Klotho

Klotho is a protein encoded by the KL gene, which was originally identified as an aging-suppressor gene: in mice, overexpression of the gene extends lifespan while mutations shorten it. ^{[1] [2]} It exists in two principal forms, a single-pass transmembrane (membrane-bound) form and a soluble form released by ectodomain shedding, which have distinct functions. ^{[2] [3]} Klotho is expressed most prominently in the kidney, but also in the brain, pancreas, and other tissues. ^{[4] [3]}

Membrane Klotho acts as an obligate co-receptor that forms a complex with fibroblast growth factor (FGF) receptors, making them specific for the bone-derived hormone FGF23. ^{[2] [5]} Through this FGF23–Klotho axis, Klotho regulates renal phosphate excretion and vitamin D metabolism, and lack of Klotho or FGF23 results in hyperphosphatemia. ^{[3] [6]} Soluble Klotho acts as a pleiotropic endocrine factor and can serve as a circulating co-receptor for FGF23 in tissues that do not express Klotho. ^{[7] [8]} Klotho inhibits four pathways linked to aging, transforming growth factor beta (TGF-beta), insulin-like growth factor 1 (IGF-1), Wnt, and NF-kappaB, and it counteracts inflammation, in part by inhibiting the NLRP3 inflammasome. ^[3]

Mice homozygous for a hypomorphic Klotho gene show a shortened lifespan together with renal disease, hyperphosphatemia, vascular calcification, cardiac hypertrophy, cognitive impairment, and multi-organ atrophy and fibrosis. ^[3] In humans, Klotho levels decline with age, chronic kidney disease, diabetes, and Alzheimer's disease, and low Klotho levels correlate with increased all-cause mortality. ^[3] Decreased Klotho expression appears as early as stage 1 chronic kidney disease and continues to decline as CKD progresses, and it has been proposed as the earliest biomarker of CKD. ^[6] Preclinical Klotho therapy has ameliorated renal, cardiovascular, diabetes-related, and neurodegenerative disease as well as cancer, but soluble-Klotho protein injection requires further investigation. ^[3]

In progressive CKD, rising FGF23 combined with falling kidney Klotho expression drives Klotho-independent effects of FGF23 on the heart that promote left ventricular hypertrophy, heart failure, atrial fibrillation, and death. ^[7] Klotho is implicated in vascular and endothelial aging and is one of the antiaging factors regulating endothelial cell senescence. ^{[9] [10]} Several clinically used drugs, including renin-angiotensin system inhibitors, a statin, and mTOR inhibitors, have been reported to increase circulating Klotho, and exercise also raised Klotho. ^[3]