Klotho (KL) (KL)

Klotho (KL) is a pleiotropic protein primarily expressed in the renal distal convoluted tubules and the choroid plexus of the brain, serving as a key regulator of the aging process and mineral homeostasis. It exists in two functional forms: a membrane-bound form that acts as an obligatory co-receptor for fibroblast growth factor 23 (FGF23) and a secreted soluble form that circulates as a hormone (UniProt P78424). Klotho deficiency is a hallmark of chronic kidney disease (CKD) and is associated with accelerated aging, vascular calcification, and cognitive decline, whereas its overexpression has been shown to extend lifespan and provide neuroprotection in animal models (PubMed: 9367946, 24816231). As a therapeutic target, Klotho is being explored through strategies such as recombinant protein replacement, gene therapy, and the use of small molecules like PPAR-gamma agonists or statins to upregulate its endogenous expression (PubMed: 33613465). Its ability to suppress oxidative stress and modulate growth factor signaling makes it a high-priority target for treating age-related pathologies, including cardiovascular disease and neurodegeneration (PubMed: 22034014).

Other names

alpha-KlothoKlotho proteinKLKuro-o protein

The primary mechanisms of action for targeting Klotho include the upregulation of endogenous expression through pharmacological agents like PPAR-gamma agonists, the administration of recombinant soluble Klotho protein as a replacement therapy, and the use of gene therapy to restore protein levels in deficient states (PubMed: 33613465). Additionally, modulating the FGF23-Klotho-FGFR signaling axis is a key strategy for managing mineral metabolism disorders (UniProt P78424).