The World Health Organization (WHO) developed an assessment for healthy aging termed intrinsic capacity (IC). However, the association between IC and depression/anxiety remains poorly understood, with limited understanding of the underlying metabolic mechanisms.

This prospective cohort study comprised 212,033 UK Biobank participants recruited between 2006 and 2010. We calculated a UK Biobank-adapted four-domain IC deficit score using seven functional status indicators across psychological, sensory, vitality, and locomotor domains. Elastic net regression was employed to derive a metabolic signature that represented IC status. Polygenic risk scores (PRS) for depression and anxiety were computed from associated risk variants.

Compared with a 0 IC deficit score, participants with a 4+ score had higher risk, with hazard ratios (HRs) (95% CIs) of 3.96 (3.72–4.21) for depression and 3.03 (2.82–3.25) for anxiety. The metabolic signature of IC comprised 59 metabolites, with mediation effects of 1.007 (1.005, 1.008) for depression and 1.006 (1.004, 1.007) for anxiety. The highest hazards were observed in participants with high PRS and 4+ IC score; the HRs were 4.36 (3.70–5.13) for depression and 3.46 (2.87–4.17) for anxiety.

IC is associated with a higher risk of depression and anxiety, possibly mediated by its metabolic signature, with enhanced effects in genetically susceptible individuals.