Klotho Gene: Anti-aging superpowers?

I’ve been fascinated with the Klotho gene for a while now, partly because it has a cool name. It gets its name from one of the Three Fates in Greek mythology who spins the thread of Life. Klotho (or Clotho) was responsible for the thread of life for all mortals, when they were born and when they died. As you will see, this aptly named gene is intertwined with lifespan.

What does the KLOTHO gene do?

In humans, the KL gene codes for the klotho protein. While its functionality is not yet fully understood, klotho levels are related to aging. Low klotho levels relate to accelerated aging, and high levels relate to delayed aging. [ref]

Klotho, found in the cerebrospinal fluid, plasma, and membranes, is involved in maintaining calcium homeostasis (kidneys) and controlling insulin and insulin-like growth factor-1 (IGF-1). It is mainly found in the kidneys and the brain. Klotho also causes increased production of SOD (superoxide dismutase) which is an important intracellular antioxidant. [ref][ref]

All of these things – calcium regulation, insulin, IGF-1, and oxidative stress – are important in aging. Klotho weaves them all together (yes, another ‘thread’ pun).

Klotho levels and mortality

In humans, klotho levels have shown to predict mortality. A six-year-long study of 804 adults, aged 65 or older, found that those with lower klotho levels had a 78% greater mortality risk. Lower klotho levels were defined as being in the bottom 25%. [ref]

Let’s put that into context. Everyone knows that uncontrolled high blood pressure will kill you, right? A big study that followed participants for almost 20 years found that people with uncontrolled high blood pressure had an increased all-cause mortality risk of 69%. [ref]  Compare this to the low klotho level correlating to a 78% increase in mortality…

To clarify, does it mean low klotho levels are more predictive of mortality than high blood pressure? In some ways. But  –  klotho also ties into cardiovascular function through the regulation of calcium and is thus interconnected to the mortality risk. [ref]

There’s more to aging than death…

Associations exist between klotho levels and with the ‘signs of aging’ or ‘aging faster’.

In studies, researchers are looking at cognitive impairment, cardiovascular disease, kidney stones, cancer, and longevity to determine the effects of klotho levels.

Genetic variants linked to higher klotho levels also increase longevity. These same variants decrease the risks of:[ref]

  • kidney stones,
  • cancer,
  • cardiovascular disease

The studies on how klotho levels influence cognitive decline or dementia seem to have conflicting results.

  • One study of 527 men found that those who should have had genetically higher klotho levels were at an increased risk of dementia. [ref]
  • Other studies came up with the opposite results. Higher klotho levels were protective against dementia. [ref]
  • A very interesting study found that elderly people who carry the APOE E4 allele (high risk for Alzheimer’s) had lower β-amyloid if they also carried the KL variant that increases klotho. [ref]

Klotho and brain health:

A study looked at older adults (Caucasian population) who carried the genetic variant associated with increased klotho in comparison to a similar group without the klotho variant. They found that the KLOTHO variant carriers had increased brain volume in a prefrontal cortex region. The variant carriers (more klotho) also had a better executive function, which included better working memory and processing speed. [ref]

To emphasize, another study in humans backed up these results: it also showed that older adults (age 52-85) who carry the KL variant associated with higher klotho levels also had a significantly better cognitive function. Importantly, this increase in klotho was stable as people aged. For example, people in their 50s with higher klotho had better cognitive function scores when matched with people their same age with typical klotho levels. Likewise, people in their 70s with higher klotho had better cognitive score than their age-matched peers. [ref]

Animal studies are better able to define the function of this gene. Researchers eliminatee the klotho gene in mice during development.The results show that the gene is important in brain development and myelination of the neurons. [ref] Decreased klotho in mice causes cognitive impairment. [ref]

Another animal study shows that injecting klotho protein into the mice enhanced cognitive function. [ref]

Klotho and diabetes:

Klotho isn’t all in your head…

The beta cells of the pancreas produce klotho. In type-1 and type-2 diabetes, klotho levels are decreased.[ref]  In patients with type-2 diabetes, low klotho levels may also be a biomarker for early kidney disease.[ref]

In diabetic mice, a pre-treatment of klotho injections showed protection from diabetic cardiomyopathy. It reduced the oxidative stress triggered by high blood glucose levels. [ref]


Genetic variants of KL (klotho gene):

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This is the main klotho variant studied for longevity:

Check your genetic data for rs9536314 (23andMe v4; AncestryDNA):

  • G/G: increased klotho, increased lifespan, decreased cognitive decline in aging, known as KL-VS variant [ref][ref][ref]
  • G/T: increased klotho, known as KL-VS (most of the studies on longevity are looking at this variant)
  • T/T: typical

Members: Your genotype for rs9536314 is .

Other klotho variants have been associated with increased/decreased risk of kidney disease and heart disease:

Check your genetic data for rs3752472 (23andMe v5 only):

  • C/C: a 2-fold increase in the risk of kidney stones [ref]
  • C/T: typical risk of kidney stones
  • T/T: typical risk of kidney stones

Members: Your genotype for rs3752472 is .

Check your genetic data for rs650439 (23andMe v4 only):

  • T/T: increased carotid atherosclerosis in patients with hypertension [ref] lower klotho; increased risk of stroke [ref]
  • A/T: increased carotid atherosclerosis in patients with hypertension
  • A/A: typical

Members: Your genotype for rs650439 is .

 


Lifehacks:

Diet and Exercise:

Cordyceps mushrooms: Several studies show that cordyceps mushrooms may increase klotho levels.

  • An extract of cordyceps was tested on kidney cells. The cordyceps increased the expression of klotho.[ref]
  • An animal study also showed that cordyceps improved klotho protein levels in a mouse model that mimicked kidney problems. [ref]

Cordyceps mushroom extract is available as a powder, making it easy to add to any beverage.

Exercise increases klotho: A study on sedentary middle-aged adults found that exercise (moderate, high intensity, or high intensity plus electromyostimulation) all increased klotho plasma levels. There was no difference between the types of exercise. So get active to increase klotho. [ref][ref]

Decrease alcohol consumption: Increasing levels of alcohol consumption correlates to lower klotho levels in middle-aged adults. [ref]

Medications and supplements:

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.