Klotho is a protein that acts as a master regulator of aging. Named after the Greek goddess who spins the thread of life, it protects the brain, heart, and kidneys while suppressing inflammation and oxidative stress. People with higher Klotho levels live longer and stay cognitively sharper — and scientists are now racing to develop drugs that boost it.
Your body is like a car. Over time, things start to wear out — parts get rusty, the engine runs slower, and things don't work as well as they used to. That's kind of what happens when we get older.
Klotho is like a super mechanic that lives inside your body. It goes around fixing things, cleaning up rust, and keeping your engine running smoothly. People who have lots of Klotho stay healthier longer — their brains think better, their hearts pump stronger, and they feel more energetic.
The cool part? Scientists are figuring out how to give people more Klotho, which could help everyone stay healthier as they grow up and get older!
Historical context: Klotho was discovered in 1997 by Dr. Makoto Kuro-o at the University of Texas. He found it by accident while studying mice with a genetic mutation. These mice aged incredibly fast — they developed osteoporosis, hardened arteries, and died young. When he traced the cause, he found a single defective gene. He named the protein it produces "Klotho" after the Greek Fate who spins the thread of life.
The discovery was revolutionary because it suggested aging might be controlled by specific genes rather than being inevitable decay. If one broken gene could accelerate aging so dramatically, maybe fixing or boosting that gene could slow it down.
What Klotho does:
The aging connection: Klotho levels naturally decline as we age — a 70-year-old has about half the Klotho of a 20-year-old. This decline correlates with age-related diseases: heart disease, dementia, osteoporosis, and cancer.
A genetic variant called KL-VS gives some people naturally higher Klotho levels. Studies show these people live longer, score better on cognitive tests even into old age, and have larger brain regions associated with memory. About 20% of people carry this "longevity variant."
Molecular biology of Klotho:
The KL gene encodes a single-pass transmembrane protein with two forms:
Key signaling pathways:
Tissue expression and effects:
In 2014, Dena Dubal at UCSF showed that elevating Klotho in mice improved their performance in cognitive tests — regardless of age. The mice showed enhanced long-term potentiation (LTP), the cellular basis of learning. This sparked intense interest in Klotho as a cognitive enhancer, not just a longevity factor.
Klotho's mechanism in cognition:
The cognitive benefits of Klotho appear to work through GluN2B-containing NMDA receptors. Klotho enhances GluN2B surface expression and synaptic localization, increasing NMDA receptor function in the hippocampus and prefrontal cortex. This explains the enhanced LTP and improved spatial and working memory observed in Klotho-overexpressing mice.
Crucially, blocking GluN2B abolishes Klotho's cognitive benefits, confirming the mechanism. This suggests potential therapeutic strategies: either boost Klotho directly, or target the downstream GluN2B pathway.
Klotho and the aging kidney:
Chronic kidney disease (CKD) is essentially a state of Klotho deficiency. As kidney function declines, Klotho production drops, creating a vicious cycle:
This explains why CKD patients have accelerated cardiovascular aging (calcified arteries, cardiac hypertrophy) and cognitive decline — they're experiencing systemic Klotho deficiency.
Therapeutic approaches under investigation:
When old mice are surgically connected to young mice (sharing blood circulation), the old mice show rejuvenation. Recent work suggests Klotho is one of the key "young blood factors." Injecting Klotho protein into old mice recapitulates some — but not all — of parabiosis benefits, particularly in the brain.
Klotho structure-function and fragment biology:
Soluble Klotho exists in multiple forms: the full-length ectodomain (~130 kDa) and two KL domains (KL1 and KL2) that can be independently cleaved. Recent structural work reveals that KL1 retains most anti-aging activity, including FGF23 co-receptor function and Wnt inhibition. KL2's role remains less clear, though it may have independent sialidase activity affecting glycoprotein function.
ADAM10 and ADAM17 (α-secretases) cleave membrane Klotho to generate sKlotho. This cleavage is regulated by inflammatory cytokines and may be a therapeutic target — enhancing α-secretase activity could increase circulating Klotho.
Klotho in cancer — a paradox:
Klotho generally acts as a tumor suppressor: it inhibits Wnt/β-catenin (oncogenic in many cancers), IGF-1 signaling, and TGF-β pathway. Klotho is epigenetically silenced in multiple cancers (breast, lung, colon, liver) and its re-expression suppresses tumor growth.
However, the relationship is complex. FGF23-Klotho signaling can promote certain tumors, and very high Klotho might enhance cancer cell survival under stress. The therapeutic window needs careful definition.
Biomarker and clinical translation challenges:
Emerging directions:
Dubal's group showed that a single injection of Klotho protein fragment (KL1) improved cognitive function in both young and old mice within hours — and the effect lasted weeks. The fragment doesn't cross the BBB, suggesting peripheral Klotho triggers central effects, possibly via the choroid plexus or vagus nerve. This "peripheral-to-central" mechanism opens new therapeutic possibilities.
Senolytic drug developer exploring Klotho pathway intersection. Public company (UBX), focus on age-related diseases. Their work on clearing senescent cells connects to Klotho's anti-senescence effects.
Spun out of Stanford parabiosis research. Developing plasma-derived therapies for aging, including factors like Klotho. Acquired by Grifols for $146M. GRF6019 in clinical trials.
Harvard spinout focused on GDF11 and related circulating factors. Raised $58M. While focused on GDF11, their "young blood factor" approach overlaps with Klotho biology.
AI-driven drug discovery platform with longevity focus. Identified novel Klotho-boosting compounds through generative chemistry. $255M raised, dual-listed. Hong Kong-based.
Platform company attacking aging through multiple pathways including cellular senescence and mitochondrial dysfunction. $100M+ raised. Klotho-related mechanisms in their research scope.
Gene therapy for aging, founded by George Church. Developing AAV-based delivery of longevity genes including Klotho. Started with dog trials. Raised $10M+ seed.
Tackling arterial plaque and vascular aging — directly relevant to Klotho's vascular protection role. Cyclodextrin-based approach. $16M Series A.
Specifically focused on Klotho-based therapeutics. Early-stage startup developing recombinant Klotho and Klotho gene therapy. Preclinical stage.
$3B mega-funded longevity company pursuing cellular reprogramming. While focused on Yamanaka factors, their comprehensive aging research includes Klotho pathway investigation. Founded 2022.
mTOR-focused longevity company. mTOR and Klotho pathways intersect through IGF-1 signaling. Developing next-gen rapalogs. Raised $30M.