Abstract
Background: The relationship between total cholesterol (TC) levels and mortality in older adults is complex and may differ from younger populations. While hypercholesterolemia is a known midlife risk factor, this association may weaken or reverse with age. Biological differences in cholesterol metabolism-particularly hormonal changes-may contribute to sex-specific mortality risks, but this remains underexplored. We examined the association between TC and all-cause mortality in older adults, assessing sex-specific differences. Methods: We used data from the InCHIANTI study, a longitudinal, population-based study conducted in Tuscany, Italy. From the original cohort (N = 1453), 999 participants ≥ 65 years with baseline TC and mortality data were included. TC levels were categorized as <200 mg/dL, 200-239 mg/dL, and ≥240 mg/dL. The primary outcome was all-cause mortality over 6-years. Kaplan-Meier curves and Cox proportional hazards models assessed mortality risk across TC categories in the overall population and by sex. Restricted cubic splines explored non-linear associations. Models were adjusted for age, sex (only in overall population), BMI, physical activity, diabetes, COPD, hypertension, eGFR, polypharmacy and frailty. Results: A threshold effect was observed: mortality risk rose sharply below ~200 mg/dL and remained stable above. Compared to the <200 mg/dL group, intermediate and high TC levels were associated with lower mortality risk (HR 0.72; 95% CI: 0.53-0.99 and HR 0.71; 95% CI: 0.49-1.02, respectively). In sex-stratified analyses, this pattern was pronounced in women but weaker and not statistically significant in men. Results held after excluding statin users and were confirmed by spline analysis. Conclusions: In older adults, particularly women, low TC may signal underlying vulnerability, including malnutrition or inflammation.