Low Serum Klotho Associated With All-cause Mortality Among a Nationally Representative Sample of American Adults

α-Klotho (klotho) is a protein involved in suppressing oxidative stress and inflammation. In animal models, it is reported to underlie numerous aging phenotypes and longevity. Among a nationally representative sample of adults aged 40-79 years in the United States, we investigated whether circulating concentrations of klotho is a marker of mortality risk. Serum klotho was measured by ELISA on 10 069 individuals enrolled in the National Health and Nutrition Examination Survey between 2007 and 2014. Mortality follow-up data based on the National Death Index were available through December 31, 2015. After a mean follow-up of 58 months (range: 1-108), 616 incident deaths occurred. Using survey-weighted Cox regression models adjusted for age, sex, and survey cycle, low serum klotho concentration (<666 pg/mL) was associated with a 31% higher risk of death (compared to klotho concentration > 985 pg/mL, hazard ratio [HR]: 1.31, 95% confidence interval [CI]: 1.00, 1.71, p = .05). Associations were consistent for mortality caused by heart disease or cancer. Associations of klotho with all-cause mortality did not appear to differ by most participant characteristics. However, we observed effect modification by physical activity, such that low levels of serum klotho were more strongly associated with mortality among individuals who did not meet recommendation-based physical activity guidelines. Our findings suggest that, among the general population of American adults, circulating levels of klotho may serve as a marker of mortality risk.