Klotho Gene: Anti-aging superpowers?

I’ve been fascinated by the Klotho gene for a while now, partly because it has a cool name. It is named after one of the Three Fates in Greek mythology who spin 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 is an aptly named gene that is intertwined with lifespan.

What does the KLOTHO gene do?

In humans, the KL gene codes for the klotho protein. While its function is still not fully understood, klotho levels are related to aging. Lower klotho levels are associated with accelerated aging and high levels with delayed aging. [ref]

Klotho is found in the cerebrospinal fluid, plasma, and in membranes. It is involved in calcium homeostasis (kidneys) and in 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 been shown to predict mortality. A six-year-long study of 804 adults who were age 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]

Low klotho levels are more predictive of mortality than high blood pressure? Yes… But perhaps klotho ties into cardiovascular function, as well, through the regulation of calcium. [ref]

There’s more to aging than death…

Klotho levels are associated with the ‘signs of aging’ or faster aging. In studies, researchers are looking at cognitive impairment, cardiovascular disease, kidney stones, cancer, and longevity to determine the effects of klotho levels.  Genetic variants that increase klotho are linked to decreased risks of kidney stones, cancer, cardiovascular disease, and increased longevity. [ref]

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) who carried the genetic variant associated with increased klotho compared to a similar group without the klotho variant. They found that the KLOTHO variant carriers had increased brain volume in a pre-frontal cortex region. The variant carriers (more klotho) also had better executive function, which included better working memory and processing speed. [ref]

Another study in humans backed up these results, showing that older adults (age 52-85) who carry the KL variant associated with higher klotho levels also had significantly better cognitive function. This looked to be stable over age – so those people in their 50s with higher klotho had better cognitive scores matched with people their same age. Likewise, people in their 70s with higher klotho had better scores than people their age. [ref]

Mouse studies where they knock out the klotho gene during development shows that it is important in brain development and myelination of the neurons.[ref]  Decreased klotho in mice causes cognitive impairment by age 7 weeks.[ref]

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

Klotho and diabetes:

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 be a biomarker for early kidney disease also. [ref]

In diabetic mice, pre-treatment with injections of klotho was found to protect from diabetic cardiomyopathy. It reduced the oxidative stress that was triggered by high blood glucose levels. [ref]

 


Genetic variants of KL (klotho gene):

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: normal

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

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: normal

 


Lifehacks:

Cordyceps mushrooms:

An extract of cordyceps was tested on kidney cells. The cordyceps increased the expression of klotho. Whether this would increase klotho throughout the body or not, I don’t know. But it may be something to try if you have high blood pressure and want to prevent kidney damage. [ref]

An animal study also showed that cordyceps improved klotho protein levels in a mouse model that mimicked kidney problems.[ref]

My favorite way to incorporate cordyceps is in my morning cup of coffee.

Exercise

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]

Growth Hormones

A very small study (16 participants) found that growth hormone injections for 7 days increased klotho concentrations.  This was true both for healthy participants and patients with mild chronic kidney disease. [ref]

Decrease alcohol consumption:

Alcohol consumption correlates to lower klotho levels in middle-aged adults. [ref]

Statin plus angiotensin II drug:

A trial of fluvastatin and valsartan (a statin plus angiotensin II blood pressure med) increased klotho by 70% over a 30 day treatment period. The increased klotho returned to baseline five months after the treatment was discontinued. [ref]

GABA (mouse study):

GABA significantly increased klotho levels in mice with type-1 diabetes. [ref] A human cell study showed a similar increase in klotho levels from GABA, but there don’t seem to be any actual human trials. [ref]

Calcitriol plus Resveratrol (rat study):

In a study using an animal model of induced aging, calcitriol plus resveratrol increased serum klotho levels. [ref] Calcitriol is the active form of vitamin D that is available via prescription.

 

 

 

2 Comments on “Klotho Gene: Anti-aging superpowers?

  1. I have 23 and Me v.5 results. No rs9536314 is on the list. Nor rs650439. Was this measure removed after v4?

    • Hi Carol,
      Yes. If you look at the links above for 23andMe, I indicate whether they are in the v4 or v5 data. I do that on most of my more recent articles to save you some time and frustration on hunting for the rs ids (and I’m working on editing the older articles as well).
      Debbie

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