food intake, energy balance, metabolism, and nutrient utilization. This suggests a potential connection between diet, lifestyle factors, brain aging, and changes that could impact our vulnerability to age-related brain disorders.

“Our hypothesis is that those cell types are becoming less adept at processing signals from our environment or from what we ingest,” stated Kelly Jin, Ph.D., a scientist at the Allen Institute for Brain Science and the study’s leading author. “And that decline in efficiency somehow contributes to what we perceive as aging in the rest of our body. I find that quite remarkable, and it’s impressive that we can identify those specific changes using the methods we are employing.”

To carry out the study, funded by the National Institutes of Health (NIH), researchers utilized advanced single-cell RNA sequencing and sophisticated brain mapping technologies developed through NIH’s The BRAIN Initiative® to map over 1.2 million brain cells from both young (two months old) and aged (18 months old) mice across 16 extensive brain regions. The aged mice are considered equivalent to late middle-aged humans. Mouse brains exhibit numerous similarities to human brains concerning structure, function, genes, and cell types.

“Aging is the primary risk factor for Alzheimer’s disease and various other devastating brain disorders. These findings offer a highly detailed mapping of which brain cells might be most affected by aging,” commented Richard J. Hodes, M.D., director of NIH’s National Institute on Aging. “This novel map may fundamentally reshape how scientists understand the impact of aging on the brain and also serves as a guide for developing new treatments for aging-related brain diseases.”

A pathway to new treatments

Understanding this specific area within the hypothalamus makes it a key point for future investigations. Along with identifying which cells to target, this could facilitate the creation of age-related therapeutics, aiding in the preservation of function and the prevention of neurodegenerative diseases.

“We aspire to develop tools that can specifically focus on those cell types,” said Hongkui Zeng, Ph.D., executive vice president and director of the Allen Institute for Brain Science. “If we enhance the functionality of those cells, will we be able to slow down the aging process?”

The recent findings also correlate with earlier research linking aging to metabolic changes, as well as studies suggesting that intermittent fasting, balanced diets, or calorie restriction can influence or possibly extend lifespan.

“It’s not something we explicitly tested in this study,” explained Jin. “But to me, it highlights the potential entities involved in the process, which I consider a significant matter because this represents a very specific, rare population of neurons that express highly specific genes that researchers can develop tools for to target and investigate further.”

Future research on brain aging

This research establishes a foundation for new strategies in diet and therapeutic methods aimed at preserving brain health into old age, alongside further exploration of the intricacies of advanced aging in the brain. As scientists delve deeper into these connections, research may unveil more specific dietary or pharmacological interventions to combat or slow aging at a cellular level.

“The crucial aspect of our study is that we identified the key players — the genuine key players — and the biological foundations for this process,” remarked Zeng. “To piece together this puzzle, it is essential to identify the right players. It exemplifies why studying the brain and body at this cell type-specific level is necessary. Otherwise, alterations occurring in particular cell types could be averaged out and overlooked if different types of cells are mixed together.”

This research was supported by NIH grants R01AG066027 and U19MH114830. The content solely reflects the authors’ perspectives and does not necessarily represent the official views of the National Institutes of Health.