One of the proven approaches to slowing the aging process is dietary restriction, but new research in the Linus Pauling Institute at Oregon State University is helping to explain the action of one of the only drugs that appears to mimic that process – rapamycin.
Rapamycin, an antibiotic and immunosuppressant approved for use about 15 years ago, has drawn extensive interest for its apparent ability – at least in laboratory animal tests – to emulate the ability of dietary restriction in helping animals to live both longer and healthier.
However, this medication has some drawbacks, including an increase in insulin resistance that could set the stage for diabetes. The new findings, published in the Journals of Gerontology: Biological Sciences, help to explain why that happens and what could be done to address it.
They suggest that a combination of rapamycin and another drug to offset that increase in insulin resistance might provide the benefits of this medication without the unwanted side effect.
“This could be an important advance if it helps us find a way to gain the apparent benefits of rapamycin without increasing insulin resistance,” said Viviana Perez, assistant professor in Biochemistry and Biophysics in the College of Science and principal investigator with the Linus Pauling Institute.
“This could provide a way not only to increase lifespan but to address some age-related diseases and improve general health,” Perez said.
“We might find a way for people not only to live longer, but to live better and with a higher quality of life.”
Rapamycin, first discovered from the soils of Easter Island in the South Pacific Ocean, is primarily used as an immunosuppressant to prevent rejection of organs and tissues. In recent years scientists observed that it can also function as a metabolic “signaler” that inhibits a biological pathway found in most higher life forms – the ability to sense when food has been eaten, energy is available and time for cell proliferation, protein synthesis and growth to occur.
This pathway has a critical evolutionary value – it helps an organism avoid too much cellular expansion and growth when energy supplies are insufficient. This is why some form of the pathway has been conserved across such many species, from yeast to fish to humans.
“Dietary restriction is one of the few interventions that inhibits this mTOR pathway,” Perez said. “And a restricted diet in laboratory animals has been shown to increase their lifespan about 25-3%.
"Human groups who eat less calories, such as some Asian cultures, also live longer.”
Besides reducing calorie intake by 40% than what’s normal in laboratory mice, another way to activate this pathway is with rapamycin. This drug appears to have a significant impact even when used late in life. Some clinical trials are already underway to explore this potential.
A significant drawback to long-term use of rapamycin is an increase in insulin resistance, which has been observed in both humans and laboratory animals. This occurs because both dietary restriction and rapamycin inhibit lipid synthesis, but only dietary restriction increases the oxidation of those lipids in order to produce energy.
Rapamycin, by contrast, allowed a buildup of fatty acids and eventually an increase in insulin resistance, which can lead to diabetes.
Researchers also noted that drugs are available to address that concern, including metformin, which is already given to some diabetic patients to increase lipid oxidation. In lab tests, the combined use of rapamycin and metformin prevented the unwanted side effect.
“If proven true, then combined use of metformin and rapamycin for treating aging and age-associated diseases in humans may be possible,” the researchers wrote in their conclusion.
Age-related diseases include many of the degenerative diseases that affect billions of people around the world and are among the leading causes of death: cardiovascular disease, diabetes, Alzheimer’s disease and cancer.
Laboratory mice that have received rapamycin have reduced the age-dependent decline in spontaneous activity, demonstrated more fitness, improved cognition and cardiovascular health, had less cancer and lived substantially longer than mice fed a normal diet.
This work was supported by the National Institutes of Health. Collaborators included researchers from Oklahoma University Health Science Center, the Oklahoma City VA Medical Center, University of Michigan-Flint, and South Texas Veterans Health Care System.
“There’s still substantial work to do, and it may not be realistic to expect with humans what we have been able to accomplish with laboratory animals,” Perez said.
“People don’t live in a cage and eat only the exact diet they are given. Nonetheless, the potential of this work is exciting.”
This research was funded by the National Institutes of Health, grant numbers AG036613 and AG021890.
