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 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.