Metabolic Profiling Identifies Infertile Men at Risk of Accelerated Aging: Implications for Systemic and Reproductive Health

INTRODUCTION: Male infertility is increasingly recognized as a systemic condition associated with impaired long-term health, yet clinically applicable frameworks linking reproductive dysfunction to comorbidity burden remain limited. Here, we investigated whether a composite immuno-metabolic signature could capture comorbidity burden and reduced reproductive capacity in men with primary male factor infertility (MFI). METHODS AND MATERIALS: In a cross-sectional cohort of 2953 men, metabolic and inflammatory variables were systematically screened for directional and independent associations with comorbidity burden, defined by the Charlson Comorbidity Index (CCI) ≥1, and impaired reproductive capacity, assessed by total motile sperm count (TMSC) <5 million. Three variables-LDL cholesterol, waist circumference, and C-reactive protein (CRP)-met selection criteria and were integrated into an unweighted standardized score. RESULTS: Three variables met selection criteria: LDL cholesterol, waist circumference, and C-reactive protein. Higher immuno-metabolic scores were observed in men with comorbidity burden (0.20 ± 0.73 vs. -0.02 ± 0.62, p < 0.001) and in those with TMSC <5M (0.13 ± 0.64 vs. -0.07 ± 0.62, p < 0.001). Each unit increase in the score was independently associated with comorbidity burden (OR 1.50, 95% CI 1.23-1.82, p < 0.001) and TMSC <5M (OR 1.67, 95% CI 1.48-1.89, p < 0.001). Predicted probabilities rose across the score range from 2% to 40% for comorbidity and from 12% to 75% for reduced reproductive capacity. CONCLUSION: These findings identify a biologically coherent immuno-metabolic signature linking spermatogenic impairment with systemic comorbidity in men with primary MFI and support a model in which male infertility reflects broader immuno-metabolic vulnerability. Prospective external validation is warranted before clinical implementation.