Klotho is a longevity-associated protein discovered in 1997 by Professor Makoto Kuro-o at the University of Texas Southwestern Medical Center. Named after the Greek goddess of fate who spins the thread of life, Klotho-deficient mice exhibit a syndrome resembling premature human aging, while overexpression extends lifespan by ~30%. Higher Klotho levels in humans are correlated with healthy aging, better cognition, and reduced disease risk.
The Klotho protein exists in three forms: a membrane-bound form that serves as a co-receptor for FGF signaling, a soluble form (shed by proteolytic cleavage) that circulates in blood and CSF as an endocrine factor, and a secreted splice variant (KL1). Soluble Klotho acts as a humoral factor regulating oxidative stress, inflammation, mineral metabolism, and multiple growth factor signaling cascades.
Kuro-o et al. Nature 1997Primary longevity gene. Predominantly expressed in kidney distal tubules and brain choroid plexus. Functions as FGF23 co-receptor and circulating anti-aging factor. Regulates phosphate/calcium homeostasis, suppresses insulin/IGF-1, Wnt, TGF-β, and NF-κB signaling. Deficiency causes premature aging; overexpression extends lifespan ~30% in mice.
Key substrates: FGF23, FGFR1c, IGF-1R, TGF-βRII, TRPV5, NaPi-2a
Circulates in: Blood, cerebrospinal fluid, urine
Review: IJN 2025Metabolic regulator. Expressed in liver, adipose tissue, and pancreas. Co-receptor for FGF19 (bile acid metabolism) and FGF21 (energy metabolism, insulin sensitivity). FGF21 binding to βKlotho-FGFR1c activates metabolic pathways affecting glucose homeostasis, lipid metabolism, and neuroprotection.
Key substrates: FGF19, FGF21, FGFR1c, FGFR4
Key roles: Bile acid synthesis, glucose sensing, adipocyte browning
Least characterized member. Also known as Lactase-like (LCTL). Expressed in kidney, skin, and adipose tissue. Emerging evidence suggests roles in FGF signaling modulation and mineral metabolism. Further research needed to elucidate full functional repertoire.
Status: Under investigation
Expression: Kidney, skin, adipose, eye
Single-pass transmembrane protein. Functions as obligate co-receptor for FGF23, forming the FGF23-FGFR-Klotho ternary complex. Expressed in kidney distal tubules and brain choroid plexus.
Cleaved from membrane by ADAM10/ADAM17 secretases. Circulates in blood, CSF, and urine as endocrine factor. Regulates ion channels (TRPV5, ROMK), suppresses growth factor signaling, and provides systemic anti-aging effects.
Alternative splice variant encoding only the KL1 domain. Directly secreted without membrane anchoring. May contribute to circulating Klotho pool and FGF23-independent signaling.
α-Klotho is highly expressed in the choroid plexus, the tissue that produces cerebrospinal fluid. Soluble Klotho crosses the blood-brain barrier and modulates cognitive function through multiple mechanisms.
Klotho deficiency accelerates vascular calcification, cardiac hypertrophy, and endothelial dysfunction — hallmarks of cardiovascular aging.
Emerging evidence links Klotho to lung health, particularly in COPD, pulmonary fibrosis, and acute lung injury.
β-Klotho is the primary Klotho family member in liver, serving as co-receptor for FGF19 and FGF21 — critical metabolic hormones.
The kidney is the primary source of circulating soluble α-Klotho. Distal convoluted tubules produce the most Klotho of any tissue, and renal Klotho loss is one of the earliest markers of kidney disease and aging.
Klotho-deficient mice develop severe osteoporosis and ectopic calcification. The Klotho-FGF23 axis is central to skeletal mineral balance.
Klotho modulates at least 5 major aging-related pathways. Click any node to highlight its connections. Klotho uniquely inhibits four pro-aging pathways (Wnt, IGF-1, TGF-β, NF-κB) while activating the anti-aging FoxO antioxidant response.
Serum soluble α-Klotho peaks in childhood (~1,500 pg/mL) and declines ~30-40% by age 70. Based on population studies (Yamazaki et al. J Clin Endocrinol Metab 2010).
FGF23 (orange) rises with age while its co-receptor Klotho (blue) declines — creating a signaling imbalance linked to cardiovascular disease, CKD, and mortality.
In Klotho⁻/⁻ mice, premature aging phenotypes emerge sequentially from 3 weeks of age. Death occurs by ~8-9 weeks.
Higher serum Klotho is associated with lower risk across multiple age-related diseases. Relative risk for highest vs lowest Klotho quartile.
The first-ever clinical trial specifically targeting Klotho upregulation for lifespan extension launched in February 2026. The field is transitioning from preclinical promise to human validation.
