Klotho: The Longevity Protein With a Complicated Human Record

Written by the Nuvirox Research Team

Short answer: klotho is one of the most interesting longevity proteins ever identified, and the human evidence is genuinely contradictory in ways the popular coverage rarely mentions. Carrying a single copy of the KL-VS variant is associated with higher serum klotho and, in several cohorts, better cognitive performance. Carrying two copies lowers serum klotho. One large population-based study found no cognitive advantage at all. And one longitudinal study reported the variant increased dementia incidence. This is not a settled story.

What is klotho?

Klotho is a protein produced primarily in the kidney and in the choroid plexus of the brain. It exists in a membrane-bound form, where it acts as a co-receptor governing phosphate and vitamin D handling, and in a shed soluble form that circulates in blood and cerebrospinal fluid and appears to act as a hormone in its own right.

The gene got its name from mouse work: animals lacking functional klotho develop a syndrome resembling accelerated aging, while overexpression extends lifespan. That combination — loss shortens life, excess extends it — is rare and is what put klotho on the longevity map alongside the pathways we cover in mTOR and the hallmarks of aging. Klotho is described in the literature as interacting with insulin and Wnt signalling, inhibiting oxidative stress, and regulating phosphate and calcium handling.

What is the KL-VS variant, and why does it behave so strangely?

KL-VS is a haplotype defined by six linked single nucleotide polymorphisms, two of which change amino acids (F352V at rs9536314 and C370S at rs9527025). Roughly a quarter of people of European ancestry carry one copy.

The genotype effect is not linear, and this is the crux of the whole klotho story. Yokoyama and colleagues measured fasting morning serum klotho in healthy older adults — 98 non-carriers, 33 heterozygotes and 5 homozygotes — and found a significant genotype effect (p = 0.004 unadjusted, 0.007 adjusted for age, sex and APOE ε4 dose). Heterozygotes had significantly elevated serum klotho. Homozygotes had significantly lower serum klotho than non-carriers. One copy helps; two copies do the opposite. Consistent with this, the KL-VS haplotype in the homozygous state is reported to be less frequent in very old individuals than in newborns.

The non-linear genotype effect is the single most important thing to understand about klotho genetics.

What human studies actually show

The founding human finding was positive. Dubal and colleagues, in 2014, reported that the KL-VS variant was associated with enhanced cognition in heterozygous carriers, and showed that transgenic mice overexpressing klotho performed better on multiple learning and memory tests, with enhanced long-term potentiation and enriched synaptic GluN2B, an NMDA receptor subunit central to learning.

Subsequent human work has broadly supported an association with brain measures. Elevated serum klotho related to KLOTHO variation has been associated with better cognition, greater structural reserve of the prefrontal cortex in normal aging, and greater connectivity between cortical regions. A 2026 study reported that in people with Parkinson’s disease, the KL-VS variant was associated with better executive cognition across two independent cohorts. A 2025 cross-sectional study of 296 participants from the Czech Brain Aging Study examined KL-VS status alongside CSF and serum soluble α-klotho in Alzheimer’s dementia, amnestic MCI and unimpaired controls.

Now the counterweight, which is genuinely damaging to the simple version of the story. The Heinz Nixdorf Recall Study analysed 1,812 adults aged 55–87 from a population-based sample, comparing KL-VS heterozygotes against non-carriers across word list recall, Trail Making Test A and B, a maze test, Stroop interference and verbal fluency. It found no cognitive benefit. The authors noted plainly that prior results have been inconsistent. Separately, a 10-year longitudinal study of 527 men aged 71–87 who were free of cognitive impairment at baseline reported that the KL-VS variant increased dementia incidence in a dose-dependent fashion — the opposite direction from the founding hypothesis. Both of these are larger or longer than several of the positive studies.

What klotho won’t do

It will not currently be measured or modified in any clinically meaningful way outside research. There is no validated consumer klotho test with an interpretable reference range, and no approved therapy that raises it. Assays for soluble klotho vary between laboratories, which is a familiar problem across aging biomarkers — the same measurement issues undermine much of the biological age testing market.

There is also no supplement demonstrated to raise circulating klotho in humans with any clinical consequence. Products marketed on the klotho story are trading on mouse genetics and human association studies, not on intervention data. That gap is the entire distance between an interesting protein and a usable one.

