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,
- 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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