Biomarker
Alpha-Klotho (Circulating)
Serum concentration of the soluble anti-aging protein alpha-Klotho, which falls with age and predicts all-cause mortality in older adults.
Summary What does blood Klotho tell you about ageing and lifespan? Show / hide ↓
Alpha-Klotho is a protein made mainly in the kidneys and brain, and a soluble form can be measured in blood. Lower levels are often found in older adults and may be linked with earlier death. In an Italian study of 804 adults aged 65 and over, people in the lowest third had about 78% higher death risk over six years than those in the highest third. In a US study of 10,069 adults, the lowest group initially had 31% higher risk, but this fell to 24% after fuller adjustments and was no longer statistically clear. A 12-week trial, where 74 adults were assigned by chance to different exercise plans, found that exercise raised Klotho levels, but no supplement has been shown in a randomized trial to do this. Blood test results can also differ between laboratory kits, so one number is not a reliable personal target.
What this means for you: Klotho is an interesting research marker, not a proven way to measure or extend lifespan. Exercise has some evidence of raising it, but there is not enough evidence to buy a Klotho supplement or rely on one blood result.
conflicting evidenceAlpha-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.
References
Every numbered citation in this entry links here. Each reference links out to the primary source.
-
[1]
Mutation of the mouse klotho gene leads to a syndrome resembling ageing Tier 2
Nature 390(6655):45-51; klotho-deficient mice show a compressed aging syndrome.
-
[2]
Plasma klotho and mortality risk in older community-dwelling adults Tier 2
InCHIANTI, N=804 aged 65+, 194 deaths over 6 years; lowest tertile <575 pg/mL vs highest >763 pg/mL, HR 1.78 (95% CI 1.20-2.63).
-
[3]
NHANES, N=10,069 aged 40-79, 616 deaths, mean 57.7 months; <666 vs >985 pg/mL HR 1.31 (1.00-1.71, p=.05); log-rank p=.006.
-
[4]
Klotho antiaging protein: molecular mechanisms and therapeutic potential in diseases Tier 4
Klotho as FGFR co-receptor; serum Klotho negatively correlated with age in 346 healthy adults aged 18-85.
-
[5]
FIT-AGEING RCT, N=74, mean age 53.4 years, 12 weeks; all exercise arms raised soluble Klotho, all P<=0.019.
Further reading
Curated external sources for a deeper dive. External links open in a new tab.
- Plasma klotho and mortality risk in older community-dwelling adults J Gerontol A Biol Sci Med Sci
- Low Serum Klotho Associated With All-cause Mortality in American Adults J Gerontol A Biol Sci Med Sci
Follow Alpha-Klotho (Circulating) through the chain: the mechanism that moves it, the molecule that targets it, the products that dose it, and the trials that tested it.
See Alpha-Klotho (Circulating) on the Longevity Map →