📚 Wiki Longevity & Anti-Aging Klotho

Klotho

● Preclinical
Klotho Protein Fragment (α-Klotho)
Also known as: alpha-Klotho, KL fragment, soluble Klotho, sKL
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Quick Summary

Klotho is an anti-aging protein encoded by the KL gene, named after the Greek Fate who spins the thread of life. α-Klotho exists as a transmembrane protein primarily in the kidney and choroid plexus, and is shed as a soluble circulating form (sKL).

Longevity & Anti-Aging Preclinical
Klotho is an anti-aging protein encoded by the KL gene, named after the Greek Fate who spins the thread of life. α-Klotho exists as a transmembrane protein primarily in the kidney and choroid plexus, and is shed as a soluble circulating form (sKL). Klotho levels decline sharply with age and are inversely correlated with kidney disease, cardiovascular disease, and cognitive decline. Research in animals shows that klotho overexpression extends lifespan by 20–30%, while klotho deficiency causes premature aging. It acts as a co-receptor for FGF23 and independently modulates ion channels, oxidative stress, and Wnt/TGF-β signaling.
Storage Stability
Lyophilized
1–2 years (-20°C)
Reconstituted
~30 days (2–8°C)
Room temp
Avoid

Mechanism of Action

FGF23 Co-receptor

Membrane Klotho forms a complex with FGFR1 to serve as the obligate co-receptor for FGF23, a bone-derived hormone that regulates phosphate and vitamin D metabolism. Without Klotho, FGF23 cannot signal effectively, leading to hyperphosphatemia and vascular calcification.

Wnt Signaling Suppression

Soluble Klotho suppresses canonical Wnt signaling, which is pro-aging in many tissues. Excess Wnt drives cellular senescence, fibrosis, and cancer; Klotho's Wnt suppression is a key mechanism of its anti-aging, anti-fibrotic effects.

Oxidative Stress Reduction

Klotho activates FOXO transcription factors and suppresses IGF-1/PI3K/AKT signaling, increasing resistance to oxidative stress and extending cellular lifespan.

Ion Channel Regulation

Klotho regulates TRPV5 calcium channels (kidney calcium reabsorption) and ROMK potassium channels, maintaining mineral homeostasis.

Research Summary

Lifespan Extension in Mice

Kuro-o et al. showed transgenic mice overexpressing Klotho live 20–30% longer than controls, with delayed age-related pathologies including atherosclerosis, sarcopenia, and skin atrophy.

Cognitive Function

Elevated circulating Klotho is associated with better cognitive performance in humans across multiple population studies. A single IV dose of Klotho protein acutely improved cognitive performance in aged mice and young mice with Alzheimer's-like pathology.

Kidney Protection

Klotho is dramatically depleted in chronic kidney disease (CKD). Animal models show Klotho supplementation reduces renal fibrosis, suppresses TGF-β signaling, and slows CKD progression.

Human Epidemiology

Higher serum Klotho levels (measured by ELISA) correlate with lower all-cause mortality, reduced cardiovascular events, and better renal function across multiple large cohort studies.

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Research Protocols

Note: Recombinant Klotho protein is expensive and requires cold chain. No established human dosing protocol exists.

Animal Models

IV or IP injection of recombinant soluble Klotho protein (0.01–0.1 mg/kg) in mouse models. Some protocols use adeno-associated virus (AAV) vectors for sustained Klotho expression.

Indirect Approaches

Exercise, caloric restriction, magnesium supplementation, and rapamycin have been shown to raise endogenous Klotho levels, more practical approaches than recombinant protein administration.

Storage & Handling

Store recombinant Klotho protein at -80°C for long-term; -20°C for short-term. At 2–8°C stable for days only. Avoid freeze-thaw cycles, aliquot upon receipt. Highly sensitive protein; use carrier proteins (BSA) to prevent adsorption to tubes.


References

  • [1]Kuro-o M, et al. "Mutation of the mouse klotho gene leads to a syndrome resembling ageing." Nature, 1997.
  • [2]Dubal DB, et al. "Life extension factor klotho enhances cognition." Cell Rep, 2014.
  • [3]Hu MC, et al. "Klotho deficiency causes vascular calcification in CKD." J Am Soc Nephrol, 2011.
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Data Sources & External References
Source: peer-reviewed literature  ·  Domain: ascendpeptide.org
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