**Background:** With rising life expectancy, gerontology research increasingly focuses on healthspan—the period of life free of serious disease and disability. Late-life depression (LLD) affects an estimated 13.3% of older adults globally and has been linked to higher mortality, cardiovascular disease, frailty, dementia, and disability. However, no large studies had examined the effect of LLD on healthspan using a validated measure of depressive symptoms. This study aimed to investigate whether LLD and subthreshold depressive symptoms predict lower disability-free survival in physically healthy older adults.
**Methods:** This prospective cohort study used data from the ASPirin in Reducing Events in the Elderly (ASPREE) study, a large multicenter randomized controlled trial. Participants were recruited from Australia and the United States between 2010 and 2014. Inclusion criteria required age ≥70 years (or ≥65 for African-American and Hispanic participants in the US) and absence of dementia, physical disability, and cardiovascular disease. Depressive symptoms were measured at baseline using the 10-item Centre for Epidemiological Studies Depression Scale (CES-D-10). LLD was defined as CES-D-10 ≥8, subthreshold depression as 3–7, and minimal/no depression as ≤2. The primary outcome was disability-free survival, defined as survival free of dementia (diagnosed per DSM-IV criteria) and persistent physical disability (severe difficulty or inability to perform ≥1 of 6 basic ADLs for ≥6 months). Secondary endpoints were all-cause mortality, incident dementia, and incident persistent physical disability. Cox proportional hazards regression was used with five sequential adjustment models: Model 1 (age, race); Model 2 (plus BMI, alcohol, smoking, education, accommodation); Model 3 (plus medical comorbidities and polypharmacy); Model 4 (plus grip strength, gait speed, walking endurance); Model 5 (plus antidepressant use). Analyses were stratified by sex.
**Key Results:** A total of 19,110 participants (10,799 female, 8,311 male) were followed for a median of 4.7 years (range 0–7.3). Among women, 1,248 (11.6%) had LLD and 4,378 (40.6%) had subthreshold depression; among men, 631 (7.6%) had LLD and 2,981 (35.9%) had subthreshold depression. For the primary composite endpoint, 918 women and 917 men died or developed dementia or persistent physical disability. In fully adjusted models (Model 5), LLD was significantly associated with lower disability-free survival in women (HR 1.50; 95% CI 1.23–1.82; p<0.001 for three-way comparison). In men, LLD was associated with lower disability-free survival after adjusting for sociodemographic and lifestyle factors (HR 1.30; 95% CI 1.03–1.64) but became non-significant after adjusting for medical comorbidities and polypharmacy. Subthreshold depression was associated with lower disability-free survival in women after adjusting for sociodemographic and lifestyle factors, comorbidities, and polypharmacy (HR 1.19; 95% CI 1.03–1.38), but not after further adjustment for physical function. For secondary endpoints, LLD in women was associated with all-cause mortality (HR 1.44; 95% CI 1.08–1.91), dementia (HR 1.43; 95% CI 1.01–2.03), and persistent physical disability (HR 1.87; 95% CI 1.29–2.73) in fully adjusted models. In men, subthreshold depression was associated with persistent physical disability in the fully adjusted model (HR 1.47; 95% CI 1.05–2.06).
**Clinical Implications:** This study provides the first evidence that LLD is associated with shortened healthspan in healthy older adults, with a particularly strong relationship with persistent physical disability. The findings suggest a dose-response relationship, with LLD conferring greater risk than subthreshold symptoms. The association remained robust in women after extensive adjustment, while in men it was largely explained by medical comorbidities. These results underscore the importance of identifying and treating depression in older adults as a potential strategy to extend healthspan. The strong link between LLD and physical disability (87% increased risk in women) suggests that mechanisms such as amotivation, deconditioning, poor nutrition, and apathy may be targets for intervention. Limitations include use of a screening instrument rather than diagnostic interview, single time-point assessment of depressive symptoms, relatively short follow-up (median 4.7 years), and a healthier-than-average study population limiting generalizability.