The team’s findings, published on 17 January in the journal Nature, shed new light on how the hormone, named ‘alpha-Klotho’ after the Greek goddess who spins the thread of life, transmits a signal that slows ageing.
Klotho hormones are understood to play a role in the ageing process. Studies have shown that mice with a lack of alpha-Klotho suffered from premature ageing, as well as displaying signs of ageing-associated diseases such as cancer and cardiovascular disorders. Better understanding these hormones could hold the secret to treating or reversing such diseases.
It was previously thought that alpha-Klotho was in itself responsible for the regulation of longevity and metabolism. However, the new research reveals that it is in fact fibroblast growth factor 23 (FGF23), a type of molecule which regulates metabolic processes in organs such as the brain, liver and kidneys, that is needed for this to occur.
Using X-ray crystallography in which a detailed 3D image of the molecule can be viewed, the researchers were able to determine the atomic structure of alpha-Klotho. They discovered that instead of acting on its own as a longevity factor, alpha-Klotho enables FGF23 signalling by tethering FGF23 to its receptor so it can become active.
Moosa Mohammadi, lead study author and professor in the Department of Biochemistry and Molecular Pharmacology at NYU, said: “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 ageing. Our new structural data also pave the way for the design of novel agents that can either encourage or block FGF23-alpha-Klotho signalling as needed.”
Understanding the structure of Klotho hormones means researchers can now begin to investigate potential applications of anti-ageing molecules in the treatment of medical conditions such as diabetes, obesity and some cancers.
The study also found that a related hormone, beta-Klotho, serves as the same kind of co-receptor to help FGF21, which functions by sending signals that keep blood sugar and fatty acids in balance, and could be used in the treatment of diabetes and obesity.
The researchers behind this discovery have also begun investigating how FGF23 can be used to prevent heart hypertrophy.
Yale School of Medicine chair of pharmacology Joseph Schlessinger said: “The next step will be to make better hormones, make new potent blockers, do animal studies, and move forward.”