Chronic low-grade inflammation ("inflammaging") drives age-related decline, but whether anti-inflammatory medications preserve functional performance in older age remains unknown. This study evaluated the 5-year effect of aspirin on a modified Intrinsic Capacity (IC) index in older males and females. A post-hoc analysis of a randomised controlled trial comparing daily 100 mg aspirin to placebo in prolonging dementia- and disability-free survival (DFS) in community-dwelling individuals aged ≥ 65 years. A four-domain IC score (including cognition, locomotion, vitality and psychological well-being) was calculated annually across 18,581 participants and validated against biological and clinical measures. Linear mixed models compared IC trajectories across treatment arms. Females had lower baseline IC and a steeper decline over time than males. IC correlated with chronological age (r =  - 0.30, both sexes), a system-wide deficit-accumulation index (r =  - 0.56 and - 0.54 in females and males respectively), and epigenetic clocks (e.g., PC-PhenoAge, PC-GrimAge, and DunedinPACE), particularly in females. Clinically, lower baseline IC was associated with reduced DFS in both sexes (Q1 vs. Q5: HR = 4.62, 95% CI: 3.16-6.75; HR = 4.32, 95% CI: 3.42-5.48). Females randomized to aspirin had a small but significantly accelerated decline in IC (β: - 0.006, 95% CI: - 0.01, - 0.001, p = 0.01), whereas no effect was observed in males (p = 0.86; 3-way sextreatmenttime p = 0.06). Low-dose aspirin did not prevent functional decline and unexpectedly was associated with a small additional decline in IC in older females, highlighting the need to consider sex-specific responses to therapies.
