Thread of Life: Klotho and Dementia

By Ram Rao, Ph.D., Principal Research Scientist for Apollo Health

Do you remember the Greek mythological story of the three sisters, the “Fates?” While Klotho spun the thread of human life, Lachesis dispensed the thread of fate, and the last sister, Atropos, cut the thread. Together, the three sister fates controlled the lives of each human being and had the power to decide who lived and who died. How does the Greek mythological character Klotho relate to the physiology of aging and neurodegeneration?

The Klotho gene and protein were discovered in 1997 by a Japanese scientist named Makoto Kuro-o. Klotho was discovered when researchers led by Kuro-o noticed that an inbred variant of mice had aged more quickly and had a shortened lifespan. These mice exhibited symptoms of multiple organ degeneration and cardiovascular disease, among other age-related difficulties. They tracked this abnormal physiology to a single inactivated gene called Klotho. While subsequent experiments confirmed this observation in other mouse strains, researchers also determined that higher levels of Klotho protein in mice extend lifespan significantly. When the Klotho gene was silenced or rendered defective, it resulted in animals having a shorter lifespan.

In contrast, when the gene was overexpressed, it resulted in a longer lifespan. Thus, the amount of Klotho could affect how long the rodents lived. Studies in humans have shown that while levels of Klotho diminished with age, humans who naturally have more Klotho tend to live longer. Lower levels of Klotho are associated with other symptoms of aging at the cellular level. This prompts the question of whether Klotho might be useful in treating age-related diseases.

There are three sub-families of the Klotho protein that are formed, termed alpha, beta, and gamma. While the kidney is the primary source of Klotho, it is also present in blood, urine, and cerebrospinal fluid. The alpha Klotho is the most abundant form of the protein within the brain and is present in the memory centers of the brain and the central structure of the brain called the choroid plexus, which produces the cerebrospinal fluid. Some people who carry an alteration in the Klotho gene that causes them to produce higher protein levels than average scored better than people whose brains carry normal levels of Klotho. Higher levels of Klotho have been tied to large cerebral cortex volume, strong functional connectivity, and better cognition. Additionally, research studies have associated higher circulating Klotho levels with a decreased risk for heart disease, decreased macrovascular complications in patients with type-2 diabetes, and improved grip strength.

Klotho also suppresses both oxidative stress and senescence-associated inflammation, thus functioning both as an intracellular anti-inflammatory and an anti-aging factor. Chronic inflammation in the brain is linked to Alzheimer’s disease, brain fog, and other neurodegenerative conditions. While the role of Klotho protein in human health and disease is still being studied, there are complementary approaches (see below) that may increase Klotho levels.

Exercise: Physical exercise stimulates the production of Klotho protein. Research studies indicate that any kind of physical activity secretes Klotho, which in turn offers neuroprotection.

Vitamin D: Few studies show that the administration of active vitamin D and its analog increases the secreted form of Klotho.

Probiotics: Probiotic foods contain beneficial bacteria, which convert carbohydrates into lactic acid (i.e., fermentation), which in turn creates a healthy microbiome. A few research studies now show that probiotic foods improve the expression of Klotho protein.

Medicinal Mushrooms: In addition to increasing a beneficial neurochemical called nerve growth factor (NGF), mushrooms also increase the levels of Klotho protein.

Notice that the above-mentioned complementary approaches are also part of the Bredesen Seven (or “B7”) strategies to optimize brain health. Since 20% of individuals who tend to have more Klotho live longer and have better cognitive function, the pharmaceutical industry is now investigating the protein’s potential as a therapeutic to boost the levels of Klotho for optimal brain health. If successful, the Klotho mimetic will have the power to decide the fate of humans. However, we do not need to wait for a pharmaceutical drug to enhance the levels of Klotho. We can adopt any or all of the natural approaches mentioned above to enhance Klotho levels and experience optimal lifespan.