Alpha-Klotho (Circulating)

Alpha-Klotho is a protein made mainly in the kidney and choroid plexus. The membrane-bound form acts as a co-receptor with FGFR1c, FGFR3c and FGFR4, giving those receptors the ability to bind FGF23 and regulate phosphate [4]. A cleaved soluble form circulates and is what a blood test measures. Makoto Kuro-o's 1997 Nature report established the stakes: mice lacking klotho expression develop short lifespan, arteriosclerosis, skin atrophy, osteoporosis, emphysema and infertility [1].

Richard Semba and Luigi Ferrucci provided the first mortality data in humans. In 804 InCHIANTI participants aged 65 and older in Tuscany, 194 died over 6 years, 24.1%. Participants in the lowest plasma Klotho tertile, below 575 pg/mL, had a hazard ratio for death of 1.78 (95% CI 1.20-2.63) against those in the highest tertile above 763 pg/mL, in a Cox model adjusted for age, sex, education, BMI, physical activity, total and HDL cholesterol, cognition, 25-hydroxyvitamin D, parathyroid hormone, serum calcium, mean arterial pressure and chronic diseases [2].

Jacob Kresovich and Catherine Bulka tested it in a nationally representative sample: 10,069 NHANES participants aged 40 to 79 across the 2007-2014 cycles, with 616 deaths over a mean 57.7 months of National Death Index follow-up. Those with serum Klotho below 666 pg/mL had a hazard ratio of 1.31 (95% CI 1.00-1.71, p = .05) against those above 985 pg/mL, and 1.24 (95% CI 0.96-1.61, p = .10) in the fully adjusted model. Survival was worse in the lowest quartile by log-rank test, p = .006, but per 1-SD decrease of 276 pg/mL the hazard ratio was only 1.06 (95% CI 0.93-1.20, p = .36) [3].

How it is measured: ELISA on serum. That matters, because absolute values are assay-dependent and cut-points from one study do not transfer to another lab's kit. The NHANES quartile boundaries of 666 and 985 pg/mL are the most widely reproduced reference points [3]. A separate cross-sectional cohort of 346 healthy adults aged 18 to 85 found the lowest levels in the 55 to 85 group [4].

How to move it: exercise, with randomised evidence. Francisco Amaro-Gahete's FIT-AGEING trial randomised 74 sedentary adults, mean age 53.4 years, 52.7% women, into four arms for 12 weeks. All training modalities raised soluble Klotho, all P <= 0.019, with no difference between them, all P >= 0.696. Gains tracked with increased lean mass index and decreased fat mass [5]. No oral supplement has randomised evidence of raising circulating Klotho.