Could a Protein Called Klotho Block Dementia and Aging?

Could a Protein Called Klotho Block Dementia and Aging?

Summary: Genetically increasing klotho helps boost cognitive function in mice models of Alzheimer’s disease, researchers report.

Source: UCSF.

Neurologist and neuroscientist Dena Dubal, MD, PhD, is taking an innovative approach to battling neurodegenerative diseases like Alzheimer’s disease and dementia. Rather than trying to understand the specific mechanisms that cause each disease, she took a step back and asked, “What do all these conditions have in common?”

The answer: old age.

Over time, something happens to our cells and organs, and in the past three decades scientists have begun to unravel exactly what that something is – and the cellular mechanisms our bodies use to fight it.

Dubal, an associate professor of neurology at UC San Francisco, thinks we can use the science of aging to help stave off these neurodegenerative diseases.

“Aging is the biggest risk factor for cognitive problems, and cognitive problems are one of the biggest biomedical challenges that we face,” she said. “Why don’t we just block aging?”

Blocking aging is easier said than done, but Dubal jumped head first into the problem by studying a protein called klotho.

Klotho was named after the Greek fate Clotho, a mythological figure who spun the thread of life and had say over when gods and mortals lived and died. The Japanese researchers who named the protein found that the amount of klotho produced by mice could affect how long the rodents lived. Other researchers later discovered that humans who naturally have more klotho tend to live longer.

Living longer is one thing, but Dubal, a member of the UCSF Weill Institute for Neurosciences, wanted to know if klotho could help our brains stay healthier and more resilient to cognitive problems. Could klotho levels predict how quickly subjects solved a variety of puzzles that test cognition? In both humans and mice, she found the same result: more klotho meant better cognitive function.

To bring this boost in brain health to everyone, and not just the 20 percent of people who happen to have naturally high klotho, Dubal is testing the protein’s potential as a therapeutic.

The protein can exist in two forms: the first is anchored to the cell membranes of your organs, mostly your brain and kidneys; and the second occurs when the protein is cut loose from its anchor and freed to float around the bloodstream.

Dubal found that by simply injecting this floating form into mice, she could re-create the cognitive boost she found by genetically increasing klotho.

brain

“We found that those mice that had been treated, within four hours had better brain function,” she said. This worked in young mice, old mice, and mice that had a condition similar to Alzheimer’s.

Next, Dubal’s lab will try to understand how klotho acts on the brain without crossing the blood-brain barrier. And ultimately, could klotho become a therapy for humans to improve brain health and protect against aging and disease?

“For humans, the end game really is: how can we increase our ‘healthspan?’” said Dubal. “And that may go hand in hand with an increase in life span, because the things that help us to live longer are also the things that help us to live better.”

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Klotho enzyme , calcium, insulin , Vitamin D and Alzheimer

Klotho is an enzyme that in humans is encoded by the KL gene.[5]

This gene encodes a type-I membrane protein that is related to β-glucuronidases. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing, bone loss and alcohol consumption.[6][7]Transgenic mice that overexpress Klotho live longer than wild-type mice.[8]

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Function

Klotho is a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in aging. Its discovery was documented in 1997 by Kuro-o et al.[9] The name of the gene comes from Klotho or Clotho, one of the Moirai, or Fates, in Greek mythology.

The Klotho protein is a novel β-glucuronidase (EC number 3.2.1.31) capable of hydrolyzing steroid β-glucuronides. Genetic variants in KLOTHO have been associated with human aging,[10][11] and Klotho protein has been shown to be a circulating factor detectable in serum that declines with age.[12]

The binding of certain fibroblast growth factors (FGF’s) viz., FGF19, FGF20, and FGR23, to their Fibroblast growth factor receptors, is promoted by their interaction with Klotho.[13]

Klotho-deficient mice manifest a syndrome resembling accelerated human aging and display extensive and accelerated arteriosclerosis. Additionally, they exhibit impaired endothelium dependent vasodilation and impaired angiogenesis, suggesting that Klotho protein may protect the cardiovascular system through endothelium-derived NO production.

Although the vast majority of research has been based on lack of Klotho, it was demonstrated that an overexpression of Klotho in mice might extend their average life span between 19% and 31% compared to normal mice.[8] In addition, variations in the Klotho gene (SNP Rs9536314) are associated with both life extension and increased cognition in human populations.[14]

The mechanism of action of klotho is not fully understood, but it changes cellular calcium homeostasis, by both increasing the expression and activity of TRPV5 and decreasing that of TRPC6.[15] Additionally, klotho increases membrane expression of the inward rectifier channel ROMK.[15]

Klotho-deficient mice show increased production of vitamin D, and altered mineral-ion homeostasis is suggested to be a cause of premature aging‑like phenotypes.

Because the lowering of vitamin D activity by dietary restriction reverses the premature aging‑like phenotypes and prolongs survival in these mutants.

These results suggest that aging‑like phenotypes were due to klotho-associated vitamin D metabolic abnormalities (hypervitaminosis).