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New Study Teases Out mTOR's Roles in Aging and Metabolism

By Anette Breindl
Science Editor

Rapamycin is a decades-old drug, but it is still learning – or rather, still teaching scientists – new tricks. This week, researchers reported new insights into how the drug affects aging and metabolism – and most saliently, that its effects on the two can be separated.

After rapamycin was discovered, its first career, as an antifungal, was short-lived because it had immunosuppressive effects. Those same immunosuppressive effects, though, did lead to its approval as a drug to prevent transplant rejection.

The drug also is in clinical trials to treat cancer, as are a number of other drugs that go after its target protein, mammalian target of rapamycin or mTOR.

And a few years ago, rapamycin also became the first compound that extended the life span of mammals. Its effects appeared to mimic those of caloric restriction – with a puzzling exception: While caloric restriction improves insulin sensitivity and glucose control, mice – and patients – taking rapamycin tended to develop problems with insulin sensitivity and glucose control over time.

Co-corresponding author Joseph Baur, an assistant professor of physiology at the University of Pennsylvania's, Perelman School of Medicine, told BioWorld Today that it was "pretty clear" from previous studies that rapamycin's effects on longevity came via its inhibition of TORC1 . In March, another group showed that activating PTEN – one consequence of which is mTOR inhibition – also extended life span in mice. (See BioWorld Today, March 7, 2012.)

"The novel aspect of our study," Baur said, "is that mTORC2 is what's mediating the metabolic effects." The work appeared in the March 30, 2012, issue of Science.

The realization than mTOR functions within two protein complexes, TORC1 and TORC2, is itself relatively new. And clinical work has been focused on getting inhibitors that will affect both complexes, since that appears to be what is necessary to treat cancer. (See BioWorld Today, Jan 14, 2010.)

The new studies, though, suggest that specific TORC1 inhibitors could have their uses, as well.

Rapamycin was once thought to be such a specific inhibitor. Acutely, it affects mainly TORC1. But in their paper, Baur and his team showed that with chronic administration, over time the drug also inhibits TORC2, and that the effect on TORC2 was what led to metabolic impairments.

Because of the lack of specific inhibitors, Baur, co-corresponding author David Sabatini, and their team used genetic methods to selectively reduce the function of the TORC1 complex. (Completely disabling the complex will kill the mice, because the corresponding signaling pathway is critical for regulating cell growth depending on the level of nutrients available.)

In those experiments, mice with selectively disabled TORC1 lived longer without developing problems with insulin sensitivity and glucose control.

The findings do not rule out that TORC2 may have additional, beneficial effects on longevity. In fact, such effects have been seen in roundworms. But they do suggest that TORC1 inhibition alone is enough to get at least some of those benefits.

In theory, the results could mean that the effects of inhibiting mTORC1 on longevity could be even greater than previous studies have indicated, because metabolic problems due to TORC2 inhibition could be partially masking the beneficial effects of TORC1 inhibition. But Baur contended that is unlikely in practice.

He said that "glucose intolerance in lean mice is just about irrelevant" to life span when mice are treated with nonspecific mTOR inhibitors. When they reach the end of their longer life, the animals die mainly of cancer and liver failure.

Baur said that he and his colleagues are interested in looking at how TORC1 inhibition affects processes such as autophagy and mitochondrial function.

Longer term, he said, they would also be interested in looking for specific pharmacological inhibitors. So far, attempts to turn up such specific inhibitors have not been "terribly successful," Baur said. But with larger-scale screening efforts, "I'd still remain hopeful" that such specific inhibitors can be found.