Alpha Klotho mRNA Therapeutic for Lifespan Extension
Randomized, double-blind, placebo-controlled trial. 21 participants (ages 25-75), 2:1 randomization. Two IV administrations of alpha Klotho mRNA in lipid nanoparticles, 4 weeks apart. Site: GARM Clinic, Prospera, Roatan, Honduras.
Primary: Safety and tolerability of repeat dosing.
Secondary: Serum alpha Klotho protein levels over time.
Exploratory: Inflammatory markers, metabolic/cardiovascular measures, sleep quality (wearables), mitochondrial function, QoL.
"The discovery of Klotho opened a new field of research into mechanisms that may influence healthy aging." — Prof. Makoto Kuro-o, discoverer of Klotho
GlobeNewsWire · Feb 19, 2026Klothea Bio's klotho mRNA candidate (in collaboration with Healthy Longevity Clinic) was named a semifinalist in the $101 million XPRIZE for Healthspan due to its ability to significantly upregulate serum α-Klotho in a dose-dependent manner.
XPRIZE HealthspanDirect administration of recombinant soluble Klotho protein has shown efficacy in mouse models of AKI, cardiac fibrosis, and cognitive decline. Single injection in aged rhesus monkeys improved working memory for 2+ weeks (Tozer et al., Stanford). Manufacturing and stability challenges remain for clinical translation.
PubMed: Klotho cognitionAdeno-associated virus (AAV) vectors delivering the Klotho gene have been tested in rodent models. A single AAV injection can restore Klotho expression in aged kidneys for months, reducing fibrosis and improving GFR. Challenges: immunogenicity, tissue targeting, long-term safety.
Originally diabetes drugs, SGLT2 inhibitors consistently upregulate renal Klotho expression in both animal and human studies. Already FDA-approved for diabetes, heart failure, and CKD. Being investigated for Klotho-mediated anti-aging effects beyond their primary indications.
FGF21 signals through βKlotho-FGFR1c. Multiple FGF21 analogs in Phase 2/3 for NASH/MASH demonstrate metabolic benefits that depend on functional βKlotho. Efruxifermin (Akero) showed significant liver fat reduction and fibrosis improvement.
Klothea Bio's scientific advisory board includes the protein's discoverer and leading longevity researchers:
Discovered Klotho protein in 1997. UT Southwestern / Jichi Medical University.
Chief Science Officer, Klothea Bio. Expert in Klotho biology and neurodegeneration.
Functional Medicine physician. SAB member, Klothea Bio.
Multiple pharmacological and lifestyle interventions can upregulate (or suppress) Klotho expression. Evidence quality varies from RCTs to animal studies.
The KL gene (chromosome 13q12) harbors several polymorphisms associated with longevity, cognition, and disease risk. The most studied is the KL-VS variant.
The longevity variant. A functional variant in exon 2 that alters a phenylalanine to valine at position 352. In linkage disequilibrium with rs9527025 (C370S).
Heterozygous (KL-VSHET): Associated with ~3-year longer lifespan, better cognitive function, larger prefrontal cortex volume, higher serum Klotho levels (~+6%), and reduced Alzheimer's neuroinflammation. Frequency ~25% in European populations.
Homozygous (KL-VSHOM): Paradoxically associated with WORSE outcomes — shorter lifespan, reduced Klotho secretion, and increased cardiovascular risk. Frequency ~3-5%. Suggests a dose-dependent or dominant-negative mechanism.
Meta-analysis: KL-VS & healthy agingPromoter variant. Located in the KL gene promoter region (-395 position). The A allele is associated with altered KL transcription.
Meta-analyses link G-395A to urolithiasis risk and cardiovascular disease but NOT cognitive impairment. The G allele may reduce Klotho expression in certain populations.
Meta-analysis: G-395A · PubMedBeyond genetic variants, KL expression is heavily regulated by epigenetic mechanisms:
DNA Methylation: KL promoter hypermethylation silences expression — observed in aging, CKD, and cancer. DNMT inhibitors can rescue Klotho expression.
Histone Modifications: H3K9 trimethylation at KL promoter reduces expression with age. HDAC inhibitors (e.g., vorinostat) upregulate Klotho.
miRNAs: miR-339 and miR-556 target KL mRNA for degradation. Antagomirs could theoretically rescue Klotho levels.
piRNAs: PIWI-interacting RNAs can modify KL translation (Regulatory Potential of piRNAs, MDPI Genes 2026).
piRNAs & Klotho · MDPI 2026Effect sizes for KL-VS heterozygotes vs non-carriers. Positive = beneficial. Based on aggregated meta-analysis data.
Klotho Longevity Atlas · Built by Q · Data from PubMed, GlobeNewsWire, PMC, Frontiers · Feb 2026
Sources: Kuro-o et al. Nature 1997 · Klothea Bio Phase 1b (2026) · IJN 2025 Review · Oxford CKD-MBD · Frontiers in Aging