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On the path to age-defying therapies

Date:
March 29, 2012
Source:
Whitehead Institute for Biomedical Research
Summary:
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 cluster known as mTORC1 prolongs life in mice without adversely affecting glucose tolerance or insulin sensitivity.

One of the secrets to a longer, healthier life is simply to eat less. When subjected to calorie restriction (CR), typically defined as a 20-40% reduction in caloric intake with corresponding maintenance of proper nutrition, animals in labs not only live longer, but also have improved insulin sensitivity and glucose tolerance, both of which decline during aging. Yet, for all of its benefits, CR's restricted diet is a stumbling block for most Americans. If only we had a drug that could do the same thing. Researchers are now testing one possibility.
Credit: anyaivanova / Fotolia

One of the secrets to a longer, healthier life is simply to eat less. When subjected to calorie restriction (CR), typically defined as a 20-40% reduction in caloric intake with corresponding maintenance of proper nutrition, animals in labs not only live longer, but also have improved insulin sensitivity and glucose tolerance, both of which decline during aging.

Yet, for all of its benefits, CR's restricted diet is a stumbling block for most Americans. If only we had a drug that could do the same thing.

Well, we do, sort of. The drug rapamycin, which is used for immunosuppression in organ transplantations, mimics the longevity effects of CR and may tap into the same cellular pathway as CR. Unlike CR, however, rapamycin actually impairs glucose tolerance and insulin sensitivity, two hallmarks of diabetes. Clearly, rapamycin is doing something CR is not.

To understand better rapamycin's benefits and risks, researchers from the lab of Whitehead Institute Member David Sabatini and Joseph Baur, assistant professor of Physiology, at the University of Pennsylvania's Perelman School of Medicine, have discovered precisely how rapamycin is behaving at the cellular level. Their intriguing results are published this week in the journal Science.

"We know that despite its adverse effects, rapamycin still prolongs lifespan, so there's a potential that we could make it better by just having lifespan affected and not induce the adverse effects," says Sabatini, who is a professor of biology at MIT and a Howard Hughes Medical Institute (HHMI) investigator. "The data in this paper suggest that it's possible."

Rapamycin, which is also called sirolimus and marketed in the United States as Rapamune, is a known inhibitor of the mechanistic target of rapamycin complex 1 (mTORC1), a protein complex that regulates many cellular processes linked to growth and differentiation. mTORC1 is part of a cellular signaling pathway, called mTOR, which responds to nutrients and growth factors. Mechanistic target of rapamycin complex 2 (mTORC2) is also part of the mTOR pathway and regulates insulin signaling.

Rapamycin has generally been thought to target primarily mTORC1. But work by Dudley Lamming and Lan Ye, co-authors of the Science paper and postdoctoral fellows in the Sabatini and Baur labs respectively, indicates that in mice, rapamycin also inhibits mTORC2, thereby reducing insulin sensitivity.

To see if rapamycin's positive effects on lifespan effects could be separated from its negative metabolic effects, Lamming and Ye bred mice whose mTORC1 activity was partially inhibited but whose mTORC2 activity remained largely intact. The females of this mouse population lived longer than control mice while maintaining normal insulin sensitivity.

"This shows that disrupting mTORC1 alone is capable of extending lifespan, if you can find a way do that," says Lamming.

For Baur, the experiments' results indicate that there is a possibility of identifying a better anti-aging drug than rapamycin.

"Our work highlights the potential utility of molecules that target mTORC1 specifically and suggests there is hope that by targeting this pathway, you could really get something that ameloriates age-related diseases without causing more problems than it solves," says Baur. "If you're taking an anti-aging drug as a preventive measure, you probably don't want to pay the price of diabetes."

This work was supported by the National Institutes of Health (NIH), the National Cancer Institute (NCI), the American Federation of Aging Research (AFAR), the Institute on Aging at the University of Pennsylvania, the Damon Runyon Cancer Research Foundation, the American Heart Association, and the Academy of Finland.


Story Source:

The above story is based on materials provided by Whitehead Institute for Biomedical Research. The original article was written by Nicole Giese Rura. 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:

Whitehead Institute for Biomedical Research. "On the path to age-defying therapies." ScienceDaily. ScienceDaily, 29 March 2012. <www.sciencedaily.com/releases/2012/03/120329141531.htm>.
Whitehead Institute for Biomedical Research. (2012, March 29). On the path to age-defying therapies. ScienceDaily. Retrieved July 29, 2014 from www.sciencedaily.com/releases/2012/03/120329141531.htm
Whitehead Institute for Biomedical Research. "On the path to age-defying therapies." ScienceDaily. www.sciencedaily.com/releases/2012/03/120329141531.htm (accessed July 29, 2014).

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Mar. 29, 2012 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 ... read more
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