New research from Dudley Lamming, PhD, associate professor, Endocrinology, Diabetes and Metabolism, is one step closer to understanding the metabolism-regulating complex mTORC2, and the role it may have in regulating lifespan.

The protein complex mTORC2 influences lifespan in yeast, worms, flies, and mice. In a 2014 study by Dr. Lamming, the loss of hepatic Rictor, an essential component of mTORC2, was shown to reduce male, but not female lifespan of mice.

When Rictor is removed from the liver, it can cause negative side effects, such as mice producing extra sugar, developing an intolerance to it, which increases risk for diabetes.

Knowing that Rictor has different lifespan and health effects in male and female mice, Dr. Lamming hypothesized that sex hormones were involved in how the mice responded to the removal of Rictor.

In his most recent study, published in eLife, Dr. Lamming found that female mice, who were ovariectomized before sexual maturity, with deleted Rictor from the liver, lived over two months longer than mice without these alterations. However, while these mice lived slightly longer, they experienced an increase in fat, a glucose intolerance, became insulin resistant, resulting in a less healthy life. This result shows that because longevity is maintained or increased while metabolic health declines, lifespan can be uncoupled from healthspan.

This finding is important for researchers studying aging, as the goal is not just to increase lifespan, but to increase the healthy portion of life. 

“Overall, it seems like ovariectomy has a small positive benefit, particularly to mice that lost hepatic mTORC2, where we deleted Rictor in the liver, and perhaps also to those don’t have mTORC2 activity,” Dr. Lamming said.

These results indicate that hepatic mTORC2 has a sex-hormone dependent role, and that something about the germline is controlling longevity.

They also tested this effect on male mice, but interestingly, there was no effect on lifespan in male mice lacking Rictor with a gonadectomy.

“The ovaries have been shown to control lifespan in other organisms, as well. There definitely seems to be something going on there that suggest that maybe this effect is even conserved in mammals, and that needs to be investigated further,” Dr. Lamming said.

Banner: Dudley Lamming, PhD, associate professor, Endocrinology, Diabetes and Metabolism, works in his lab. Credit: Clint Thayer/Department of Medicine.