Table 1.
Relationship between Klotho levels and indices of physical function and health.
| Reference | Study design | Population | Sample and technique | Key findings |
|---|---|---|---|---|
| Amaro-Gahete et al. (123) | Cross-sectional study in the FIT-AGING study cohort. | Middle-aged sedentary adults (n = 74, 35 men, age 53.7 ± 5.1 years) | -Plasma -ELISA (Demeditec, Kiel, Germany) |
-sKlotho is positively associated with lean mass index after controlling for age and sex. |
| Amaro-Gahete et al. (122) | Cross-sectional study in the FIT-AGING study cohort. | Middle-aged sedentary adults (n = 74, 35 men, age 53.7 ± 5.1 years) | -Plasma -ELISA (Demeditec, Kiel, Germany) |
-sKlotho is positively associated with VO2max, knee extension peak torque, and hand grip strength. |
| Baldan et al. (125) | Cross-sectional study. | β-thalassemia major (ß-TM) patients (n = 106, 43 men, age 38.6 ± 6.5 years) and healthy blood donors (n = 95, 70 men, age 40.9 ± 7.8 years) | -Plasma -ELISA (IBL Ltd., Takasaki, Japan) |
-sKlotho levels are lower in patients with ß-TM compared to healthy controls. -Up to an estimated sKlotho's threshold value of 580 ± 149 pg/mL, a weak linear correlation was observed between sKlotho and normalized hand-grip strength in ß-TM patients. -No correlation was found for Klotho values above 580 pg/mL. |
| Chalhoub et al. (126) | -Prospective study in the Health, Aging, and Body Composition (Health ABC) study cohort. -Patients were followed up for a median of 5 years. |
Well-functioning older adults (n = 2,776, aged 70 to 79 years) were divided into sKlotho quartiles: quartile 1: 320.6–437.3 pg/mL; quartile 2: 521.6–592.1 pg/mL; quartile 3: 670.1–756.2 pg/mL; and quartile 4: 887.7–1186.4 pg/mL. | -Serum -ELISA (IBL Ltd., Takasaki, Japan) |
-No differences were observed between quartiles on gait speed, grip strength, or appendicular lean mass. -sKlotho levels are not associated with bone mineral density, bone loss, or fracture risk in older individuals. |
| Crasto et al. (7) | Cross-sectional study in the Invecchiare in Chianti (InCHIANTI) study cohort. | Population-based sample of 802 adults aged 65 years and older divided into sKlotho tertiles: tertile 1: <575 pg/mL; tertile 2: 575–763 pg/mL; and tertile 3: >763 pg/mL | -Plasma -ELISA (IBL Ltd., Takasaki, Japan) |
-Lower levels of sKlotho were associated with older age, lower SPPB score, lower cognitive function, and higher ADL disability. -Low sKlotho was associated with ADL disability after adjusting for age, education, SPPB, congestive heart failure, and diabetes. |
| Dote-Montero et al. (127) | Cross-sectional study in the FIT-AGING study cohort. | Middle-aged sedentary adults (n = 73, 34 men, age 53.8 ± 5.1 years) | -Plasma -ELISA (Demeditec, Kiel, Germany) |
-sKlotho was positively associated with DHEAS in men but not women, but this disappeared after adjusting for age. -sKlotho was positively associated with testosterone in both men and women. -The association between sKlotho and testosterone disappeared after adjusting for age in men, but not in women. |
| Fukasawa et al. (128) | Cross-sectional study. | Hemodialysis patients (n = 77, 52 men, median age = 67.0 years, IQR = 60.0–73.0 years) | -Plasma -ELISA (IBL Ltd., Takasaki, Japan) |
No significant correlation between sKlotho levels and abdominal muscle area or creatinine production. |
| Matsubara et al. (129) | Cross-sectional study. | Healthy and postmenopausal women (n = 69, aged 60 ± 1) | -Plasma -ELISA (IBL Ltd., Tokyo, Japan) |
-sKlotho and carotid arterial compliance were positively correlated after adjusting for age, pulse pressure, and BMI. -sKlotho is positively correlated with VO2 at VT after adjusting for age and BMI. |
