Klotho proteins have been researched for years; this family of proteins are shown to have roles in longevity. Earlier studies in the 1990s revealed that rodents with mutated Klotho genes exhibited premature aging symptoms, shorter lifespans, infertility and early onset of age-related diseases such as osteoporosis and arteriosclerosis. A later study in mice showed that overexpression of Klotho genes extended longevity by affecting signaling of insulin and insulin-like growth factor 1 (IGF1).
A new study by researchers from Yale University, published in the journal Nature, focused on the mechanisms of action of beta klotho and alpha klotho, which are receptor proteins found on some tissue membranes and work with endocrine FGS, which regulate metabolism in the kidneys, liver and the brain.
The researchers’ investigation yielded several insights. First, they found that 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. The researchers commented that this relationship between beta-Klotho and FGF21 can serve to galvanize the development of therapies for conditions blood sugar dysfunction in obese individuals.
Senior study author Joseph Schlessinger, chair of pharmacology at Yale School of Medicine, said, “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.”
The authors also describe a new variant of FGF21 that they said has 10 times higher potency and cellular activity. Additionally, the research team presented evidence of how the enzyme glycosidase, which breaks down sugars, evolved into a receptor for a hormone that lowers blood sugar, which may not be a coincidence, Schlessinger added.
Lee, S., et al. “Structures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signaling” Nature volume553, pages 501–505, Jan 2018