Why do Some Researchers Call this the Longevity Gene? (KLOTHO)

Klotho was discovered in mice in 1997. In experimental animals, it was observed that a deficiency of klotho, a protein found in cell membranes that seems to interact with insulin, caused the mice to age and die prematurely. It was named for Clotho, one of the three Greek Fates who spins the “thread of life” and controls the lives of mortals [R, R].

Of course, this discovery immediately made klotho the focus of a great deal of longevity research. By 2002, variations in the human KLOTHO gene had been linked with lifespan in human populations. In 2005, these same variations had been further associated with cholesterol levels, blood pressure, and incidence of stroke [R, R].

Since then, over a dozen KLOTHO variants have been identified and linked either directly with longevity or indirectly with age-related disease.

Discovered in mice in 1997 and named for one of the Greek Fates, klotho was quickly linked to premature aging and longevity in humans.

An Antioxidant Mechanism

Like so many other genes implicated in aging, klotho is closely related to the body’s antioxidant defense system. High klotho is associated with high levels of superoxide dismutase (SOD) enzymes, which transform superoxide (a powerful reactive oxygen species) into hydrogen peroxide and oxygen to reduce oxidative stress. This mechanism is believed to protect against all sorts of diseases and conditions [R].

The More, the Merrier

As far as we know, higher expression of klotho is better — that is, there has been no study so far to suggest that klotho becomes detrimental above a certain level. In fact, overexpression of klotho increased the lifespan of experimental mice by nearly a third [R].

The KL-VS Haplotype

The best-studied variants of KLOTHO are part of what’s called the KL-VS haplotype, a block of six SNPs that are always inherited together. Two of these SNPs (represented by the V and S of KL-VS) change the structure and sequence of the KLOTHO gene; these are believed to be responsible for the effects of the haplotype [R, R].

The SNPs responsible for KL-VS are rs9536314-G and rs9527025-C, and their effect on klotho is complex. One copy of KL-VS significantly increases circulating klotho protein, and seems to be associated with increased life expectancy. By contrast, two copies of KL-VS decreases klotho and is associated with decreased life expectancy [R].

To simplify, one copy of KL-VS seems better than no copies, and no copies seems better than two copies.

KL-VS is a haplotype of six SNPs, including two that change the structure and sequence of the KLOTHO gene. One copy of KL-VS is associated with increased klotho, while two is detrimental.

KL-VS and Disease

The dramatic increase and decrease in klotho associated with KL-VS has also been studied in relation to various diseases. The same relationship between genotype and outcome (i.e. one copy of KL-VS being best) has been found for cholesterol levels, blood pressure, and stroke [R].

A single copy of KL-VS (and the high klotho levels it confers) also appears to protect against retinopathy in people with type 1 diabetes [R].

The one exception to the single-copy rule so far has been in a study on cognitive decline in 527 older men. In this study, the TT genotype at rs9536314 (i.e. no copies of KL-VS) was associated with lower rates of dementia than GT or GG. Notably, however, the GG genotype (two copies of KL-VS) was linked to considerably higher rates of dementia than GT [R].

KL-VS has been linked to an impressive number of health markers and diseases already, including cholesterol, blood pressure, and stroke.

Other Variants

Unfortunately, most commercial DNA testing chips don’t include the SNPs responsible for KL-VS. However, you can still get some information about whether you’re likely to have high or low klotho from other SNPs.

Variants that increase or decrease klotho activity have been associated with:

• Cognitive decline (rs1207568) [R]
• Stroke (rs1207568, rs650439) [R, R]
• High blood pressure (rs1207568) [R]
• Osteoarthritis (rs1207568) [R]
• Metabolic syndrome (rs1207568) [R]
• Atherosclerosis (rs3752472, rs650439) [R, R]
• Non-diabetic kidney disease (rs525014, rs526906, rs571118, rs643780) [R, R]
• Mortality from hemodialysis (rs577912) [R]

Additional studies are currently underway to investigate whether klotho has an effect on a broad spectrum of other diseases, as well.

