Lifetime Oestrogen Exposure Indices in Relation to Biological Aging and Future Life Expectancy: A Prospective Study of Two Cohorts

OBJECTIVE: To investigate the associations of lifetime oestrogen exposure indices with biological aging, mortality and life expectancy. DESIGN: Population-based cohort study. SETTING: UK Biobank and the US National Health and Nutrition Examination Survey (NHANES). POPULATION OR SAMPLE: 112 381 postmenopausal women, including 107 218 from UK Biobank and 5163 from US NHANES. METHODS: Lifetime oestrogen exposure was assessed using three reproductive-history-based indices: reproductive lifespan (RLS), endogenous oestrogen exposure (EEE), and total oestrogen exposure (TEE). Biological aging was measured by phenotypic age (PA). Multivariable linear regression examined associations with PA acceleration, Cox models assessed mortality, and flexible parametric survival models estimated life expectancy, with covariate adjustment. MAIN OUTCOME MEASURES: PA acceleration, all-cause and cause-specific mortality, and estimated life expectancy. RESULTS: In the UK Biobank, higher RLS, EEE, and TEE were inversely related to PA acceleration, with estimates generally strongest for RLS and TEE (e.g., highest quartile RLS: β = -0.31, 95% CI: -0.40 to -0.22). In the US NHANES, inverse associations were clearest for TEE. Higher RLS and TEE were generally associated with lower risks of all-cause, cardiovascular, and respiratory mortality across both cohorts. The highest quartile of TEE was associated with increase in life expectancy of 0.64 years (95% CI: 0.30 to 0.97) in the UK Biobank and 1.35 years (95% CI: 0.20 to 2.50) in the US NHANES at age 45. In UK Biobank, RLS and EEE were associated with higher endometrial cancer incidence, and all three indices with higher breast cancer incidence. CONCLUSIONS: Higher lifetime oestrogen exposure indices, particularly TEE, were generally associated with delayed biological aging and longer estimated life expectancy.