Secrets of longevity protein revealed

Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent study, researchers revealed the three-dimensional structure of one of these proteins, beta-Klotho, illuminating its intricate mechanism and therapeutic potential.

The study findings, could have implications for therapies developed to treat a wide range of medical conditions, including diabetes, obesity, and certain cancers, the researchers said.

The Klotho family of two receptor proteins are located on the surface of cells of specific tissues. The proteins bind to a family of hormones, designated endocrine FGFs, that regulate critical metabolic processes in the liver, kidneys, and brain, among other organs. To understand how beta-Klotho works, the research team used X-ray crystallography, a technique that provides high-resolution, three-dimensional views of these proteins.

The researchers’ analysis yielded several insights. First, beta-Klotho is the primary receptor that binds to FGF21, a key hormone produced upon starvation. When bound to beta-Klotho, FGF21 stimulates insulin sensitivity and glucose metabolism, causing weight loss. This new understanding of beta-Klotho and FGF21 can guide the development of therapies for conditions such as type 2 diabetes in obese patients, the researchers said.

“Like insulin, FGF21 stimulates metabolism including glucose uptake,” said a senior author. “In animals and in some clinical trials of FGF21, it shows that you can increase burning of calories without changing food intake, and we now understand how to improve the biological activity of FGF21.” The authors also describe a new variant of FGF21 that has 10 times higher potency and cellular activity.

Additionally, the research team presented evidence of how a structurally-related enzyme, glycosidase, which breaks down sugars, evolved into a receptor for a hormone that lowers blood sugar—which may not be a coincidence, the researcher added.

Having untangled the structure of beta-Klotho, the researchers have a platform for exploring potential therapies for multiple diseases. By developing drugs that enhance the pathway, he said, researchers can target diabetes and obesity. Conversely, using agents that block the pathway, they hope to explore therapies for conditions such as liver cancer and bone diseases, among others.

“The next step will be to make better hormones, make new potent blockers, do animal studies, and move forward,” the researcher said.

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New anti-ageing protein may combat obesity, cancers

Scientists have revealed the three-dimensional (3D) structure of an anti-ageing protein, that may not only increase human lifespan but also help develop therapies for age-related diseases such as diabetes, obesity and cancers.

 The Klotho proteins -- alpha and beta -- named after the Greek goddess Clotho, who spun the thread of life, play an important role in the regulation of longevity and metabolism. 

 Both work in tandem with molecules called endocrine FGFs, which regulate metabolic processes in tissues and organs including the brain, liver and kidneys, among other organs. 

In the study,  the team found that beta-Klotho is the primary receptor that binds to FGF21 -- a key hormone produced upon starvation. 

FGF21 has the potential for boosting insulin sensitivity and glucose metabolism, causing weight loss.
This new understanding of beta-Klotho and FGF21 can guide the development of therapies for conditions such as Type 2 diabetes in obese patients, the researchers said, in a paper published . 

"Like insulin, FGF21 stimulates metabolism including glucose uptake. In animals and in some clinical trials of FGF21, it shows that you can increase burning of calories without changing food intake, and we now understand how to improve the biological activity of FGF21," said a researcher.
A new variant of FGF21 with 10 times higher potency and cellular activity was also unveiled.

By developing drugs that enhance the pathway, the researcher said, researchers can target diabetes and obesity.

Conversely, using agents that block the pathway, they also hope to explore therapies for conditions such as liver cancer and bone diseases, among others.

"The next step will be to make better hormones, make new potent blockers, do animal studies, and move forward," the researcher said.

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Protein klotho can protect against Alzheimer's symptoms

A new research has revealed that a protein linked to longevity and enhanced cognition can protect against Alzheimer's symptoms.

Scientists from the Gladstone Institutes and the University of California, San Francisco reported that raising levels of the life-extending protein klotho can protect against learning and memory deficits in a mouse model of Alzheimer's disease and this boost in cognition occurred despite the accumulation of Alzheimer-related toxins in the brain, such as amyloid-beta and tau.

Ordinarily, Alzheimer's model mice have cognitive deficits, abnormal brain activity, and premature death, but raising klotho levels ameliorated these problems. The cognition-enhancing effects of the protein were powerful enough to counteract the effects of Alzheimer-related toxins, whose levels were unchanged.

Lead author Dena Dubal said that it's remarkable that they can improve cognition in a diseased brain despite the fact that it's riddled with toxins and in addition to making healthy mice smarter, they can make the brain resistant to Alzheimer-related toxicity. Without having to target the complex disease itself, they can provide greater resilience and boost brain functions.

Klotho's benefits may be due to its effect on a certain type of neurotransmitter receptor in the brain, called NMDA, that is crucially involved in learning and memory.

Senior author Lennart Mucke added that the next step will be to identify and test drugs that can elevate klotho or mimic its effects on the brain. They are encouraged in this regard by the strong similarities we found between klotho's effects in humans and mice in their earlier study. Mucke added that they think this provides good support for pursuing klotho as a potential drug target to treat cognitive disorders in humans, including Alzheimer's disease.

The study is published in the Journal of Neuroscience.

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