Klotho Gene: Increased Longevity and Brain Health

Key takeaways:
~ Higher Klotho levels are linked to longer lifespan and slower aging.
~ Klotho helps balance calcium, phosphate, and vitamin D through its role with FGF23.
~ Higher Klotho levels improve cognitive function and may protect against dementia.
~ Genetic variants that impact Klotho levels are associated with better cognition in aging and longevity.

What is Klotho?

Klotho proteins, which include αKlotho and βKlotho, are produced in the brain, kidneys, and a few other tissues. This article primarily focuses on αKlotho, and for simplicity’s sake, it will be referred to just as Klotho.

Klotho is found in two forms:

• Membrane-bound: On the cell membrane, Klotho acts as a co-receptor that enhances the binding of fibroblast growth factors (FGFs), specifically FGF23.
• Soluble: Circulates in the blood and acts both as an antioxidant and to further facilitate FGF23 signaling.

The name “Klotho” comes from the Greek Fate who spins the thread of life—an apt metaphor, as this protein is deeply tied to lifespan and aging. Studies show that:[ref]

• Low Klotho = faster aging, higher disease risk
• High Klotho = longer lifespan, better health

Klotho’s role in aging:

The klotho protein was originally identified in mice that carried a mutation that caused accelerated aging. These mice were found to have a loss-of-function mutation in the Klotho gene, which caused atherosclerosis, osteoporosis, muscle loss, kidney disease, and sagging skin – starting at 3 to 4 weeks of age. Likewise, creating a mouse strain that overexpresses the klotho gene causes a longer lifespan.[ref][ref]

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

All of these things – calcium and phosphate regulation, vitamin D levels, insulin, IGF-1, and oxidative stress – are integral in aging. Klotho weaves them all together (yes, a ‘thread’ pun).

Mineral Balance and Kidney Function:

Fibroblast growth factors, FGFs, are a family of signaling molecules that control cell growth, tissue repair, development, and more.

Klotho works with FGF23, which is produced by the bone marrow and plays an important role in how the kidneys regulate phosphate and calcium levels, as well as vitamin D metabolism. When active vitamin D (1,25(OH)₂) and phosphate levels are high, FGF23 is produced in the bones and binds to its receptor with Klotho in the kidneys, promoting phosphate excretion and inhibiting vitamin D production.[ref][ref][ref]

Just as a little context, phosphate and calcium levels are critical for the way that muscles and nerves function. We can’t live without them at the right levels. The levels are tightly controlled in the body, with both being stored in the bones as a reservoir. Magnesium also comes into play here in the way that the levels of calcium and phosphorus are regulated. Essentially, we get calcium, phosphorus, and magnesium from food, and calcium is then stored in the bones until needed. The levels of calcium and phosphorus in the body are regulated by parathyroid hormone, vitamin D, calcitonin, and FGF23. Phosphorus is used for ATP, phospholipids, and DNA synthesis, while calcium is integral to the way that ion channels work, such as in neurons and the heart muscle.[ref] Basically, when the diet is high in phosphate, klotho causes lower active vitamin D (1,25 OH-D).[ref]

Klotho and Lifespan:

In humans, klotho levels have been 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? An extensive 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…

In studies, researchers look 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.[ref]

The studies on how klotho levels influence cognitive decline or dementia 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]

The difference may be the presence of the APOE E4 allele (risk factor for Alzheimer’s).  A fascinating study found that older adults who carry the APOE E4 allele had lower β-amyloid if they also carried the KL variant that increases klotho.[ref]

Related article: How to find out your APOE type

Klotho and Brain Health:

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

Another study 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 scores than their age-matched peers.[ref]

Animal studies are better able to define the function of this gene.

• Researchers eliminated the klotho gene in mice during development and found that it was important in brain development and myelination of the neurons.[ref]
• Decreased klotho in mice causes cognitive impairment.[ref]
• Injecting klotho protein into mice enhances cognitive function.[ref]

Klotho and chronic disease:

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 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]

Related article: Diabetes and genetic risk factors

Cardiovascular disease: Klotho also ties into cardiovascular function through the regulation of calcium and is thus interconnected to the mortality risk.[ref]

Lifehacks:

Lifestyle changes for increasing Klotho:

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.[ref][ref]

Decrease alcohol consumption: 
Higher levels of alcohol consumption correlate with lower klotho levels in middle-aged adults.[ref]

Medications and natural supplements that increase klotho levels:

Related Articles and Topics:

Longevity Genes: Hacking Healthspan Using Genomics

Telomere Length: How your Genes affect Telomeres and Aging

References: