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, 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."

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