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

Kai Wei; Qing Zhang; Chun Chen; Yanping Yang; Shuimei Sun; Libin Wang; M S Xiaotong Chen; Xinhua Luo; Qi Chen

doi:10.1093/gerona/glaf109

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

J Gerontol A Biol Sci Med Sci. 2025 May 20:glaf109. doi: 10.1093/gerona/glaf109. Online ahead of print.

Authors

Kai Wei¹, Qing Zhang², Chun Chen¹, Yanping Yang¹, Shuimei Sun¹, Libin Wang¹, M S Xiaotong Chen³, Xinhua Luo², Qi Chen¹

Affiliations

¹ Department of Pharmacy, Guizhou Provincial People's Hospital, 83 East Zhongshan Road, Guiyang, Guizhou Province, 550002, China.
² Department of Infectious Diseases, Guizhou Provincial People's Hospital, 83 East Zhongshan Road, Guiyang, Guizhou Province, 550002, China.
³ Department of Laboratory Medicine, Jing'an District Central Hospital of Shanghai, Jing'an Branch Affiliated to Huashan Hospital, Fudan University, Shanghai, China.

PMID: 40392566
DOI: 10.1093/gerona/glaf109

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.

Keywords: Liver fibrosis; Mediation analysis; Mortality; α-klotho.

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