Blood glucose and systemic inflammation mediate the association between lifestyle factors and serum Klotho levels in US adults

This study aimed to explore the relationship between lifestyle factors and serum Klotho levels, as well as the mediating effect of blood glucose and systemic inflammation, in US adults. We analyzed data from 6024 participants (weighted to represent 245,378,415 U S. adults) aged ≥40 years from the National Health and Nutrition Examination Survey (NHANES) 2007-2016, using multiple linear regression and mediation analysis to investigate the associations between lifestyle factors, serum Klotho levels, blood glucose, and systemic immune-inflammation index(SII). Additionally, key cardiometabolic factors (blood pressure and low-density lipoprotein cholesterol, LDL-C) were incorporated as covariates, and both weighted and unweighted analyses were performed to validate result robustness. Results showed that lifestyle factors affect serum Klotho through metabolic and inflammatory pathways: systemic inflammation (SII) played a statistically significant but moderate mediating role in the association between lifestyle factors and serum Klotho, while glucose metabolism did not exhibit a significant mediating effect; physical activity (PA) showed no direct association with Klotho but had an indirect link via SII, with PA classified by intensity and age stratification. The study reveals complex interactions between lifestyle factors and serum Klotho levels, with blood glucose and systemic inflammation identified as potential key mediators of this association.