A family of longevity proteins has been examined in detail for the first time. The new insight may help create innovative treatments for a range of diseases, including some cancers, obesity, and diabetes.
A family of molecules called Klotho proteins has intrigued researchers interested in the aging process for decades.
They are “named after the Greek goddess who spun the thread of life.” Involved in metabolism, they also appear to play a role in longevity.
Studies in the late 1990s showed that mice with mutated Klotho genes suffer from a condition similar to premature aging: they had much shorter lifespans, became infertile, and even developed arteriosclerosis, osteoporosis, and emphysema, as well as skin atrophy.
A recent study takes a fresh, more detailed look at the structure of these proteins. The researchers set out to get a better understanding of what they do in the body and how they do it. The scientists, from Yale University in New Haven, CT, believe that their findings have implications for the future treatment of many conditions, including obesity, diabetes, and some cancers.
There are two proteins in the Klotho family: alpha and beta. Both are receptors that sit on the membranes of certain tissues. They work in conjunction with molecules called endocrine FGFs, which regulate metabolic processes in tissues and organs including the brain, liver, and kidneys.
Klotho proteins and FGFs operate in close quarters. In fact, those interested in longevity have, for some time, debated whether Klotho proteins or FGFs are the molecules responsible for altering aging.
Using X-ray crystallography, the team built up a detailed picture of beta-Klotho’s structure. The results are published this week in the journal Nature.
Their first discovery was that beta-Klotho is the primary receptor for FGF21, a hormone that is produced during starvation. FGF21 has a range of effects — for instance, it increases insulin sensitivity and enhances glucose metabolism to induce weight loss.
Senior study author Joseph Schlessinger, who is chair of pharmacology at Yale School of Medicine, explains the significance of this finding, saying, “Like insulin, FGF21 stimulates metabolism including glucose uptake.
“In animals and in some clinical trials of FGF21,” he continues, “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.”
If the activity of this hormone could be stimulated pharmacologically, it might be useful in treating conditions such as diabetes and obesity. In the paper, the team also describes a variant of FGF21 that is 10 times more potent, potentially offering an even greater therapeutic advantage.
Additionally, they found evidence of how glycosidase — a similarly structured enzyme that breaks down sugars — evolved into a hormone receptor “that lowers blood sugar.” As Schlessinger adds, this “may not be a coincidence.”
There is a huge need for more effective treatments for obesity and diabetes, so anything that can offer a novel route is likely to gain a great deal of attention.
Enhancing this pathway could be of benefit. On the other side of the coin, the authors believe that blocking the pathway might lead to better treatments for liver cancer and bone diseases.
Schlessinger concludes by summarizing the long road ahead: “The next step will be to make better hormones, make new potent blockers, do animal studies, and move forward.” More studies are already in the pipeline.