Aging suppressor protein Klotho: prospects in diagnostics and therapeutics, a meta-analysis of Klotho studies conducted around the world
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Abstract
The aging population is growing, both in the United States and globally. And with aging, the prevalence of chronic, non-communicable diseases is increasing, as well as the associated health care costs expended to provide treatment, aide services, and medications. One fascinating molecule of interest is the Klotho protein, which has been shown to have anti-aging, anti-inflammatory, anti-oxidative, and anti-tumor properties. Since its serendipitous discovery in 1997, Klotho, whose levels decline with age, has been implicated in many cellular pathways and just as many disease states. As an example of one of its many investigated functions, Klotho serves as a co-receptor for fibroblast growth factor-23. This thereby implicates Klotho in the regulation of mineral homeostasis. Furthermore, Klotho levels have been found to be downregulated in a variety of diseases, including chronic kidney disease, Alzheimer’s disease, and most types of cancer. Given the important roles that Klotho plays in normal homeostatic conditions and illness, it is imperative to study the diagnostic and therapeutic potential of this intriguing protein.
The objective of the present study is to perform a meta-analysis of studies that have measured Klotho in blood, cerebrospinal fluid, urine, and whole biopsy/necropsy tissue. It is hoped that such an analysis will provide a comprehensive review of trends in Klotho levels across age groups in healthy and diseased individuals. The elucidated patterns in Klotho concentration will provide insight into how Klotho can potentially be used as a biomarker and diagnostic tool, and in which types of diseases. Moreover, the therapeutic capabilities of Klotho will be better defined, as profiling Klotho levels in different types of tissue will illuminate if and how Klotho concentrations vary in differing components of the body. This will help guide the development of future therapeutics, especially in terms of the pharmacokinetics and pharmacodynamics of potential drugs. In addition, the prognostic value of Klotho cannot be ignored. Knowing how Klotho levels correlate with the severity of a disease, from kidney disease to various cancers, will be immensely useful when utilizing Klotho as a biomarker.
Among healthy individuals and in blood, this study found a statistically significant decrease in mean Klotho levels with age, when comparing infants aged 0-1 years (n=23), children aged 2-16 years (n=116), and adults aged 18 years and above (n=971). Differences in mean Klotho between these groups all had a p-value<0.001. There were also significant differences in median blood Klotho levels between healthy infants aged 0-1 years (n=15), children aged 2-18 years (n=159), and adults aged 50 years and above (n=11,690), all with p-value<0.001. Among individuals with renal conditions, there were significant differences in median blood Klotho concentrations between children aged 5-20 years (n=144), adults aged 21-49 years (n=16), and elderly individuals aged 50 years and greater (n=175), all with p-value<0.001. Lastly, among individuals with metabolic/endocrine conditions, there were significant differences (p-value<0.001) in mean blood Klotho levels between infants aged 0-1 years (n=72) and children aged 2+ years (n=58). Klotho levels are thus significantly lower in older age groups compared to younger age groups in blood, not only among healthy populations, but also among individuals with renal and metabolic/endocrine conditions.
Aging in the U.S. and global population is a serious medical and public health concern. Klotho is an anti-aging protein with great diagnostic and therapeutic potential, which is explored in this study. To the author’s knowledge, this study is the first of its kind to conduct a comprehensive meta-analysis of studies that have measured Klotho in blood, cerebrospinal fluid, urine, and whole tissue samples, across healthy and diseased individuals. This study yields insight into the exciting clinical implications of Klotho in renal, cardiovascular, pulmonary, metabolic/endocrine, neurodegenerative, geriatric, and oncological conditions. Furthermore, when Klotho boosting therapeutics become available, it will be pertinent to know the normal, baseline levels of Klotho in body fluids for the follow-up of the therapeutics’ effectiveness in elevating Klotho levels.
In contemplation of future steps, it may be valuable to establish a database to collect Klotho measurements from studies as they are published. This paper serves as a summary of articles published on Klotho measurements up to contemporary times, but a future database may be able to compile data in real-time. This could help consolidate the growing amount of data on Klotho, and serve as a more comprehensive tool with which researchers and clinicians can confidently predict baseline Klotho values for individuals who are healthy or have various diseases.
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