Klotho is one of the few robustly demonstrated longevity-associated genes. Greater expression extends life in mice, while reduced expression shortens life. Present investigations of the mechanisms by which klotho produces effects on life span are largely focused on the direct actions of klotho in the kidney, and then the effects of kidney function on broader health. Kidney function influences cardiovascular decline and the aging of other organs through a variety of mechanisms. While klotho level is well known to correlate with the degree of cognitive decline with age, this is most likely a demonstration of the importance of kidney function and cardiovascular function on overall health. The brain suffers when its supporting organ systems suffer.
Klotho is a membrane-bound protein acting as an obligatory coreceptor for fibroblast growth factor 23 (FGF23) in the kidney and parathyroid glands. The extracellular portion of its molecule may be cleaved and released into the blood and produces multiple endocrine effects. Klotho exerts anti-inflammatory and antioxidative activities that may explain its ageing suppression effects evidenced in mice; it also modulates mineral metabolism and FGF23 activities and limits their negative impact on cardiovascular system.
Clinical studies have found that circulating Klotho is associated with myocardial hypertrophy, coronary artery disease, and stroke, and may also be involved in the pathogenesis of salt-sensitive hypertension with a mechanism sustained by inflammatory cytokines. As a consequence, patients maintaining high serum levels of Klotho not only show decreased cardiovascular mortality but also non-cardiovascular mortality.
These findings suggest that Klotho may represent a bridge between inflammation, salt sensitivity, hypertension and mortality. This may be particularly relevant in patients with chronic kidney disease who have decreased Klotho levels in tissues and blood.