Klotho is one of the few longevity-associated genes with robustly demonstrated effects in both directions: reduce its expression and life span is reduced, increase its expression and life span is increased. Klotho levels decline with age, and this decline is strongly associated with loss of cognitive function, but, interestingly, this may be a very indirect effect that exists due to klotho’s influence over kidney function in aging. More klotho implies a slower decline in kidney function, and loss of kidney function is also shown to be a contributing factor in cognitive decline. Thus there is some interest in the research community in developing therapies based on delivery of klotho to patients; Unity Biotechnology added klotho to its otherwise senolytics-focused pipeline last year, for example.
Klotho has been recognized as a gene involved in the aging process in mammals for over 30 years, where it regulates phosphate homeostasis and the activity of members of the fibroblast growth factor (FGF) family. The α-Klotho protein is the receptor for Fibroblast Growth Factor-23 (FGF23), regulating phosphate homeostasis and vitamin D metabolism. Phosphate toxicity is a hallmark of mammalian aging and correlates with diminution of Klotho levels with increasing age. As such, modulation of Klotho activity is an attractive target for therapeutic intervention in aging; in particular for chronic kidney disease (CKD), where Klotho has been implicated directly in the pathophysiology.
Klotho expression levels and its circulating level decline during aging. In humans, Klotho deficiency features medial calcification, intima hyperplasia, endothelial dysfunction, arterial stiffening, hypertension, impaired angiogenesis, and vasculogenesis (i.e., characteristics of early vascular aging). As Klotho-deficient phenotypes have been attenuated and rescued by Klotho gene expression, or supplementation, it is suggestive that Klotho has a protective effect with regard to the vasculature.
A range of strategies have been developed to directly or indirectly influence Klotho expression, with varying degrees of success. These include administration of exogenous Klotho, synthetic and natural Klotho agonists, and indirect approaches, via modulation of diet and the gut microbiota. All these approaches have significant potential to mitigate loss of physiological function and resilience accompanying old age and to improve outcomes of aging.