Castration Model Illuminates Sex Differences in Healthy Aging: Insights from Metabolome and Transcriptome Analyses

Females typically outlive males, a disparity mitigated by castration, yet the molecular underpinnings remain elusive. Our study integrates multi-omics and behavioral analyses to uncover the pivotal compounds and genes influencing healthy aging post-castration, examining serum, kidney, and liver biospecimens from 12-week and 18-month old castrated male mice and their unaltered counterparts. Behavioral tests and LC-MS/MS metabolomics reveal that castrated males exhibit altered steroid hormones, superior cognitive performance, and higher levels of anti-oxidative compounds like taurine, despite identical diets. Integrated metabolome-transcriptome analysis confirms reduced lipid peroxidation and oxidative stress in female and castrated male mice, suggesting a protective mechanism against aging. Histological examinations post-cisplatin treatment highlight the model’s applicability in studying sex-dependent drug toxicity and reveal varying susceptibility in organ-specific toxicities, underlining the crucial role of sex hormones in physiological defenses. In essence, our castration model unveils a feminized metabolic and transcriptomic intermediary, serving as a robust tool for studying sex-specific aspects of healthy aging and exploring sex hormone-induced differences in diverse biomedical domains. ### Competing Interest Statement The authors have declared no competing interest.