How social isolation, loneliness and frailty play roles in all-cause death in later life? Global evidence from cohort studies across 31 countries

BACKGROUND: Social isolation, loneliness and frailty commonly emerge in later life, yet understanding of how their interrelationships relate to all-cause death remains limited. This longitudinal study aimed to examine the associations between social isolation and loneliness and risk of all-cause death and to examine the mediating role of frailty in these associations. METHODS: This study analysed data from four large international cohorts (Health and Retirement Study, China Health and Retirement Longitudinal Study, Survey of Health, Ageing and Retirement in Europe and Mexican Health and Ageing Study) covering 31 countries. Cox proportional hazards models were used to estimate the associations of social isolation and loneliness with frailty and all-cause death. A random-effects meta-analytic model was used to pool cohort-specific estimates. Finally, mediation analysis was conducted to quantify the mediating effect of frailty in the associations between social isolation, loneliness and all-cause death. RESULTS: Over a mean follow-up of 7.07 years, there were 20 504 (25.61%) participants who developed frailty and 6212 (7.76%) all-cause death among total of 80 050 participants. Social isolation was associated with increased risks of frailty (pooled HR = 1.26, 95% CI: 1.09-1.44) and all-cause death (pooled HR = 1.33, 95% CI: 1.12-1.56). Loneliness was associated with an increased risk of frailty (pooled HR = 1.19, 95% CI: 1.00-1.41) and all-cause death (pooled HR = 1.25, 95% CI: 1.10-1.41). Frailty mediated 24.43% (17.35%-34.43%) of the association between social isolation and all-cause death and 55.18% (47.12%-64.43%) of the association between loneliness and all-cause death. CONCLUSION: In later life, social isolation and loneliness increased risks of all-cause death and frailty served as a key mediator. These findings underscore the urgent need for public health policies and clinical practice to prioritise systematic identification and intervention targeting social isolation and loneliness, while integrating frailty screening and management into healthy ageing strategies.