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Review
. 2025 Jan 8;113(1):2-6.
doi: 10.1016/j.neuron.2024.12.005.

Biological sex matters in brain aging

Dena B Dubal  1 , Coleen T Murphy  2 , Yousin Suh  3 , Bérénice A Benayoun  4
Affiliations
Review

Biological sex matters in brain aging

Dena B Dubal et al. Neuron. .

Abstract

Every cell in the body has a biological sex. The expansion of aging research to investigate female- and male-specific biology heralds a major advance for human health. Unraveling and harnessing mechanistic etiologies of sex differences may reveal new diagnostics and therapeutics for the aging brain.

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Conflict of interest statement

Declaration of interests D.B.D. consulted for Unity Biotechnology and SV Health Investors, serves on the board of the Glenn Foundation for Medical Research, and is an associate editor for JAMA Neurology.

Figures

Figure 1.
Figure 1.. Investigating sex differences in brain aging and cognition
Unraveling sex differences in the biology of brain aging and cognitive decline in humans and across model organisms may reveal potent and conserved targets for treatment of the human condition. Strategies to dissect sex differences include determining whether the X chromosome, the Y chromosome, estrogen, progesterone, or testosterone underlies observed differences. Genetic models of sex biology in mice dissect etiologies of sex differences. Four core genotype (FCG) mice disentangle gonadal versus sex chromosomal effects. When there is a sex chromosomal effect, the XY* mouse model discerns whether the X or the Y chromosome drives the sex difference. The aOTT model assesses how adult testosterone exposure modifies XX mice. Identifying sex differences and their etiologies can apply to studying measures such as hallmarks of aging in the brain. More broadly, cellular, molecular, electrophysiologic, circuitlevel, genetic, and epigenetic studies of the aging brain will identify targets of sex-based resilience or vulnerability. Identifying and then modulating new targets through CRISPR editing, gene therapies, small molecules, biologics, and other interventions may pave the path to new treatments for the aging brains of men, women, or both. Artwork by Elena Kakoshina.
See this image and copyright information in PMC

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