| Mostafidi et al. (130) | -Cross-sectional study. -Blood samples were obtained after an 8 hour fast the morning following an afternoon training session. |
Healthy male football players (n = 30, aged 18–22 years) who were performing daily morning and evening exercise training and healthy non-athlete male controls (n = 28, age 18–27 years). | -Plasma -ELISA (Hangzhou Eastgbiopharm Co., Ltd., Hangzhou, China) |
-sKlotho levels are significantly higher in football players compared to healthy controls with normal physical activity levels. |
| Patel et al. (131) | Cross-sectional study. | Never smokers (n = 13, 10 men, age 65 ± 8), smokers with normal spirometry (n = 13, 5 men, age 51 ± 7), and COPD patients (n = 61, 38 men, age 64 ± 10). | -Vastus lateralis protein expression and serum. -ELISA (IBL Ltd., Japan) -Immunohistochemistry (rabbit anti-Klotho antibody [diluted 1:100], Aviva Systems Biology, San Diego, CA, USA) |
-Quadriceps Klotho levels were lower in smokers compared to non-smokers. -Quadriceps Klotho levels were higher in patients with low fat free mass index and low quadriceps strength. -sKlotho had an independent association with quadriceps strength but did not relate to quadriceps Klotho levels. -Klotho protein was localized to the muscle fiber membrane and associated with centralized nuclei. |
| Patel et al. (131) | Mice exposed to air or 4% cigarette smoke for 2 hours/day, 5 days/week, for 77 weeks were evaluated for Klotho expression in the context of muscle damage induced by electroporation. | Female C57BL/6 mice, 3–4 months of age divided into sham (n = 9) or cigarette smoke (n = 19). | Gastrocnemius protein expression -ELISA (IBL Ltd., Japan) -Immunohistochemistry (rabbit anti-Klotho antibody [diluted 1:100], Aviva Systems Biology, San Diego, CA, USA) |
-Significant Klotho protein expression present in damaged skeletal muscle tissue, but not healthy tissue. -Klotho co-localized to both the plasma membrane and to centralized nuclei. -↓ in gastrocnemius Klotho protein levels in mice exposed to smoke compared to sham. |
| Phelps et al. (3) | Klotho deficient mice were compared to transgenic Klotho overexpressing mice and wildtype mice for strength and running endurance. | Klotho deficient mice (Klotho homozygous males, C57BL/6), transgenic Klotho overexpressing mice (EFmKL46, homozygous, males and females, C57BL/6), and wildtype mice. | -Kidney and Gastrocnemius mRNA expression -RT-qPCR analysis |
-Gastrocnemius Klotho mRNA expression level in EFmKL46 mice was 70-fold higher compared to wildtype mice. -Klotho expression was not detected in the gastrocnemius of Klotho deficient mice. -Forelimb grip force 53% and 51% lower in Klotho deficient mice compared to wildtype and EFmKL46 mice, respectively. -Klotho deficient mice spent 66% and 62% less time running than wildtype and EFmKL46 mice, respectively. |
| Polat et al. (132) | Cross-sectional study. | Frail (n = 45, 14 men, age 79.4 ± 6.9 years) and non-frail (n = 44, 17 men, age 72.7 ± 4.5 years) older adults. | -Serum -ELISA (IBL Ltd., Takasaki, Japan) |
-No significant difference in sKlotho between frail and non-frail patients. -No significant correlation between sKlotho and frail score. |
| Rosa et al. (133) | Cross-sectional study. | Master endurance runners (n = 18, age 53 ± 8.2 years), master sprinters (n = 13, age 50 ± 8.9 years), untrained healthy young (n = 17, age 22.7 ± 3.9 years), and untrained middle-aged (n = 12, age 45.5 ± 9.8 years) men. | -Serum -ELISA (IBL Ltd., Japan) |
