Featured Research

from universities, journals, and other organizations

Duality of longevity drug explained

Date:
March 29, 2012
Source:
Perelman School of Medicine at the University of Pennsylvania
Summary:
Scientists have now 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.

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 beneficial effects of rapamycin on aging and disease, and leaving behind the insulin-resistance 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 type 2 diabetes and metabolic syndrome."

One Compound, Many Effects Rapamycin extends the lifespan of yeast, flies, and mice and is also an immunosuppressant drug for organ transplants and an anti-cancer drug. It was first discovered as a byproduct of Streptomycin hygroscopicus, a bacterium found in a soil sample from Easter Island, 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 lifespan 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.


Story Source:

The above story is based on materials provided by Perelman School of Medicine at the University of Pennsylvania. Note: Materials may be edited for content and length.


Journal Reference:

  1. Lamming, et al. Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity. Science, 30 March 2012: 1638-1643 DOI: 10.1126/science.1215135

Cite This Page:

Perelman School of Medicine at the University of Pennsylvania. "Duality of longevity drug explained." ScienceDaily. ScienceDaily, 29 March 2012. <www.sciencedaily.com/releases/2012/03/120329141529.htm>.
Perelman School of Medicine at the University of Pennsylvania. (2012, March 29). Duality of longevity drug explained. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2012/03/120329141529.htm
Perelman School of Medicine at the University of Pennsylvania. "Duality of longevity drug explained." ScienceDaily. www.sciencedaily.com/releases/2012/03/120329141529.htm (accessed July 31, 2014).

Share This




More Health & Medicine News

Thursday, July 31, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Dangerous Bacteria Kills One in Florida

Dangerous Bacteria Kills One in Florida

AP (July 31, 2014) Sarasota County, Florida health officials have issued a warning against eating raw oysters and exposing open wounds to coastal and inland waters after a dangerous bacteria killed one person and made another sick. (July 31) Video provided by AP
Powered by NewsLook.com
Health Insurers' Profits Slide

Health Insurers' Profits Slide

Reuters - Business Video Online (July 30, 2014) Obamacare-related costs were said to be behind the profit plunge at Wellpoint and Humana, but Wellpoint sees the new exchanges boosting its earnings for the full year. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Peace Corps Pulls Workers From W. Africa Over Ebola Fears

Peace Corps Pulls Workers From W. Africa Over Ebola Fears

Newsy (July 30, 2014) The Peace Corps is one of several U.S.-based organizations to pull workers out of West Africa because of the Ebola outbreak. Video provided by Newsy
Powered by NewsLook.com
Weather Kills 2K A Year, But Storms Aren't The Main Offender

Weather Kills 2K A Year, But Storms Aren't The Main Offender

Newsy (July 30, 2014) Health officials say 2,000 deaths occur each year in the U.S. due to weather, but it's excessive heat and cold that claim the most lives. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

More Coverage


On the Path to Age-Defying Therapies

Mar. 29, 2012 The drug rapamycin extends lifespan in lab animals, yet it's linked to two hallmarks of diabetes. By teasing apart its activity, researchers have determined that inhibiting only the protein ... read more
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

    Environment News

    Technology News



      Save/Print:
      Share:

      Free Subscriptions


      Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

      Get Social & Mobile


      Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

      Have Feedback?


      Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
      Mobile: iPhone Android Web
      Follow: Facebook Twitter Google+
      Subscribe: RSS Feeds Email Newsletters
      Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins