PURPOSE: Ikigai, a psychological concept in Japanese culture representing a life worth living, contributes to health outcomes. This study examined the association between Ikigai and the incidence of frailty and sought to investigate the underlying biological mechanism by exploring inflammatory cytokines. MATERIALS AND METHODS: In the 2016 Kashiwa Cohort Study, 832 community-dwelling older adults without frailty were enrolled. Participants reported their Ikigai status at baseline. Frailty was defined as meeting three of Fried's five phenotypic criteria. Plasma concentrations of inflammatory cytokines, including interleukins (ILs) and tumor necrosis factor α, were measured at baseline using immunoassays. Cox regression was used to analyze the association between Ikigai and new-onset frailty stratified by sex after adjusting for relevant confounders. RESULTS: Overall, 7.1 % of 832 participants (75.8 ± 4.7 years, women 47.0 %) developed new-onset frailty during the 5-year follow-up. Older adults with Ikigai (n = 749) had better vitality and mental health and fewer depressive symptoms than those without Ikigai. In women, Ikigai was associated with a lower risk of developing frailty (a fully-adjusted hazard ratio=0.24, 95 % confidence interval: 0.08-0.73, P = 0.012). Notably, a significantly lower prevalence of exhaustion was observed in women with Ikigai (P <
0.001). A higher concentration of IL-6 was observed in women with Ikigai at baseline than in those without Ikigai who developed frailty (P = 0.036). CONCLUSIONS: This study demonstrated that Ikigai could prevent frailty in women, which might be attributed to mitigate exhaustion. Furthermore, the biological actions of Ikigai are associated with high IL-6 levels. Our findings suggest that sex-specific frailty prevention should be considered with Ikigai.