A recent study in The Journals of Gerontology, Series A has associated low klotho levels with mortality in Americans over the age of 40.
Klotho and aging
Prediction of mortality is a major interest of the aging field and the broader medical field. Epigenetic clocks, senescent cell accumulation, and telomere length have all received recent attention for their abilities to predict mortality beyond chronological age. The klotho gene has been associated with aging and mortality in various observational and interventional studies, with lower levels resulting in shorter lifespans and vice versa . Therefore, it may also serve as a measure of biological aging and a risk factor for mortality.
Initial studies have found this to be true in patients with chronic kidney disease  and older adults . A recent collaboration between the University of North Carolina at Chapel Hill and the National Institute of Environmental Health Sciences within the NIH has investigated this in a more general population .
Are serum klotho levels predictive of mortality?
Data from the American National Health and Nutrition Examination Survey (NHANES) was used in this study. 10,069 participants qualified for inclusion in the study, ranging from 40 to 79 years old with an average age of 56. The participant population was slightly healthier compared to the general American population of the same age based on BMI, physical activity levels, smoking history, and alcohol consumption. Of these participants, 616 (4.3%) had deceased after a mean follow-up of 5 years.
Serum klotho levels were measured for each of these participants. Age, BMI, income, and alcohol consumption were weakly and negatively associated with klotho levels. Females, non-Hispanic blacks, college graduates, and people who had never smoked had higher klotho levels than their counterparts.
Grouping by quartile based on klotho concentration, the lowest quartile had a 31% higher rate of death than the highest quartile. Further adjustments for kidney function, BMI, income, ethnicity, smoking status, and education very slightly decreased this association, but alcohol consumption had no effect. Looking into specific causes of death, cause-specific associations were each similar to all-cause mortality.
Impact of physical activity
One novel finding from this study was the relationship between klotho, physical activity, and mortality. No difference in serum klotho levels was found based on activity level. However, when relating klotho levels to mortality, adjusting for physical activity did slightly reduce the correlation between klotho and mortality.
Additionally, those who participated in little to no exercise had an even stronger klotho-to-mortality association than the dataset as a whole. Meanwhile, klotho levels were not associated with mortality in people who achieved the recommended amount of weekly exercise. A similar effect was not found for any of the other surveyed participant characteristics.
a-Klotho (klotho) is a protein involved in suppressing oxidative stress and inflammation. In animal models, it is reported to underlie numerous aging phenotypes and longevity. Among a nationally representative sample of adults aged 40 to 79 in the United States, we investigated whether circulating concentrations of klotho is a marker of mortality risk. Serum klotho was measured by ELISA on 10,069 individuals enrolled in the National Health and Nutrition Examination Survey between 2007-2014. Mortality follow-up data based on the National Death Index were available through December 31, 2015. After a mean follow-up of 58 months (range: 1-108), 616 incident deaths occurred. Using survey-weighted Cox regression models adjusted for age, sex and survey cycle, low serum klotho concentration (< 666 pg/mL) was associated with a 31% higher risk of death (compared to klotho concentration > 985 pg/mL, HR: 1.31, 95% CI: 1.00, 1.71, P= 0.05). Associations were consistent for mortality caused by heart disease or cancer. Associations of klotho with all-cause mortality did not appear to differ by most participant characteristics. However, we observed effect modification by physical activity, such that low levels of serum klotho were more strongly associated with mortality among individuals who did not meet recommendation-based physical activity guidelines. Our findings suggest that, among the general population of American adults, circulating levels of klotho may serve as a marker of mortality risk.
This was the first survey done comparing klotho serum levels to mortality in participants who were younger than 65 and/or without chronic kidney disease. This study did not include young adults, and therefore these findings cannot be applied to that population. However, mortality risk is extremely low below age 40 and is mostly caused by accidents, physical injury, and self-harm – factors that klotho levels would be unlikely to predict.
One unanswered question surrounding klotho is whether low levels are simply detrimental or if high levels can also be protective. For mortality in this dataset, the second, third, and highest quartile all had similar survival curves. Meanwhile, survival of participants in the lowest quartile for klotho concentration was significantly decreased. This could suggest that higher levels of klotho are not associated with a survival benefit, at least within physiological levels. If klotho is a driver rather than a result of the aging process, it is possible that klotho-targeting treatments could still provide benefits by boosting levels beyond these ranges or by only treating patients with low klotho levels.
Perhaps the most interesting component of this study is the impact of exercise on the klotho-mortality relationship. Notably, the survey only collected data about current levels of activity, not a history of exercise, which may have a larger impact on overall health. There could be a number of explanations for why klotho was only predictive of mortality in low-exercise participants, which warrants further investigation.
Lastly, it is important to note that this was an association study that did not look at cause and effect. These results are still positive news for klotho-targeting interventions, at least for non-Hispanic white Americans over the age of 40 with low exercise levels and in the bottom quartile of serum klotho concentrations. Nevertheless, it cannot be said from this experimental design whether or not klotho contributed to the increase in mortality in these participants.
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 Kuro-O.M. The Klotho proteins in health and disease. Nature Reviews Nephrology (2019). https://doi.org/10.1038/s41581-018-0078-3
 Charoenngam, N., Ponvilawan, B., and Ungprasert, P. Lower circulating soluble Klotho level is associated with increased risk of all-cause mortality in chronic kidney disease patients: a systematic review and meta-analysis. Int Urol Nephrol (2020). https://doi.org/10.1007/s11255-020-02510-1
 Semba, R.D. et al. Plasma klotho and mortality risk in older community-dwelling adults. J Gerontol A Biol Sci Med Sci (2011). https://doi.org/10.1093/gerona/glr058
 Kresovich, J.K. and Bulka, C.M. Low serum klotho associated with all-cause mortality among a nationally representative sample of American adults. J Gerontol A Biol Sci Med Sci (2021). https://doi.org/10.1093/gerona/glab308
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