A new federally-funded research project at the Ohio University Edison Biotechnology Institute and Heritage College of Osteopathic Medicine could lead to treatments that extend human lifespan and allow people to enjoy better health in their old age. The study, led by John Kopchick, Ph.D., has been awarded a five-year grant for more than $2.23 million from the National Institutes of Health.
"We're very excited about it," said Kopchick, Goll-Ohio Eminent Scholar and Distinguished Professor of Molecular Biology in the Department of Biomedical Sciences at the Heritage College, and principal investigator at the Edison Biotechnology Institute at Ohio University. He noted that one of the main objectives of NIH's National Institute on Aging is funding research to increase human "healthspan," which translates as "a better old age; a healthier old age."
Among those collaborating with Kopchick on the new research will be co-investigators Darlene Berryman, Ph.D., R.D., L.D., associate dean for research and innovation at the Heritage College, and Edward List, Ph.D., associate investigator with the Edison Biotechnology Institute.
"Dr. Kopchick's research on growth hormone has been tremendously important for our college, the University and the whole field of endocrinology," said Ken Johnson, D.O., executive dean of the Heritage College and OHIO's chief medical affairs officer. "This new avenue of that research, in collaboration with Dr. Berryman and Dr. List, has the potential to make real improvements in the health and wellness of our aging population. It's very exciting that it's happening here."
Kopchick, who is principal investigator on the new project, said it builds on his past research in growth hormone, which led to the discovery of the GH receptor antagonist drug, pegvisomant (trade name Somavert®). This drug, the first specific drug of its kind, is used to treat the disease acromegaly, and its commercialization has yielded $97 million in royalty income to Ohio University as of 2018.
"Dr. Kopchick is a world-renowned researcher whose work has been life-changing for those who suffer from acromegaly," Ohio University President Dr. M. Duane Nellis said. "With this grant, Dr. Kopchick and his team will remain on the cutting edge of growth hormone research and its impact on aging. We're proud that such revolutionary work is happening here at OHIO."
Unlocking the secrets of the world's oldest mouse
In the early 1990s, Kopchick and a graduate assistant genetically engineered a strain of mouse in which the receptor gene for GH was disrupted, preventing it from working. The dwarf mouse that resulted was found to live longer than normal mice (it holds the world record for oldest lab mouse) and to be healthier in significant ways. These mice are resistant to cancer, diabetes and cognitive decline and show less accumulation of senescent cells (cells that have stopped dividing and that play a role in aging). Kopchick's team has supplied these long-lived mice to gerontology researchers all over the world.
The long-term goal of the new project, according to a description given to NIH, is "to determine the molecular mechanisms that are responsible for these remarkable health and longevity benefits."
The researchers will investigate whether the health and lifespan improvements seen in the mice that were genetically modified in utero can be replicated if the disruption of the GH receptor gene is initiated in adult mice at six months of age - corresponding to about 25 years old for a human. They also want to see if lifespan can be further extended by treating the animals with rapamycin, a drug known to lengthen the lives of mice.
"There are two aims in the grant," Kopchick explained. "One is disrupting the gene in the early adult life of a mouse. The second is to take the long-lived mouse, the longest-lived mouse in the world, and see if we can make it live longer and healthier by adding rapamycin, which in normal mice will promote longevity a bit. So we want to tweak what we already did to see if we can make it better."
A promising approach to life extension
Kopchick noted that at a workshop of scientific experts on aging, held in Italy in 2013, participants discussed the various types of interventions now available for extending human lifespan. An article on the workshop in the journal Aging Cell, titled "Interventions to slow aging in humans: Are we ready?" recounted that the participants voted on six known life-extending strategies, ranking Kopchick's drug, the GH receptor antagonist, as the most promising.
"That's really what led to us doing all this work," Kopchick said. "The idea is, could a drug - our drug or similar compound - be used, not to delete the growth hormone receptor in humans, but to tie it up, to antagonize it, to prevent it from working." If the two aims of the research are successful, he believes this would suggest the approach should be tried with humans. He added that his team has already disrupted the GH receptor gene in mice of about six weeks old and found that in mice so treated, females do live longer.
"So we have the longest-lived mouse, and we know that in young life we can see the [increased longevity] effect in females," he said. "Now we want to see if we can see it in later adult life, and if we can, then can we use our drug or some similar yet-to-be-discovered compound to slow aging?"