Aging is the biggest risk factor for developing sporadic Alzheimer’s disease. But the changes that take place in the human brain as we age, leading to increased risk, remain largely unknown. A new investigation set out to identify the molecular underpinnings that occur in the aging brain. As a result, it was discovered that previously unsuspected regions of the brain are more vulnerable to aging, and two anti-aging treatments can rejuvenate the brain in unexpected ways.

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The use of magnetic resonance imaging (MRI) has revealed that the human brain does not age uniformly. While these imaging studies provide a broad view of structural changes in the brain, they do not reveal the molecular underpinning of the aging process. Instead, understanding how gene activity changes—which genes are turned on or off—may be a better indicator of how the brain ages.

To gain systematic insight, the researchers in this study developed a workflow to assess gene activity changes across the whole brain of male and female mice, resulting in the most comprehensive atlas of the aging brain. Fifteen regions in both brain hemispheres were studied in mice, whose ages were equivalent to 20–80 human years. A set of 82 genes whose activity changed over time across all regions was identified, and this common aging signature was compared across different regions as the mice aged. The set included an increase in activity of genes regulating inflammation, and a drop in that of genes regulating protein quality control.

Comparing the common aging signature across brain regions revealed that certain regions were more vulnerable to aging, while others remained relatively unchanged. The earliest and strongest gene activity changes occurred in regions rich in white matter, such as the corpus callosum and cerebellum, two areas often overlooked in the research of aging. These changes were observed in mice whose age was equivalent to a person in their 50s. Roughly half of the brain is composed of white matter, which plays a crucial role in transmitting signals across the brain and primarily is made up of myelinated nerve fibers. White matter vulnerability to aging is a new discovery, challenging previous focus on grey matter-rich regions, like the cortex or hippocampus, whose aging was slower in comparison (grey matter contains the brain’s neuronal cell bodies).

The study also revealed that aging impacts cells in the brain differently based on their location. Glial cells, which play a role in inflammation, had the strongest changes of the common aging signature throughout the brain, with white matter glia aging more rapidly than their cortical counterparts. This highlights the possibility that white matter glial cells may be driving overall brain aging. Meanwhile, neurons showed region-specific aging signatures, reflective of the neurons and regions’ functional roles.

Designed to understand how aging may be reversed at the molecular level, the study also included the testing of two interventions. The first was a dietary intervention of caloric reduction over a four-week period. The second was the injection of plasma from young mice into older mice. While both interventions have been proposed to redress aging, they had very different effects on gene activity across various brain regions, suggesting that multiple potential pathways to redress aging could be in play. Results showed that the dietary intervention activated genes linked to circadian rhythms across the whole brain, an observation that is in line with prior research suggesting that the effects of caloric reduction on longevity may depend on the timing of food intake. In contrast, the plasma intervention had a direct effect on the common aging signature, and reversed it in several different brain regions.

The study also examined whether genes linked to disease also changed in region-specific ways with aging. The results revealed that the activity of the APOE gene (whose APOE4 variant is the strongest genetic risk factors for sporadic AD) changed most profoundly with age regions not unusually associated with AD. “The region-specific differential regulation of such genes could be an additional factor modulating disease risk,” the authors wrote.

In summary, the findings of the research suggest that regions of the brain age differently on the molecular level. This provides insights into why certain regions of the brain are more susceptible to disease, and provides a valuable resource for future discovery of targets for novel Alzheimer’s therapeutics. An outcome of the study is available to the entire science community and includes an online interactive data visualization resource of the results to facilitate future scientific advancements. 

Published in Cell:

Atlas of the Aging Mouse Brain Reveals White Matter as Vulnerable Foci

Tony Wyss-Coray, Ph.D., Stanford University