Public release date: 29-Mar-2012 [ | E-mail | Share ]

Contact: Nicole Giese Rura rura@wi.mit.edu 617-258-6851 Whitehead Institute for Biomedical Research

FINDINGS: The drug rapamycin has been shown to extend lifespan in lab animals, yet rapamycin has also been linked to impaired glucose tolerance and insulin sensitivity, two hallmarks of diabetes. By teasing apart rapamycin's activity at the cellular level, researchers at Whitehead Institute and the University of Pennsylvania have determined that inhibiting only the protein cluster known as the mechanistic target of rapamycin complex 1 (mTORC1) prolongs life in mice without adversely affecting glucose tolerance or insulin sensitivity.

RELEVANCE: With this novel understanding of how rapamycin produces its anti-aging effects, researchers may be able to develop a drug that specifically targets mTORC1, thereby promoting longevity while preventing the adverse effects associated with rapamycin.

CAMBRIDGE, Mass. (March 29, 2012) 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.

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On the path to age-defying therapies