Research explains action of drug that may slow aging and related disease

May 20, 2014
Research explains action of drug that may slow aging and related disease
This graphic outlines the mechanism of action of rapamycin in its ability to mimic dietary restriction and slow the aging process. Credit: Oregon State University

A proven approach to slow the aging process is dietary restriction, but new research in the Linus Pauling Institute at Oregon State University helps explain the action of a drug 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 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, an assistant professor in the Department of Biochemistry and Biophysics in the OSU College of Science.

"It 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."

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.

Rapamycin, first discovered from the soils of Easter Island, or Rapa Nui in the South Pacific Ocean, is primarily used as an immunosuppressant to prevent rejection of organs and tissues. In recent years it was also observed that it can function as a metabolic "signaler" that inhibits a biological pathway found in almost all higher life forms – the ability to sense when food has been eaten, energy is available and it's okay for cell proliferation, protein synthesis and growth to proceed.

Called mTOR in mammals, for the term "mammalian target of rapamycin," this pathway has a critical evolutionary value – it helps an organism avoid too much cellular expansion and growth when energy supplies are insufficient. That helps explain why some form of the pathway has been conserved across such a multitude of 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 25-30 percent. Human groups who eat fewer calories, such as some Asian cultures, also live longer."

Aside from a food intake in that's about 40 percent fewer calories than normal, however, it's been found that another way to activate this pathway is with rapamycin, which appears to have a significant impact even when used late in life. Some human clinical trials are already underway exploring this potential.

A big drawback to long-term use of rapamycin, however, is the increase in insulin resistance, observed in both humans and laboratory animals. The new research identified why that is happening. It found that both dietary restriction and rapamycin inhibited lipid synthesis, but only dietary restriction increased the oxidation of those lipids in order to produce energy.

Rapamycin, by contrast, allowed a buildup of fatty acids and eventually an increase in , which in humans can lead to diabetes. However, the drug metformin can address that concern, and 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 for treating aging and age-associated diseases in humans may be possible," the researchers wrote in their conclusion.

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."

Explore further: A lifespan-extending drug has limited effects on aging

More information: Paper: ir.library.oregonstate.edu/xmlui/handle/1957/48128

Related Stories

A lifespan-extending drug has limited effects on aging

July 25, 2013
The immunosuppressive drug rapamycin has been shown to increase longevity in mice even when treatment begins at an advanced age. It is unclear if the extension of life also correlates with prolonged health and vigor.

Study reveals how cancer drug causes diabetic-like state

April 3, 2012
Scientists at Dana-Farber Cancer Institute have discovered why diabetic-like symptoms develop in some patients given rapamycin, an immune-suppressant drug that also has shown anti-cancer activity and may even slow ageing.

Therapeutic agent reduces age-related sleep problems in fruit flies

April 1, 2014
Elderly flies do not sleep well – they frequently wake up during the night and wander around restlessly. The same is true of humans. For researchers at the Max Planck Institute for Biology of Ageing in Cologne, the sleeplessness ...

Eat more, die young: Why eating a diet very low in nutrients can extend lifespan

March 17, 2014
A new evolutionary theory in BioEssays claims that consuming a diet very low in nutrients can extend lifespan in laboratory animals, a finding which could hold clues to promoting healthier ageing in humans.

Researchers examine molecular relationships between diabetes and heart disease

February 19, 2014
(Medical Xpress)—Chronic treatment with low doses of a drug used to boost organ survival in transplant patients has been found to improve metabolism and heart dysfunction in an animal model, according to a new study from ...

New study explains duality of longevity drug rapamycin

March 29, 2012
A Penn- and MIT-led team explained how rapamycin, a drug that extends mouse lifespan, also causes insulin resistance. The researchers showed in an animal model that they could, in principle, separate the effects, which depend ...

Recommended for you

Molecular hitchhiker on human protein signals tumors to self-destruct

July 24, 2017
Powerful molecules can hitch rides on a plentiful human protein and signal tumors to self-destruct, a team of Vanderbilt University engineers found.

New vaccine production could improve flu shot accuracy

July 24, 2017
A new way of producing the seasonal flu vaccine could speed up the process and provide better protection against infection.

Researchers develop new method to generate human antibodies

July 24, 2017
An international team of scientists has developed a method to rapidly produce specific human antibodies in the laboratory. The technique, which will be described in a paper to be published July 24 in The Journal of Experimental ...

A sodium surprise: Engineers find unexpected result during cardiac research

July 20, 2017
Irregular heartbeat—or arrhythmia—can have sudden and often fatal consequences. A biomedical engineering team at Washington University in St. Louis examining molecular behavior in cardiac tissue recently made a surprising ...

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

'Smart' robot technology could give stroke rehab a boost

July 19, 2017
Scientists say they have developed a "smart" robotic harness that might make it easier for people to learn to walk again after a stroke or spinal cord injury.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.