Abstract / Summary
Abstract The Kyotango Declaration of Healthy Aging formulated at the First World Longevity Summit proposes four interconnected pillars as the foundation of healthy longevity: dietary diversity, life-long physical activity (PA), strong social ties, and ikigai. Nonetheless, the mutual quantitative relationships among these pillars have not yet been formally investigated. This cross-sectional study aimed to quantify pathways linking the Lubben Social Network Scale-6, an ikigai composite (WHO-5 well-being + life-satisfaction score), and total PA to the Mitnitski–Rockwood frailty index in 751 community-dwelling older adults (mean age: 72.9 ± 5.8 years; women, 59.4%) from the Kyotango Multipurpose Cohort. In a serial-mediation model, the indirect pathway through ikigai alone accounted for 95.3% of the total indirect effect (β = −0.00845, 95% bootstrap confidence interval: [− 0.01101, − 0.00610]), whereas the a priori three-step serial chain was statistically null (β = −0.00005 [− 0.00023, + 0.00008]). PA operated as an independent parallel pathway (β = −0.006, p = 0.002), uncoupled from ikigai ( d = + 0.025, p = 0.485). Findings were robust across four prespecified versions of the frailty index and remained unchanged after adjustment for dietary fiber intake, indicating independence from the diet–microbiota pathway previously reported in the same cohort. Integrating these results with our previously reported paradoxical observation of significantly higher plasma interleukin (IL)-6 concentrations in non-frail individuals than in frail participants from the same cohort and with the recent Kashiwa cohort finding of increased plasma IL-6 concentrations in ikigai-positive women who did not develop frailty, we propose a unified interpretation in which IL-6 acts as a muscle-derived exerkine rather than a canonical inflammaging marker and may constitute a biological signature of successful aging in this population. These findings, along with the results of our concurrent food–microbiota–frailty analysis, provide the first quantitative empirical support for a parallel-pillar architecture of healthy longevity and highlight ikigai as a substantive, biologically plausible, and intervenable mediator of frailty prevention.