Klotho in the Pathology of Aging

Klotho is a longevity-associated protein; more of it slows aging, less of it accelerates aging, at least in animal studies. While researchers have spent considerable effort investigating the effects of klotho on the brain, as it improves cognitive function, it seems likely that its effects arise via improved kidney function in old age. Loss of kidney function, and thus clearance of metabolic toxins and waste from the bloodstream, is harmful to tissues throughout the body. Manipulation of klotho may be a good way to assess just how much harm is generated by the age-related decline of the kidneys.

The subject of this review is Klotho (kl), which is an antiaging gene, and the corresponding protein α-Klotho (henceforth denoted Klotho or KL). The gene was first identified in mice in 1997. Deficiency of the protein results in a syndrome that has several features of aging, as observed in mutant mice with a full knockout of the Klotho gene (Kl-/-). Klotho-deficient mice exhibit stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, organ fibrosis, multi-organ atrophy, osteopenia, pulmonary disease, cognitive impairment and short lifespan. Overexpression of the gene has the opposite effects, lengthening survival.

Klotho insufficiency appears to play a role in human aging and, specifically, in many of the diseases that are associated with aging. Klotho expression declines with age, renal failure, diabetes, and neurodegenerative disease. The age-related decline in serum levels appears to be similar in men and women; and reference values have recently been reported. Notably, a recent study of American adults showed that low serum Klotho levels correlate with an increased all-cause death rate.

Klotho can exist as a membrane-bound coreceptor for fibroblast growth factor 23 (FGF23), or a soluble endocrine mediator with many functions. Age-related deterioration of renal function results in Klotho insufficiency, and hyperphosphatemia that contributes greatly to the aging phenotype. Klotho protects the kidney and promotes phosphate elimination. Remarkably, independent of FGF23, it inhibits at least four pathways that have been linked to aging in various ways. Klotho blocks or inhibits transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), nuclear factor κB (NF-κB), and Wnt/β-catenin.

Consequently, Klotho exerts major effects on several biological processes relevant to aging and disease: 1) FGF23-dependent phosphate, calcium, and vitamin D regulation. 2) Antioxidant and anti-inflammatory activities. 3) Prevention of chronic fibrosis. 4) Protective effects against cardiovascular disease. 5) Anti-cancer (tumor suppressor) activities. 6) Metabolic regulatory functions relevant to diabetes. 7) Anti-apoptotic and anti-senescence functions; stem cell preservation. 8) Protection against neurodegenerative disease (Alzheimer's and other).

Link: https://doi.org/10.3389/fragi.2022.931331


can klotho be restored to youthful levels by reducing senescent cell burden?

Posted by: erasmus at August 10th, 2022 5:45 AM

Gene therapy with a lentiviral vector carrying the Klotho gene by increasing Klotho synthesis improved aging-associated memory deficits and oxidative stress in senescent mice, which opens the possibility of using α-klotho to combat age-related cognitive dysfunction and early manifestations of neurodegeneration See: PMC8204227 & PMID: 33527303, PMID: 30851437
Administration of the adenoviral vector Klotho (AAV-Kl) can reverse the decline in muscle function when administered to aged mice, but this effect is lost when AAV-Klotho is administered to the oldest (27-29 months) mice. See: https://elifesciences.org/articles/61138/figures
Pentoxifylline prevents a decrease in the level of soluble protein Klotho, which prevents the development of many diseases of the elderly See: PMID 29866645

Posted by: Dmitry Dzhagarov at August 10th, 2022 3:52 PM

Some interesting interview clips on klotho, calcium/phosphorus balance, and their impacts on the aging process.

Type clotho not klotho into the search field to bring up the interview clips as the software does an audio search and pickups up klotho spelled clotho.


Posted by: Neal G at August 14th, 2022 10:11 AM
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