On the path to age-defying therapies

Image:  Computer-generated model of mTORC1

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. This computer-generated model of mTORC1 is based on almost 30,000 cryo-electron microscopy images of the molecule. 

Image: Courtesy of Science/AAAS.

March 29, 2012

Tags: Sabatini LabProtein Function

CAMBRIDGE, Mass. — 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.

Written by Nicole Giese Rura

* * * 

David Sabatini's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.

* * *

Full Citation:

“Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity”

Science, published March 30, 2012

Dudley W. Lamming (1*), Lan Ye (2*), Pekka Katajisto (1), Marcus D. Goncalves (3), Maki Saitoh (1), Deanna M. Stevens (1), James G. Davis (2), Adam B. Salmon (4), Arlan Richardson (4), Rexford S. Ahima (3), David A. Guertin (1,5), David M. Sabatini (1), and Joseph A. Baur (2).

1. Whitehead Institute for Biomedical Research, Cambridge MA 02142; Department of Biology, MIT, Cambridge, MA 02139; Howard Hughes Medical Institute, MIT, Cambridge, MA 02139; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA 02142; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139
2,3. Institute for Diabetes, Obesity, and Metabolism and Departments of 2:Physiology and 3:Medicine, University of Pennsylvania School of Medicine, Philadelphia PA 19104
4. The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio TX.
5. Present Address: University of Massachusetts Medical School, Worcester, MA
* These authors contributed equally to this work

David Sabatini

Whitehead Member David Sabatini

Photo: Chris Sanchez/Whitehead


CONTACT

Nicole Giese Rura
Phone: 617-258-6851
Email: rura@wi.mit.edu


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