-sKlotho levels were higher in master sprinters than master endurance runners and untrained middle-aged men. -sKlotho levels were similar between young untrained men and master sprinters. -sKlotho levels were higher in young untrained men than master endurance runners and untrained middle-aged men. |
| Sanz et al. (134) | -Prospective study. -Patients were followed up for 6 months. |
Older adults living in nursing homes in Gipuzkoa, Spain (n = 103, 30 men, age 84.7 ± 6.96 years) | -Serum -ELISA (IBL Ltd., Gunma, Japan) |
-Low sKlotho levels were associated with a lower score in the psychological component of the Tilburg Frailty Indicator, greater dependence in activities of daily living, and more falls during the 6-month follow-up. |
| Semba et al. (8) | -Prospective study in the Invecchiare in Chianti (InCHIANTI) study cohort. -Patients were followed up for 6 years. |
Population-based sample of 804 adults aged 65 years and older. | -Plasma -ELISA (IBL Ltd., Takasaki, Japan) |
-sKlotho was positively associated with grip strength at a threshold of <681 pg/mL after adjusting for age, sex, education, smoking, physical activity, cognition, and chronic diseases. |
| Semba et al. (9) | -Prospective study in the Health, Aging, and Body Composition (Health ABC) study cohort. -Patients were followed up for 4 years. |
Well-functioning older adults (n = 2,734, aged 71 to 80 years) were divided into sKlotho tertiles: tertile 1: <536 pg/mL; tertile 2: 536–747 pg/mL; and tertile 3: >747 pg/mL. | -Plasma -ELISA (IBL Ltd., Takasaki, Japan) |
-The highest tertile of sKlotho had higher knee extension strength compared with those in the lowest tertile after adjusting for age, sex, race, smoking, study site, inflammatory markers, and diabetes. -The highest tertile of sKlotho had less of a decline in knee strength over 4 years of follow-up compared with those in the lowest tertile after adjusting for the same covariates above. |
| Shardell et al. (11) | -Prospective study in the Invecchiare in Chianti (InCHIANTI) study cohort. -Patients were followed up for 6 years. |
Population-based sample of 860 adults aged 55 years and older split by sKlotho median (669 pg/mL) | -Plasma -ELISA (IBL Ltd., Takasaki, Japan) |
-Higher sKlotho levels were associated with higher average SPPB scores after adjustment for covariates. |
| Shardell et al. (10) | -Prospective study in the Invecchiare in Chianti (InCHIANTI) study cohort. -Patients were followed up for 3 years. |
Population-based sample of 774 adults aged 65 years and older split by sKlotho median (660 pg/mL) | -Plasma -ELISA (IBL Ltd., Takasaki, Japan) |
-Higher sKlotho levels were associated with lower odds of frailty after adjustment for covariates. -Higher sKlotho was particularly associated with lower odds of exhaustion. |
| Valenzuela et al. (124) | -Prospective study in an elderly dialysis cohort. -All-cause mortality was registered 18 months later. |
ESRD male dialysis patients (n = 30, age 71 ± 9 years) split by sKlotho median (369 pg/mL) | -Plasma -ELISA (IBL Ltd., Japan) |
Lower sKlotho levels were associated with higher risk of having low handgrip strength and low performance on the 6-min walk test and the sit-to-stand test. |
ELISA, enzyme-linked immunosorbent assay; sKlotho, soluble Klotho; VO2max, maximal oxygen uptake; IBL, Immuno-Biological Laboratories; ß-TM, β-thalassemia major; SPPB, short physical performance battery; ADL, activities of daily living; DHEAS, dehydroepiandrosterone sulfate; BMI, body mass index; VO2 at VT, oxygen consumption at the point of ventilatory threshold; RT-qPCR, reverse transcription quantitative polymerase chain reaction.