Pathway
Klotho
Last updated Sun May 17 2026 00:00:00 GMT+0000 (Coordinated Universal Time)
What it is
Klotho exists as a transmembrane co-receptor for FGF23 (kidney, parathyroid) and as a circulating cleaved form that acts as a hormone. Mice lacking Klotho show accelerated aging, vascular calcification, hypogonadism, osteoporosis, and short lifespan. Mice over-expressing Klotho live longer.
Why it matters
Higher serum Klotho associates with better cognitive function, reduced frailty, and lower all-cause mortality in human cohorts. The KL-VS variant carrier state (~25% of Europeans) is associated with higher serum Klotho and modestly improved cognition.
Mechanisms
- Regulates phosphate/calcium homeostasis via FGF23.
- Suppresses insulin/IGF-1 signalling.
- Inhibits Wnt and TGF-β signalling.
- Suppresses oxidative stress and apoptosis.
- Cross-talk with sphingolipid metabolism.
Therapeutic interest
Klotho gene therapy and recombinant Klotho protein are in pre-clinical development for chronic kidney disease, cardiovascular disease, and neurodegeneration. None are approved.
Related entries
Insulin/IGF-1, Chronic kidney disease, Altered intercellular communication.
References
- Kuro-o, M. The Klotho proteins in health and disease. Nat. Rev. Nephrol. 15, 27–44 (2019).