Detailed mapping of 1.2 million brain cells has revealed that not all cell types age in the same way and that some – found in a specific ‘hot spot’ – are more sensitive to the aging process. It opens the door to developing new treatments for age-related brain diseases.
As we age, various cells and tissues accumulate damage. While it’s a natural process, it means that our biological age can differ from our chronological age. Understanding the cellular changes accompanying biological aging puts us a step closer to slowing or managing the aging process.
In a new study into brain aging, scientists from the Allen Institute for Brain Science in Seattle identified specific cell types that change as they age, as well as discovering a ‘hot spot’ where many of these changes occur.
“Our hypothesis is that those cell types are getting less efficient at integrating signals from our environment or from things that we’re consuming, and that loss of efficiency somehow contributes to what we know as aging in the rest of our body,” said Kelly Jin, PhD, a scientist at the Allen Institute and the study’s lead author. “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 we’re using.”
Jin and colleagues used cutting-edge single-cell RNA sequencing and advanced brain-mapping tools developed through the National Institutes of Health’s (NIH) The BRAIN Initiative to map roughly 1.2 million individual brain cells from young adult and aged mice of both sexes. The ‘aged’ mice were 18 months old, which in human years equates to between mid-50s and late-60s, or late middle age. Mouse brains were chosen because of their similarity to human brains in structure, function, genes, and cell types.
The researchers mapped cells across 16 broad brain regions – about 35% of the total volume of a mouse brain – chosen because of their known sensitivity to age-related diseases. Their approach allowed the researchers to identify the cells’ unique transcriptomics (the collection of all RNA present in a cell at a given time) and examine them for age-related changes to gene expression.
“For years, scientists studied the effects of aging on the brain mostly one cell at a time,” said John Ngai, PhD, director of The BRAIN Initiative. “Now, with innovative 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.”
The researchers found that it was mostly glial cells, a class of cells that support, connect, and protect the brain’s neurons, that showed significant age-related changes to gene expression. Strongly affected were immune system-related cells (microglia, oligodendrocytes, and border-associated macrophages (BAMs)) and specialized glial cells called tanycytes and ependymal cells. Tanycytes are found in the hypothalamus, primarily lining the third ventricle (see below). They’re highly unique, serving as both structural and functional barriers between the brain and cerebrospinal fluid (CSF). Ependymal cells line the spinal cord and the brain’s ventricles, the cavities that produce and store CSF, and are essential for maintaining a stable environment in these structures, ensuring that neurons and other cells function optimally.
Specifically, the researchers found increased expression of inflammatory and immune response genes in these cells and decreased expression of genes relating to neuron signaling and structure. The most significant changes were in cells near the hypothalamus’ third ventricle (V3), critical to regulating vital physiological and behavioral processes, including temperature, hunger and satiety, thirst and fluid balance, sleep-wake cycles, and circadian rhythms.
“Taken together, our results systematically reveal a wide range of cell-type-specific patterns of aging, identify age-specific cell-type clusters that show unique gene expression changes and highlight the V3 area of the hypothalamus as a potential hot spot for brain aging,” said the researchers.
The researchers hope their findings lead to further research into this newly discovered hot spot and, potentially, the development of therapeutics that slow or manage brain aging and prevent neurodegenerative disease.
“Aging is the most important risk factor for Alzheimer’s disease and many other devastating brain disorders,” said Richard Hodes, MD, the director of the NIH’s National Institute on Aging but not involved in the study. “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.”
The study was published in the journal Nature.
