Abstract
Although α-Klotho has gained attention as a promising biomarker of aging, its association with frailty and broader aging-related outcomes beyond chronic kidney disease-mineral and bone disorder remains incompletely characterized. This systematic review and meta-analysis aimed to investigate the association between circulating α-Klotho levels and aging-related outcomes, including frailty, effects of physical activity and exercise interventions, body composition, cognitive and neuropsychiatric status, sarcopenia, and bone mineral density (BMD). A comprehensive literature search was performed across multiple electronic databases, including Ovid MEDLINE, Web of Science, Scopus, PubMed, and the Cochrane Library, to identify relevant studies published up to April 30, 2025. Pooled analyses were conducted using random-effects models, with effect estimates synthesized as mean differences, odds ratios, or correlation coefficients, and heterogeneity assessed using the I(2) statistic. Risk of bias was assessed using design-specific tools, including the Newcastle-Ottawa Scale, the Risk of Bias 2 tool (RoB2) of the Cochrane collaboration, and the Joanna Briggs Institute (JBI) checklists. A total of 109 studies met the inclusion criteria and were included. In our meta-analysis, higher circulating α-Klotho levels were significantly associated with lower odds of frailty (OR = 0.61, 95% CI: 0.49, 0.77; p < 0.0001, I(2) = 0%). Exercise interventions increased circulating α-Klotho (95% CI: 93.93, 261.73, p < 0.0001; I(2) = 89%), but habitual physical activity showed no significant effect on α-Klotho compared to inactive controls (p = 0.25; I(2) = 100%). Lower circulating α-Klotho levels were observed in individuals with osteoporosis compared with those with normal BMD (95% CI: - 114.98, - 25.49; p = 0.002) and in individuals with osteopenia compared with those with normal BMD (95% CI: - 123.22, - 0.74; p = 0.05), and were associated with fractures. Based on qualitative synthesis, circulating α-Klotho levels were positively associated with multiple physical function outcomes, including grip strength, short physical performance battery scores, and sit-to-stand performance, with mixed findings for gait speed and the 6-min walk test. Circulating α-Klotho appears to be a promising biomarker for frailty, physical function, and bone health in aging; however, evidence for cognitive outcomes remains limited and inconsistent. Substantial heterogeneity and the observational nature of most studies highlight the need for more standardized and longitudinal research.