Explore how the interplay of biology and gender reveals untapped pathways to fight cognitive decline and foster healthier, sharper minds as we age.
Study: Biological sex matters in brain aging. Image Credit: Orawan Pattarawimonchai / Shutterstock
In a recent study published in the journal Neuron, a team of researchers in the United States investigated the mechanisms that govern male and female differences in cognitive resilience and decline to understand the influence of biological sex on aging. By analyzing genetic, hormonal, and cellular factors across model organisms and humans, they aimed to obtain insights into sex-specific vulnerabilities and resilience in brain health during aging.
Background
Aging affects every human brain, but the processes and outcomes often differ significantly between males and females. Women generally live longer than men and may show greater resilience in cognitive aging, with slower biological aging and better performance in baseline memory and verbal fluency. These advantages are believed to be associated with hormonal influences, chromosomal differences, and metabolic factors.
Previous studies have highlighted the role of the X chromosome and epigenetic patterns in contributing to this resilience. However, significant gaps remain in understanding the precise mechanisms underlying these sex-based differences. The study also emphasizes the “Pink Box Warning” concept, which advocates for highlighting potential differences in drug efficacy and side effects between sexes to enable informed medical decisions.
Additionally, the paper underscores how societal and gendered experiences, such as caregiving stress and occupational stress, may interact with biological sex to influence brain aging.
This gap is also exacerbated by historical biases in research, which favor male participants and exclude sex-specific analyses. Recent advancements in diagnostic tools, genetic studies, and cross-species models have provided new opportunities to explore these differences.
The authors argue that addressing these biases could prevent further disparities in healthcare and provide more equitable solutions for brain health in aging populations. Moreover, understanding the biological basis of sex differences in brain aging could help develop targeted interventions and address important problems in aging and neurodegenerative disease research.
About the Study
The present study utilized human data, genetic analyses, and model organisms to investigate sex-based differences in brain aging. The studies involving humans consisted of longitudinal assessments of cognitive performance, imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI), and biomarker analysis to track metabolic, epigenetic, and structural brain changes.
The key metrics used by the researchers included brain glucose metabolism, deoxyribonucleic acid (DNA) methylation patterns, and structural aging indicators across sexes.
In the animal model investigations, the researchers employed Caenorhabditis elegans, a species of nematodes or roundworms that has extensively been used as a model organism in biological studies, to examine neural resilience and cognitive aging, comparing male worms (with XO sex chromosomes) and hermaphrodite worms (with XX sex chromosomes).
Additionally, the researchers also used mouse models. They employed various genetic tools, including the Four Core Genotypes and XY models, to disentangle the contributions of sex chromosomes and gonadal hormones to brain aging. The study introduced advanced genetic techniques like clustered regularly interspaced short palindromic repeats (CRISPR) editing to precisely modulate specific targets and better understand sex differences in aging.
The study also included an adult somatic sex reprogramming genetic model called the aOTT model, where somatic cells from adult ovaries were reprogrammed into testes to investigate the impact of testosterone exposure in XX females and understand the hormonal influences on cognitive resilience.
Cross-species comparisons were conducted to determine conserved mechanisms, such as mitochondrial dysfunction, cellular senescence, and autophagy, as potential drivers of sex-specific aging differences. The researchers highlight that findings from model organisms, such as X chromosome gene enrichment in neural resilience, hold promise for translating these insights into human studies.
Major Findings
The results indicated that biological sex significantly impacted brain aging and influenced cognitive resilience and vulnerability. Women generally exhibited slower biological aging and younger metabolic brain profiles than men, which could contribute to better cognitive performance during aging. Brain imaging results revealed that women’s brains demonstrated a younger epigenetic clock across regions, indicating delayed aging processes.
In C. elegans, hermaphrodites with XX sex chromosomes displayed greater neural resilience, better memory, and increased expression of X chromosome genes compared to XO males. This suggested that the X chromosome plays a critical role in promoting brain resilience during aging. Similarly, in mice, the presence of a second X chromosome and estrogen signaling were associated with improved cognitive aging, while testosterone exposure had distinct effects on sex-specific resilience.
The study also highlighted the importance of sex chromosomes in modulating aging pathways. Large-scale genetic studies, such as X-wide association studies (XWAS), have begun to uncover genetic influences on aging despite previous technical challenges. For example, models that isolated chromosomal effects identified contributions from both the X and Y chromosomes.
Conclusions
Overall, the results suggested that biological sex plays a substantial role in brain aging and emphasized the sex-specific differences in resilience and cognitive decline. By uncovering genetic, hormonal, and molecular mechanisms, the researchers also provided a foundation for developing targeted therapies to address these disparities.
The authors advocate for implementing sex-specific considerations into drug trials to improve treatment efficacy and reduce healthcare burdens. They believe that future research on sex-based biology holds promise for advancing equitable and effective treatments, ultimately improving brain health and quality of life for aging populations across genders.
Journal reference:
- Dubal, D. B., Murphy, C. T., Suh, Y., & Benayoun, Bérénice A. (2025). Biological sex matters in brain aging. Neuron, 113(1), 2–6. DOI:10.1016/j.neuron.2024.12.005, https://www.cell.com/neuron/fulltext/S0896-6273(24)00883-3