Klotho

Klotho is an anti-aging transmembrane glycoprotein predominantly expressed in the kidneys, brain choroid plexus, and parathyroid glands. PMID 35903083PMID 30455427 The protein exists in multiple forms: full-length membrane-bound Klotho (mKl), which functions as an obligate coreceptor for fibroblast growth factor 23 (FGF23), and soluble Klotho (sKl), which circulates in blood, urine, and cerebrospinal fluid as a pleiotropic endocrine factor. PMID 29250031PMID 20375979

Membrane-bound Klotho complexes with FGF receptors to enable FGF23 signaling, thereby regulating phosphate excretion, calcium homeostasis, and vitamin D metabolism in the kidneys. PMID 30455427PMID 21496980 Soluble Klotho functions independently of FGF23 by binding to ganglioside-enriched lipid rafts in cell membranes, where it modulates growth factor signaling pathways (particularly insulin/IGF-1 and PI3K/Akt), regulates ion channels and transporters, and suppresses oxidative stress through Nrf2 and FoxO pathways. PMID 35903083PMID 28069944 Klotho also inhibits pro-aging pathways including TGF-β, Wnt, and NF-κB signaling. PMID 35903083

Klotho is considered an emerging exerkine, supported by systematic review and meta-analysis evidence. Chronic exercise training (minimum 12 weeks) significantly increases circulating soluble Klotho levels (Hedge's g 1.3, 95% CI 0.69-1.90, P \< 0.0001), with this effect observed regardless of health condition or most exercise modalities, though protocol duration, volume, and intensity influence the magnitude of response. PMID 36266389 Both acute high-intensity aerobic exercise and chronic training protocols elevate Klotho concentrations in young and middle-aged adults. PMID 40157803 This exercise-induced increase in Klotho, combined with its systemic anti-aging and metabolic effects, establishes its classification as an exerkine—a factor released in response to physical activity that mediates beneficial health effects. PMID 36266389

Klotho has shown therapeutic promise in several disease categories. Preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. PMID 35903083 Specifically, Klotho overexpression or supplementation protects against fibrosis in various models of renal and cardiac fibrotic disease, and has been shown to inhibit tumor growth in various animal models. PMID 28709936 In kidney disease, prevention of Klotho decline or supplementation of exogenous Klotho is associated with attenuation of renal fibrosis, retardation of CKD progression, improvement of mineral metabolism, amelioration of cardiomyopathy, and alleviation of vascular calcification. PMID 28115282

Multiple therapeutic strategies to enhance Klotho levels have been identified. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), statins (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D, and pentoxifylline. PMID 35903083 Preclinical work demonstrated that antidiabetic drugs (metformin, GLP-1-based agents, GABA, PPAR-γ agonists) also enhanced Klotho. PMID 35903083 Additionally, s-Klotho protein injection was effective in preclinical studies, though it requires further investigation. PMID 35903083

Klotho's therapeutic mechanisms involve inhibition of four pathways linked to aging: transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt, and NF-κB, which can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. PMID 35903083 Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. PMID 35903083 The protein also serves as a potential autophagy regulator, playing a dual role in restoring autophagy to beneficial levels in various diseases. PMID 34737707

Klotho has potential clinical applications in diagnosis, prognosis, and replacement therapy for systemic Klotho deficiency, particularly in AKI and CKD. PMID 32699047 Soluble Klotho could serve as an early and sensitive marker of kidney function decline, as it starts to decline early in CKD stage 2. PMID 28115282