Persistent metabolic youth in the aging female brain

Prior work has identified many sex differences in the brain, including during brain aging and in neurodegenerative diseases. Notably, many of these studies are performed by comparing age-matched females and males. Evolutionary theorists have predicted that females might have more youthful brains (neoteny) as compared with males, but until now findings in support of this theory have been limited to postmortem transcriptional analysis, some of which is contradictory. To test this hypothesis in vivo, we analyzed sex differences in a unique brain PET dataset in over 200 normal human adults across the adult life span. We find that in terms of brain metabolism, the adult female brain is on average a few years younger than the male brain.

Abstract

Sex differences influence brain morphology and physiology during both development and aging. Here we apply a machine learning algorithm to a multiparametric brain PET imaging dataset acquired in a cohort of 20- to 82-year-old, cognitively normal adults (n = 205) to define their metabolic brain age. We find that throughout the adult life span the female brain has a persistently lower metabolic brain age—relative to their chronological age—compared with the male brain. The persistence of relatively younger metabolic brain age in females throughout adulthood suggests that development might in part influence sex differences in brain aging. Our results also demonstrate that trajectories of natural brain aging vary significantly among individuals and provide a method to measure this.

Human brain aging is characterized by varying trajectories. Some individuals succumb to rapid cognitive decline, whereas other individuals retain their cognitive abilities as they age beyond the typical human life span. Accordingly, it is important to understand the factors that influence brain aging, particularly in the context of an aging population. In humans, normal aging is associated with a decline in brain metabolism (1⇓⇓–4). Our recent multitracer PET brain imaging data demonstrate that as the brain ages, its resting metabolism gradually shifts away from a mixture of nonoxidative and oxidative use of glucose to predominantly oxidative metabolism (4, 5). This occurs even in a cognitively normal, amyloid-negative cohort, suggesting that neurodegeneration alone is unlikely to explain this metabolic shift. However, the reasons for this metabolic brain aging phenomenon are currently unknown.

Full article: PNAS

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