Towards Therapies Based on Klotho

Klotho is one of the few definitively longevity-associated genes. The protein it produces is associated with a range of important processes, though its roles are far from fully understood. Evidence exists for increased klotho to improve stem cell function, enhance cognitive function and increase synaptic plasticity in older animals, though whether or not this extends to humans is a question yet to be resolved. We might take the studies showing correlations between klotho and cognition in aged human patients as a positive sign, however. As this article notes, research groups are presently working on therapies based on delivery or otherwise enhanced levels of klotho. Given the usual relationship between degree of life extension observed in mice (large) versus humans (small) for therapies of this nature, this is probably better thought of as a potential treatment for age-related neurodegeneration, or a modest enhancement for brain function at all ages, rather than a way to extend life significantly.

Neuroscientists are 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, they 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.

"Aging is the biggest risk factor for cognitive problems, and cognitive problems are one of the biggest biomedical challenges that we face. Why don't we just block aging?" Blocking aging is easier said than done, but researchers jumped head first into the problem by studying a protein called klotho. The 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 the researchers 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, they 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, researchers are 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. Researchers found that by simply injecting this floating form into mice, they could re-create the cognitive boost found by genetically increasing klotho. "We found that those mice that had been treated, within four hours had better brain function. This worked in young mice, old mice, and mice that had a condition similar to Alzheimer's. Next, researchers 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? 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."

Link: https://www.ucsf.edu/news/2018/01/409711/could-protein-called-klotho-block-dementia-and-aging

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