Higher Circulating Alpha-Klotho Levels Increase All-Cause Mortality Through Mediation Effects of Liver Fibrosis: A Second Analysis of NHANES.

Abstract

BACKGROUND Laboratory studies have demonstrated that mice with α-klotho gene deficiency experience a shortened lifespan, but epidemiological evidence linking circulating α-klotho levels and mortality remain inconclusive. This study aimed to examine the association between α-klotho and mortality and to explore how liver fibrosis mediate this association. METHODS The participants were selected from the National Health and Nutrition Examination Survey from 2007 to 2016, who were followed up through December 31, 2019. Serum α-klotho was tested by an ELISA kit. Liver fibrosis was assessed using 3 validated noninvasive algorithms: FIB-4, NFS, and APRI. Weighted Cox regression analyses, restricted cubic spline regression and mediation analyses were employed. RESULTS Throughout the follow-up period of a median of 92 [62, 122] months, the lowest and highest quintiles both showed an increased risk of all-cause mortality (hazard ratio, lowest quintile: 1.367; 95% CI: 1.125-1.661; hazard ratio, highest quintile: 1.210; 95% CI: 1.008-1.452) compared with the intermediate α-klotho quintiles. The association between α-klotho and the risk of all-cause mortality revealed a U-shaped curve (P for nonlinearity < 0.001), with an inflection point of α-klotho (log-transformed) of 6.917. The FIB-4, NFS, and APRI explained 31.85%, 27.74%, and 25.50%, respectively, of the relationships between higher α-klotho levels and all-cause mortality among individuals whose α-klotho levels were greater than the inflection point. CONCLUSIONS This study verified a U-shaped association between α-klotho and all-cause mortality in the US general population. Moreover, higher α-klotho levels were associated with an increased risk of death, partially due to liver fibrosis mediating this association.