Direction, Not Distance: A Mortality-Associated Physiological Axis Maps the Sex-Mortality Gap and Informs Sex-Balanced Trial Recruitment.

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.