The hormones alpha-Klotho and beta-Klotho were named after one of three Greek “fates”: Clotho, a goddess who lays out the thread of life, the length of which is determined by her two sisters. They’re often called “anti-aging” hormones because of their reputed role in regulating metabolism and longevity. Now two separate studies are unlocking the structure and function of Klotho proteins—and shedding new light on their true role in age-related disorders like heart disease.
Researchers led by New York University School of Medicine studied the structure of alpha-Klotho and a related protein, fibroblast growth factor 23 (FGF23). They were inspired by 20-year-old studies showing that mice engineered to lack either protein suffered prematurely from diseases of aging, according to a statement from the university.
The anti-aging effects were initially attributed to alpha-Klotho, but the NYU team determined that it’s actually FGF23 that’s modulating the aging process, and that alpha-Klotho is merely facilitating FGF23 signaling. Their discoveries were published in the journal Nature.
Using X-ray crystallography, the NYU team unlocked the atomic structure of alpha-Klotho, FGF23 and FGFR, the receptor protein that helps FGF23 deliver signals to cells. They discovered that alpha-Klotho helps FGF23 bind to its receptor and become active.
"By showing that all the ways in which [alpha-Klotho] was supposed to protect organs come instead from its ability to help FGF23 signal, we have shed new light on the underlying cause of aging," said lead author Moosa Mohammadi, Ph.D., a professor in of biochemistry and molecular pharmacology at NYU Langone Health, in the statement.
The NYU scientists also saw evidence that beta-Klotho helps boost the function of FGF21, a hormone that’s closely related to FGF23 and is at the center of another newly published Nature study. Scientists led by Yale University described the 3D structure of beta-Klotho, generating insights that they believe could lead to new therapies for diabetes, obesity, cancer and other diseases.
The Yale researchers showed that beta-Klotho binds to FGF21, thereby promoting insulin sensitivity, glucose metabolism and weight loss. Some clinical trials had shown that FGF21 can boost calorie burning without a change of diet, and the Yale team believes beta-Klotho plays a key role in that process. They also discovered a variant of FGF21 that is 10 times more potent, according to a statement.
Klotho has long been of interest to the biotech community. In 2016, Harvard and Boston University scientists launched a startup, Klogene, which is working on targeting Klotho proteins to combat a range of neurological diseases. In December, Klogene merged with another Klotho-inspired startup, Kogenix Therapeutics. The company says it is developing small molecules and gene therapy treatments centered around Klotho, but it has yet to provide details about its progress.
The Yale and NYU researchers are searching for ways to translate their discoveries into therapies for age-related diseases. Mohammadi’s team is working on developing drugs that can alter alpha-Klotho/FGF23 signaling via the newly discovered protein structures. They believe their findings could lead to new treatments for kidney and heart disease.
Joseph Schlessinger, senior author of the Yale study and chair of pharmacology at its medical school, is leading a team that’s exploring ways to both enhance and block the beta-Klotho pathway. Boosting it with drugs might alleviate diabetes and obesity, while blocking it could be a promising way to treat liver cancer, bone disorders and other diseases, they believe.
"The next step will be to make better hormones, make new potent blockers, do animal studies, and move forward," Schlessinger said in a statement.