Low Serum α-Klotho Correlates with Raised Risk of Age-Related Mortality

Klotho is one of the few longevity-associated genes shown to work in both directions; lower expression shortens life span in animal studies, while increased expression modestly slows aging. Despite several decades of research, scientists have yet to reach a full understanding of how klotho influences life span. The klotho gene produces a transmembrane protein that operates inside and on the surface of cells, as well as a section of the protein, α-klotho, that detaches to act as a signal molecule outside the cell. Study has primarily focused on the protective role of klotho in the kidneys, with the hypothesis that kidney function is important enough to organs throughout the body that slowed kidney aging has a global effect on healthspan. Since the discovery that increased circulating α-klotho improves cognitive function, even in younger animals, however, researchers have increasingly focused on how klotho might be slowing aging in the brain.

The study here is one of a number to examine human data in order to provide support for the ongoing development of therapies based on delivery of an optimized α-klotho version. Does the evidence in humans suggest that the broad base of animal study data will hold up in our species? Largely yes. Levels of α-klotho in blood can be measured, and those individuals with less circulating α-klotho appear to experience increased risk of age-related disease and mortality. At this point it seems likely that therapies to increase circulating α-klotho levels will emerge before a complete understanding of why it is that this increase is beneficial.

The prognostic value of serum α-klotho in age-related diseases among the US population: A prospective population-based cohort study

α-Klotho is a potential biological marker of aging with satisfactory clinical applicability. However, its prognostic significance in age-related diseases has largely been undermined. Therefore, we aimed to report the prognostic value of serum α-klotho levels in age-related diseases.

Participants with available serum α-klotho data from the National Health and Nutrition Examination Survey (2007-2016) were included. Their survival status was collected at 7.62 ± 2.99 years after serum α-klotho data was collected, and the endpoint was all-cause and cardiovascular mortality. A Cox regression model was established to examine the association between serum α-klotho levels and all-cause and cardiovascular mortality.

The present study included 13,746 U.S. adults with a survey-weighted mean age of 56.19 ± 10.42 years old. The optimal cutoff value of serum α-klotho for predicting all-cause mortality risk in the general population was 603.5 pg/ml. Individuals with low serum α-klotho (less than 603.5 pg/ml) had a significantly higher risk of all-cause (adjusted hazard ratio: 1.34) and cardiovascular mortality (adjusted hazard ratio: 1.63). Subgroup analysis showed that low serum α-klotho level was an independent risk factor for all-cause and cardiovascular mortality in people with hypertension, congestive heart failure, diabetes mellitus, and emphysema, while it was an independent risk factor for all-cause mortality in patients with renal insufficiency.

A low serum α-klotho concentration (less than 603.5 pg/ml) could serve as a marker of all-cause and cardiovascular mortality in the general population and in people with age-related diseases, including hypertension, congestive heart failure, diabetes mellitus, and emphysema.

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