The Female Biomarker Challenge: Sex-Specific Network Robustness Constrains Biological Age Estimation and Geroscience Trial Design

Abstract

Geroscience has more candidate interventions than it can afford to test. Trials powered for mortality or functional decline require large cohorts and long follow-up, and the persistent female survival advantage could further increase sample-size requirements if women and men age through different biology. Existing ageing biomarkers -- including frailty indices, biological-age clocks, allostatic load and homeostatic dysregulation -- compress multidimensional physiology to a scalar, discarding which combination of biomarkers changed. In 29,053 US adults measured on 38 routine laboratory and examination markers, we decomposed displacement from sex-specific young-healthy physiology into total magnitude and alignment with a cross-fitted mortality-associated direction. Women were no closer to young-health than men but had substantially lower disease mortality. Adjustment for magnitude widened the female survival advantage; adjustment for mortality-directed projection attenuated 87% of the sex difference on the log-hazard scale. Sex-specific directions transferred almost without loss, indicating a substantially shared predictive geometry with different positions along it. Across the population, a median 68% of the positive mortality-associated contribution came from measurements lying within conventional clinical limits and 57% from within the young-healthy range; these shares reflect how numerous such measurements are, not greater information per measurement. Ten routine measurements reproduced the 38-marker direction, and seven of eight predictions registered before analysis were confirmed in NHANES III. High-sensitivity C-reactive protein was strongly prognostic alone but showed no incremental information beyond the routine panel, whereas measuring lung-function added more held-out prognostic information than 33 of 34 individual blood and urine markers in the replication cohort. Retrospective sorting on this geometry produced mortality-enriched and physiologically displaced candidate trial groups; pooled thresholds were strongly sex-imbalanced, whereas within-sex thresholds restored balance with only a 1.5-3.8% reduction in expected five-year events. These findings suggest that inexpensive routine biomarkers plus simple functional testing could support smaller, more informative and sex-balanced geroscience trials, but prospective validation of treatment enrichment is required.