Biological sex matters in brain aging

doi:10.1016/j.neuron.2024.12.005

Review

. 2025 Jan 8;113(1):2-6.

doi: 10.1016/j.neuron.2024.12.005.

Biological sex matters in brain aging

Dena B Dubal¹, Coleen T Murphy², Yousin Suh³, Bérénice A Benayoun⁴

Affiliations

¹ Department of Neurology and Weill Institute for Neurosciences, University of California San Franciso, San Francisco, CA, USA; Bakar Aging Research Institute, University of California San Franciso, San Francisco, CA, USA. Electronic address: dena.dubal@ucsf.edu.
² Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA; Department of Molecular Biology, Princeton University, Princeton, NJ, USA. Electronic address: ctmurphy@princeton.edu.
³ Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: ys3214@cumc.columbia.edu.
⁴ Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA; Molecular and Computational Biology Department, USC Dornsife College of Letters, Arts and Sciences, Los Angeles, CA, USA; Biochemistry and Molecular Medicine Department, USC Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA; USC Stem Cell Initiative, Los Angeles, CA, USA. Electronic address: bbenayou@usc.edu.

PMID: 39788086
PMCID: PMC12210274
DOI: 10.1016/j.neuron.2024.12.005

Review

Biological sex matters in brain aging

Dena B Dubal et al. Neuron. 2025.

. 2025 Jan 8;113(1):2-6.

doi: 10.1016/j.neuron.2024.12.005.

Authors

Dena B Dubal¹, Coleen T Murphy², Yousin Suh³, Bérénice A Benayoun⁴

Affiliations

¹ Department of Neurology and Weill Institute for Neurosciences, University of California San Franciso, San Francisco, CA, USA; Bakar Aging Research Institute, University of California San Franciso, San Francisco, CA, USA. Electronic address: dena.dubal@ucsf.edu.
² Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA; Department of Molecular Biology, Princeton University, Princeton, NJ, USA. Electronic address: ctmurphy@princeton.edu.
³ Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: ys3214@cumc.columbia.edu.
⁴ Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA; Molecular and Computational Biology Department, USC Dornsife College of Letters, Arts and Sciences, Los Angeles, CA, USA; Biochemistry and Molecular Medicine Department, USC Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA; USC Stem Cell Initiative, Los Angeles, CA, USA. Electronic address: bbenayou@usc.edu.

PMID: 39788086
PMCID: PMC12210274
DOI: 10.1016/j.neuron.2024.12.005

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.. 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.

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Cited by

Aging activates escape of the silent X chromosome in the female mouse hippocampus.
Gadek M, Shaw CK, Abdulai-Saiku S, Saloner R, Marino F, Wang D, Bonham LW, Yokoyama JS, Panning B, Benayoun BA, Casaletto KB, Ramani V, Dubal DB. Gadek M, et al. Sci Adv. 2025 Mar 7;11(10):eads8169. doi: 10.1126/sciadv.ads8169. Epub 2025 Mar 5. Sci Adv. 2025. PMID: 40043106 Free PMC article.

References

1. Arnold AP, Klein SL, McCarthy MM, and Mogil JS (2024). Male-female comparisons are powerful in biomedical research - don’t abandon them. Nature 629, 37–40. 10.1038/d41586-024-01205-2. - DOI - PubMed
1. Zucker I, and Prendergast BJ (2020). Sex differences in pharmacokinetics predict adverse drug reactions in women. Biol. Sex Differ. 11, 32. 10.1186/s13293-020-00308-5. - DOI - PMC - PubMed
1. Marino F, Wang D, Merrihew GE, MacCoss MJ, and Dubal DB (2024). A second X chromosome improves cognition in aging male and female mice. Preprint at bioRxiv. 10.1101/2024.07.26.605328. - DOI
1. Cheng CJ, Gelfond JAL, Strong R, and Nelson JF (2019). Genetically heterogeneous mice exhibit a female survival advantage that is age- and site-specific: Results from a large multi-site study. Aging Cell 18, e12905. 10.1111/acel.12905. - DOI - PMC - PubMed
1. Goyal MS, Blazey TM, Su Y, Couture LE, Durbin TJ, Bateman RJ, Benzinger TLS, Morris JC, Raichle ME, and Vlassenko AG (2019). Persistent metabolic youth in the aging female brain. Proc. Natl. Acad. Sci. USA 116, 3251–3255. 10.1073/pnas.1815917116. - DOI - PMC - PubMed

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[1] Arnold AP, Klein SL, McCarthy MM, and Mogil JS (2024). Male-female comparisons are powerful in biomedical research - don’t abandon them. Nature 629, 37–40. 10.1038/d41586-024-01205-2. - DOI - PubMed

[2] Arnold AP, Klein SL, McCarthy MM, and Mogil JS (2024). Male-female comparisons are powerful in biomedical research - don’t abandon them. Nature 629, 37–40. 10.1038/d41586-024-01205-2. - DOI - PubMed

[3] Zucker I, and Prendergast BJ (2020). Sex differences in pharmacokinetics predict adverse drug reactions in women. Biol. Sex Differ. 11, 32. 10.1186/s13293-020-00308-5. - DOI - PMC - PubMed

[4] Zucker I, and Prendergast BJ (2020). Sex differences in pharmacokinetics predict adverse drug reactions in women. Biol. Sex Differ. 11, 32. 10.1186/s13293-020-00308-5. - DOI - PMC - PubMed

[5] Marino F, Wang D, Merrihew GE, MacCoss MJ, and Dubal DB (2024). A second X chromosome improves cognition in aging male and female mice. Preprint at bioRxiv. 10.1101/2024.07.26.605328. - DOI

[6] Marino F, Wang D, Merrihew GE, MacCoss MJ, and Dubal DB (2024). A second X chromosome improves cognition in aging male and female mice. Preprint at bioRxiv. 10.1101/2024.07.26.605328. - DOI

[7] Cheng CJ, Gelfond JAL, Strong R, and Nelson JF (2019). Genetically heterogeneous mice exhibit a female survival advantage that is age- and site-specific: Results from a large multi-site study. Aging Cell 18, e12905. 10.1111/acel.12905. - DOI - PMC - PubMed

[8] Cheng CJ, Gelfond JAL, Strong R, and Nelson JF (2019). Genetically heterogeneous mice exhibit a female survival advantage that is age- and site-specific: Results from a large multi-site study. Aging Cell 18, e12905. 10.1111/acel.12905. - DOI - PMC - PubMed

[9] Goyal MS, Blazey TM, Su Y, Couture LE, Durbin TJ, Bateman RJ, Benzinger TLS, Morris JC, Raichle ME, and Vlassenko AG (2019). Persistent metabolic youth in the aging female brain. Proc. Natl. Acad. Sci. USA 116, 3251–3255. 10.1073/pnas.1815917116. - DOI - PMC - PubMed

[10] Goyal MS, Blazey TM, Su Y, Couture LE, Durbin TJ, Bateman RJ, Benzinger TLS, Morris JC, Raichle ME, and Vlassenko AG (2019). Persistent metabolic youth in the aging female brain. Proc. Natl. Acad. Sci. USA 116, 3251–3255. 10.1073/pnas.1815917116. - DOI - PMC - PubMed

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Biological sex matters in brain aging

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Biological sex matters in brain aging

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