Where the research is actually heading

The most promising direction is klotho as a therapeutic protein rather than a genotype. A 2023 Nature Aging paper reported that klotho enhanced cognition in aged nonhuman primates — a meaningful step up from rodents, and the closest thing to a proof of concept the field has. Whether an administered protein can be delivered safely and effectively to the human brain, at what dose and with what durability, is entirely unanswered.

The genetics, meanwhile, may prove more useful as a clue than as a target. The non-linear relationship between copy number and serum level suggests klotho has an optimal range rather than a “more is better” profile — a pattern that recurs across biology and one that any future intervention would need to respect.

Frequently asked questions

Can I get my klotho levels tested?

Research laboratories measure soluble klotho by ELISA, and some direct-to-consumer panels offer it. There is no established reference range for interpreting a result clinically, and assay variability between labs is a real problem. A number without a validated interpretation is not information.

Do exercise or fasting raise klotho?

Some studies report associations between physical activity and klotho levels, and klotho has been associated with physical performance in aging. Whether exercise raises klotho enough to matter, and whether that mediates any of exercise's benefits, has not been established in controlled human work.

Should I get genotyped for KL-VS?

There is nothing actionable to do with the result. One copy is associated with higher klotho and, inconsistently, better cognition; two copies with lower klotho. Neither finding changes any recommendation a clinician would make.

Is klotho related to NAD+?

They are distinct systems. Klotho is a hormone and co-receptor; NAD+ is a metabolic coenzyme. Both are studied under the aging-biology umbrella, and both decline in at least some tissues with age, but no established human evidence links raising one to raising the other.

Why do headlines say klotho reverses aging?

Because the mouse data are genuinely dramatic and the primate cognition result is real. The human genetic data are far more equivocal, and the contradictory studies rarely make the coverage.

From Nuvirox

Why we formulated NAD+ Restore

Klotho is fascinating and, for now, entirely untranslated — there is no way to buy it, raise it, or interpret it. We built NAD+ Restore around a different part of the aging-biology map: the one place where human placebo-controlled trials consistently show that oral supplementation moves the intended marker.

• 500 mg nicotinamide riboside chloride (NR) — one of the two most-researched NAD+ precursors, within the dose range used in published human trials.
• 150 mg trans-resveratrol (Japanese knotweed) and 50 mg quercetin (Sophora japonica) — polyphenols studied alongside NAD+ pathways for cellular health support.
• 10 mg galactomannans from fenugreek — to support absorption.
• 60-day money-back guarantee — long enough to actually evaluate it the way the research says you should.

Learn more about NAD+ Restore →

The bottom line

Klotho earns its mythological name in mice and earns considerably more scepticism in people. One copy of KL-VS raises circulating klotho and has been linked to better cognition in multiple cohorts; two copies lower it; a 1,812-person population study found nothing; and a 10-year cohort of 527 men found increased dementia risk. The primate result is genuinely exciting and is a long way from a treatment. The fair reading is that klotho is a serious research target and a poor basis for any consumer product currently sold on its name.

References

1. Dubal DB, et al. Life extension factor klotho enhances cognition. 2014. PMID: 24813892.
2. Systemic klotho is associated with KLOTHO variation and predicts intrinsic cortical connectivity in healthy human aging. 2016. PMID: 27714549.
3. Klotho KL-VS haplotype does not improve cognition in a population-based sample of adults age 55–87 years (Heinz Nixdorf Recall Study; n = 1,812). PMCID: PMC8257625.
4. Longevity Klotho gene polymorphism and the risk of dementia in older men (prospective cohort, n = 527, 10-year follow-up). 2017. ScienceDirect PII: S037851221730124X.
5. Longevity factor klotho enhances cognition in aged nonhuman primates. Nat Aging. 2023. DOI: 10.1038/s43587-023-00441-x.
6. KLOTHO-VS heterozygosity, α-klotho protein levels and cognitive performance in Alzheimer's disease. Alzheimers Res Ther. 2025. DOI: 10.1186/s13195-025-01878-5. PMCID: PMC12574126.

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. This article is for informational purposes only and is not a substitute for professional medical advice.