Dietary restriction has been proven to slow the aging process. Now, research from Oregon State University explains the action of rapamycin, a drug that seems to mimic the action of dietary restriction.
An antibiotic and immunosuppressant, rapamycin (also known as Sirolimus) has generated widespread interest for its apparent ability, in lab animal tests, to imitate the ability of dietary restriction to aid animals to live both longer and healthier.
Rapamycin has some drawbacks however, including an increase in insulin resistance that could set the stage for diabetes. The findings help explain why that happens, and what might be done to address it.
Combining rapamycin and another drug to offset the increase in insulin resistance might provide the benefits of this medication without the unwanted side effect.
Increasing Lifespan and General Health
Laboratory mice given rapamycin had reduced age-dependent decline in spontaneous activity, demonstrated more fitness, improved cognition and cardiovascular health, had less cancer and lived significantly longer than mice fed a normal diet.
“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 OSU College of Sciences Viviana Perez. “It could provide a way not only to increase lifespan but to address some age-related diseases and improve general health. We might find a way for people not only to live longer, but to live better and with a higher quality of life.”
Rapamycin was first derived from the soils of Easter Island, also known as Rapa Nui. It is mainly used as an immunosuppressant for preventing the rejection of organs and tissues.
More recently it was observed that it can also 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.
Mammalian Target of Rapamycin
Termed mTOR in mammals, for the term Mammalian Target of Rapamycin, this pathway (shown in the illustration above) has a critical evolutionary value.
mTOR helps an organism avoid excessive 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.”
The new research found that both dietary restriction and rapamycin inhibited lipid synthesis. But it was only dietary restriction that increased the oxidation of those lipids in order to produce energy.
Rapamycin, on the other hand, allowed a buildup of fatty acids and eventually an increase in insulin resistance, 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 rapamycin for treating aging and age-associated diseases in humans may be possible,” the researchers concluded.
Yu, Z., Wang, R., Fok, W. C., Coles, A., Salmon, A. B., & Pérez, V. I. (2014).
Rapamycin and Dietary Restriction Induce Metabolically Distinctive Changes in Mouse Liver.
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. doi:10.1093/gerona/glu053
Image: Oregon State University