The following SNPs and alleles have been associated with klotho levels, disease, longevity, or all three in existing studies. Klotho is currently the subject of intensive research, and it is likely that other SNPs that affect klotho will come to light. Furthermore, many KLOTHO variants are missing from commercial DNA tests. This is therefore probably an incomplete picture of your KLOTHO gene, let alone your likely lifespan. Take these results with a grain of salt!

SNP Summary and Table

Directly Correlated with Longevity

KLOTHO rs9536314

• ‘G’ = Part of KL-VS haplotype, one copy associated with increased klotho & lifespan
• ‘T’ = Not a part of KL-VS haplotype
• About 21% of all people have the beneficial heterozygous (KL-VS) genotype

KLOTHO rs9527025

• ‘C’ = Part of the KL-VS haplotype, one copy associated with increased klotho & lifespan
• ‘G’ = Not a part of KL-VS haplotype

Indirectly Correlated with Longevity

KLOTHO rs7323281

• ‘A’ = Not associated with carotid atherosclerosis; presumed increased klotho
• ‘G’ = Associated with carotid atherosclerosis; presumed decreased klotho
• About 10% of all people have the ‘GG’ genotype

KLOTHO rs562020

• ‘A’ = Associated with cognitive decline in haplotype with rs398655-C, presumed decreased klotho in old age
• ‘G’ = Presumed increased klotho in old age
• About 10% of all people have the ‘GG’ genotype

KLOTHO rs398655

• ‘C’ = Associated with cognitive decline in haplotype with rs562020-A, presumed decreased klotho in old age
• ‘A’ = Presumed increased klotho in old age

KLOTHO rs1207568

• ‘A’ = Presumed increased klotho
• ‘G’ = Associated with cognitive decline, high blood pressure, osteoarthritis, presumed decreased klotho
• About 29% of all people have at least one copy of the ‘A’ allele, and only 3% have the ‘AA’ genotype

KLOTHO rs3752472

• ‘C’ = Presumed increased klotho
• ‘T’ = Associated with carotid atherosclerosis, presumed decreased klotho
• Only 7% of all people around the world have even a single copy of the ‘T’ allele
• No one on record of European ancestry has the ‘T’ allele

KLOTHO rs526906

• ‘A’ = Presumed increased klotho
• ‘G’ = Associated with non-diabetic kidney disease, presumed decreased klotho
• Part of GGC haplotype with rs525014 and rs571118
• About 13% of all people have the ‘AA’ genotype (no chance of GGC haplotype)

KLOTHO rs525014

• ‘A’ = Presumed increased klotho
• ‘G’ = Associated with non-diabetic kidney disease, presumed decreased klotho
• Part of GGC haplotype with rs526906 and rs571118
• About 22% of all people have the ‘AA’ genotype (no chance of GGC haplotype)

KLOTHO rs571118

• ‘T’ = Presumed increased klotho
• ‘C’ = Associated with non-diabetic kidney disease, presumed decreased klotho
• Part of GGC haplotype with rs526906 and rs525014
• About 33% of all people have the ‘TT’ genotype (no chance of GGC haplotype)

KLOTHO rs577912

• ‘T’ = Presumed increased klotho
• ‘G’ = Associated with mortality from hemodialysis, presumed decreased klotho
• About 35% of all people have at least one copy of the ‘T’ allele

KLOTHO rs643780

• ‘G’ = Presumed increased klotho
• ‘A’ = Associated with non-diabetic kidney disease, presumed decreased klotho
• Over half (57%) of all people have the ‘GG’ genotype

KLOTHO rs650439

• ‘A’ = Increased klotho
• ‘T’ = Associated with stroke and atherosclerosis in people with hypertension, decreased klotho
• About 42% of all people have at least one copy of the ‘A’ allele