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 on inhibiting two protein complexes, mTORC1 and mTORC2, respectively.

The study suggests that molecules that specifically inhibit mTORC1 may combat age-related diseases without the insulin-resistance side effect, which can predispose people to diabetes.

Senior author Joseph A. Baur, PhD, assistant professor of Physiology, Perelman School of Medicine, University of Pennsylvania, and colleagues at the Whitehead Institute for Biomedical Research and Broad Institute, Massachusetts Institute of Technology, in Cambridge, MA, describe their work in this week's issue of Science. Baur is also a member of Penn's Institute for Diabetes, Obesity, and Metabolism.

"The hope is that in the future, we will be able to develop molecules that target mTORC1 specifically, separating out the of rapamycin on aging and disease, and leaving behind the side effect," says Baur.

"Our results demonstrate that reduced mTORC1 signaling is sufficient to extend lifespan and mTORC2 signaling has profound effects on metabolism," says co-first author Lan Ye, PhD, postdoctoral fellow in the Baur lab. "Our findings indicate that mTORC2 may be an important player in the pathogenesis of and ."

One Compound, Many Effects

Rapamycin extends the lifespan of yeast, flies, and mice and is also an immunosuppressant drug for and an anti-cancer drug. It was first discovered as a of Streptomycin hygroscopicus, a bacterium found in a soil sample from , an island also known as Rapa Nui, hence the name. Rapamycin was originally developed as an antifungal agent, but that use was abandoned when it was discovered to have immunosuppressive properties.

The mTOR complexes, for mammalian (or mechanistic) target of rapamycin, are proteins that regulate cell growth, movement, and survival, as well as protein synthesis and transcription. Specifically, there are two mTOR complexes and one mTOR protein. The mTOR protein is the core of both complexes (mTORC1 and mTORC2), which behave differently based on their associated proteins. One or both of the mTOR complexes can be inappropriately activated in certain cancers, and dual-specific inhibitors are being developed as chemotherapeutic agents.

Several theories have been put forward by researchers to explain the observations that patients receiving rapamycin are more prone to developing glucose intolerance, which can lead to diabetes. Chronic treatment with rapamycin impairs glucose metabolism and the correct functioning of insulin in mice, despite extending lifespan. The research team demonstrated that rapamycin disrupts mTORC2 in the mice, and that mTORC2 is required for the insulin-mediated suppression of glucose metabolism in the liver.

On the other hand, they also demonstrated that decreasing mTORC1 signaling was sufficient to extend lifespan independently from changes in glucose metabolism. They used a mouse strain in which mTORC1 activity was decreased and saw that was extended by 14 percent, yet the animals had normal glucose metabolism and insulin sensitivity.

"Besides developing more specific inhibitors for mTORC1, we remain very interested in understanding why mTORC1 inhibition extends life in the first place," explains Baur. "We're currently looking at the interactions between mTORC1 and other pathways that influence longevity, as well as its effects on things like free radical generation and protein quality control."

The MIT colleagues on the Science paper are co-first author Dudley W. Lamming, PhD, Whitehead Institute, and co-senior author David M. Sabatini, MD, PhD, member of Whitehead Institute, Howard Hughes Medical Institute investigator, and professor of biology at MIT. This study was funded by grants from the American Federation for Aging Research, the National Cancer Institute, and the Bingham Trust, through Penn's Institute on Aging.

Explore further: Researchers find possible therapeutic strategy to combat premature birth

More information: "Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity" Science, published March 30, 2012

Related Stories

Researchers find possible therapeutic strategy to combat premature birth

October 24, 2011
Scientists who developed a novel mouse model mimicking human preterm labor have described a molecular signaling pathway underlying preterm birth and targeted it to stop the problem.

Scientists discover new component of key growth-regulating signaling pathway

June 14, 2011
(PhysOrg.com) -- Researchers in the lab of Whitehead Institute Member David Sabatini have identified a new substrate of the mammalian target of rapamycin (mTOR) kinase, called Grb10, by using a two-pronged approach of mass ...

Feed a cold -- starve a tumor

October 21, 2011
The condition tuberous sclerosis, due to mutation in one of two tumor suppressor genes, TSC1 or TSC2, causes the growth of non-malignant tumors throughout the body and skin. These tumors can be unsightly and cause serious ...

Penn Study Explains Paradox of Insulin Resistance Genetics

October 25, 2011
(Medical Xpress) -- Obesity and insulin resistance are almost inevitably associated with increases in lipid accumulation in the liver, a serious disease that can deteriorate to hepatitis and liver failure.  A real paradox ...

Recommended for you

Researchers describe mechanism that underlies age-associated bone loss

September 22, 2017
A major health problem in older people is age-associated osteoporosis—the thinning of bone and the loss of bone density that increases the risk of fractures. Often this is accompanied by an increase in fat cells in the ...

Researchers develop treatment to reduce rate of cleft palate relapse complication

September 22, 2017
Young people with cleft palate may one day face fewer painful surgeries and spend less time undergoing uncomfortable orthodontic treatments thanks to a new therapy developed by researchers from the UCLA School of Dentistry. ...

Exosomes are the missing link to insulin resistance in diabetes

September 21, 2017
Chronic tissue inflammation resulting from obesity is an underlying cause of insulin resistance and type 2 diabetes. But the mechanism by which this occurs has remained cloaked, until now.

Thousands of new microbial communities identified in human body

September 20, 2017
A new study of the human microbiome—the trillions of microbial organisms that live on and within our bodies—has analyzed thousands of new measurements of microbial communities from the gut, skin, mouth, and vaginal microbiome, ...

Study finds immune system is critical to regeneration

September 20, 2017
The answer to regenerative medicine's most compelling question—why some organisms can regenerate major body parts such as hearts and limbs while others, such as humans, cannot—may lie with the body's innate immune system, ...

Immune cells produce wound healing factor, could lead to new IBD treatment

September 20, 2017
Specific immune cells have the ability to produce a healing factor that can promote wound repair in the intestine, a finding that could lead to new, potential therapeutic treatments for inflammatory bowel disease (IBD), according ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

gmurphy
not rated yet Mar 29, 2012
So much money waiting for the first commercially viable life-extension drug treatment, I can't understand why there's not more research in this area, they seem to be onto several promising leads

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.