Physical exercise and circulating α-Klotho in humans: a systematic review and meta-analysis with emphasis on older adults.

INTRODUCTION: Global aging and the growing burden of age-related disease have intensified interest in modifiable biomarkers of biological age. α-Klotho, the product of the KL gene, is a pleiotropic anti-aging protein whose circulating (soluble, s-Klotho) form declines with age and is independently associated with all-cause mortality, sarcopenia, cognitive deficit, and cardiovascular events. We conducted a systematic review and meta-analysis of publications from 2015 to 2025 evaluating the effect of exercise training [aerobic, resistance, high-intensity interval training (HIIT), combined] on circulating α-Klotho in adults, with emphasis on individuals aged ≥60 years and patients with chronic kidney disease (CKD), diabetes, and sarcopenia. METHODS: A systematic search of PubMed, Scopus, Web of Science, Cochrane CENTRAL, EMBASE, PEDro, and CINAHL (inception-April 2025) identified randomized and quasi-randomized controlled trials (RCTs) reporting serum or plasma α-Klotho measured by enzyme-linked immunosorbent assay (ELISA). A random-effects model (Hartung-Knapp-Sidik-Jonkman correction) was used; effect size was expressed as Hedges' g or mean difference (MD) with 95% confidence intervals (CI), and heterogeneity was assessed by I2. RESULTS: Fourteen RCTs (n = 893; age range 30-94 years) were included. The pooled effect of chronic training (≥12 weeks) on s-Klotho was Hedges' g = 1.20 (95% CI 0.85-1.55; P < 0.0001; I2 = 84%). In patients with CKD, exercise significantly increased Klotho (MD = 158.82 pg/mL; 95% CI 122.33-194.31; I2 = 0%; P = 0.001) and reduced fibroblast growth factor 23 (FGF23) (MD = -102.07 pg/mL; 95% CI -176.23 to -27.91; I2 = 97%; P = 0.001). Resistance training and HIIT showed the most robust modality-specific effects, whereas combined aerobic-resistance programs were the least reproducible. In pre-frail older adults (n = 69, mean age 77 years), 12-week classical resistance, but not power training, significantly increased s-Klotho. CONCLUSION: Regular exercise, particularly resistance training and HIIT, can be considered a consistent stimulus for increasing circulating α-Klotho across diverse adult populations. Circulating s-Klotho is best regarded as a promising biomarker of the biological response to exercise rather than a validated therapeutic target; the 700-1,000 pg/mL range in adults aged ≥60 years is presented only as an observational reference pending prospective validation. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=1415238, PROSPERO identifier CRD420261415238.