Chained mediation of interleukins linking fluoride exposure to frailty: a cohort study of skeletal fluorosis patients in China

Abstract

Background: Chronic fluorosis, characterized by excessive exposure to fluoride, is associated with a greater risk of frailty in endemic populations. While fluoride correlates with inflammation and frailty, the mediating role of interleukins (ILs) remains unclear. This study investigated the potential multiple mediation pathways of ILs on the relationship between fluoride exposure and frailty in skeletal fluorosis patients. Methods: A multicenter cross-sectional cohort (N= 678; age: ≥40 years) from high-fluoride areas in China (2023–2024) was enrolled. Urine fluoride (uF) was used to assess exposure. Frailty was measured via the FRAIL scale, and serum ILs (IL-6, IL-8, IL-1β, and IFN-α) were measured via ELISA. Associations and potential mediating pathways were evaluated via chain mediation models (PROCESS macro, SPSS),which test IL-mediated pathways between uF and frailty and adjust for age/sex. Bootstrapping (5,000 resamples) was used to estimate 95% CIs. Results : Frailty prevalence (5.9%) surpassed that of the general population (2.3%). A high uF value was directly associated with frailty risk (β = 0.2856, P < 0.001). Two potential pathways were identified: the inflammatory cascade: uF→IL-6↑ (β= 0.2947) → IL-1β↑ (β= 0.3936) →frailty (β= 0.0893), and the indirect association accounted for 3.6% of the total effect. Muscle-nutrition depletion: IL-1β↑ → sarcopenia↑ (β= 0.1137)→ increased undernutrition risk↑ (β=–0.2148)→ frailty (β=–0.1990); the indirect association accounted for 4.2% of the total effect. IFN-α attenuated the association of fluoride with IL-1β (P = 0.0113) and was linked to lower frailty risk (β = –0.086, P < 0.01). Conclusions : The"IL-6→IL-1β" pathway is a potential mechanism for inflammation-related frailty, and nutritional interventions could disrupt the “IL-1β→sarcopenia→malnutrition” cycle. IFN-α has a protective effect on fluoride-induced inflammation.