rs9536314 — KLOTHO F352V (KL-VS)

The Klotho Paradox — A Longevity Variant with Complex, Age-Dependent Effects

The KLOTHO gene encodes an anti-aging protein named after the Greek goddess who spins the thread of life. Mice deficient in klotho exhibit accelerated aging phenotypes including atherosclerosis, osteoporosis, and shortened lifespan¹¹ Mice deficient in klotho exhibit accelerated aging phenotypes including atherosclerosis, osteoporosis, and shortened lifespan
Kuro-o M et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997, establishing klotho as a fundamental regulator of longevity. The rs9536314 variant tags the KL-VS haplotype, six single nucleotide polymorphisms in perfect linkage disequilibrium that alter klotho protein function and circulating levels.

This variant exhibits a rare phenomenon called overdominance or heterozygote advantage²² overdominance or heterozygote advantage
a genetic pattern where having one copy of a variant is beneficial, but having two copies is detrimental.

KL-VS heterozygosity occurs in about 20-25% of the population and is associated with higher cognitive performance across the adult lifespan, larger frontotemporal gray matter volume, and lower mortality . In contrast, homozygotes for the KL-VS allele show a 2.59-fold survival disadvantage across three distinct populations .

The Mechanism

The F352V substitution (phenylalanine to valine at position 352) occurs at a completely conserved amino acid in the klotho protein's first internal repeat domain.

The level of secreted klotho is increased in KL-VS heterozygotes and conversely reduced in KL-VS homozygotes compared to major allele homozygotes . This creates a U-shaped dose-response curve: one copy increases circulating klotho (protective), while two copies decrease it (harmful).

The variant alters klotho's trafficking and catalytic activity.

In vitro studies show the F352V and C370S substitutions lead to alterations in processing as seen by differences in shedding and half-life .

In transient transfection assays, secreted levels of klotho harboring V352 are reduced 6-fold , suggesting the homozygous state produces a klotho protein with impaired secretion.

Klotho acts as a co-receptor for fibroblast growth factor 23 (FGF23), regulating calcium and phosphate homeostasis.

Transgenic overexpression of klotho in mice enhances behavioral testing performance through augmentation of NMDAR-related effects, including upregulated FOS expression after learning and memory tasks and amplified LTP response in the hippocampus .

The Evidence

Longevity Studies:

In Ashkenazi Jews, heterozygous advantage for longevity was observed for individuals ≥79 years of age, with a 1.57-fold increased odds ratio for 5-year survival in two independent populations .

Prospective analysis using Cox regression indicates wild-type individuals have a 2.15-fold and homozygous KL-VS individuals a 4.49-fold increase in relative risk for mortality .

Cognitive Function:

A lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers across three independent cohorts totaling 718 aging individuals without dementia.

In adults, individuals who are heterozygous for the KL-VS allele outperform non-carriers on measures of global cognition including language, executive function, visuospatial function, learning and memory .

However, the cognitive benefits appear age-dependent.

In 1,480 Danes aged 92-100 years, heterozygotes for KL-VS had poorer cognitive function than noncarriers . This suggests the protective effects may diminish or reverse at very advanced ages.

Alzheimer's Disease:

KL-VS heterozygotes showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET compared to non-carriers .

KL-VS heterozygosity was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET .

KL-VS heterozygote status slows down the progression of cognitive decline related to Alzheimer's disease, and this effect is dependent on the absence of the APOE ε4 allele .

Cardiovascular Effects:

Cross-sectional and prospective studies confirm KL-VS heterozygotes have higher HDL cholesterol and lower systolic blood pressure; the allele confers a heterozygous advantage with a marked homozygous disadvantage for these outcomes .

The GG and GT genotypes are more represented among salt-sensitive hypertensive patients; carriers of the G allele showed a less steep pressure-natriuresis relationship .

Practical Implications

For heterozygotes (GT genotype), the evidence suggests a meaningful protective effect against cognitive decline and age-related conditions, particularly before very advanced age. The elevated circulating klotho associated with heterozygosity may act as a buffer against neurodegeneration. However, these benefits may not extend linearly into extreme old age.

For homozygotes (GG genotype), the consistent mortality disadvantage and reduced klotho levels warrant clinical attention. These individuals may benefit from interventions that support healthy aging pathways, though no specific klotho-targeted therapies are currently available. Monitoring cardiovascular risk factors and cognitive function may be particularly important.

The paradoxical age-dependency raises important questions. Studies in middle-aged and elderly adults (50s-80s) consistently show heterozygote cognitive advantages, while studies in the oldest-old (90+) show the opposite pattern. This may reflect survival bias, changing cellular environments with extreme age, or genuine biological transitions in klotho's effects.

Interactions

The KL-VS haplotype consists of six SNPs in perfect linkage disequilibrium, with rs9527025 (C370S) always co-occurring with rs9536314 (F352V). These two amino acid substitutions work together to alter klotho protein function.

An important gene-gene interaction exists between KLOTHO KL-VS and APOE ε4. In Alzheimer's disease patients, KL-VS heterozygosity confers slower cognitive decline in APOE ε4 non-carriers but not in ε4 carriers. This suggests the protective effects of elevated klotho may be overwhelmed or modified by the strong pro-degenerative effects of APOE ε4. For individuals who are KL-VS heterozygotes and lack APOE ε4, the combination provides substantial protection against cognitive decline, while KL-VS heterozygotes who carry APOE ε4 lose this advantage.