July 12, 2012

Rapamycin antiaging research and overstated diabetes risks

David Stipp - The first strong evidence that a drug could slow aging in mammals came out in 2009 when scientists reported that chronically feeding doses of rapamycin to mice significantly extended their average and maximum lifespans. Yet rapamycin, a drug used to help prevent rejection of transplanted organs, causes multiple side effects in people, including elevated triglycerides and cholesterol, increasing the risk of heart disease; moderate immune suppression, perhaps increasing infection risks; and low blood platelet levels, which raises the specter of dangerous bleeding. In recent years another especially surprising and troubling side effect has come to the fore: Chronically taking large doses of rapamycin induces “insulin insensitivity” in both rodents and humans, leading to rising blood sugar and potentially to type 2 diabetes.

The troubling data on rapamycin’s side effects have come mainly from studies in which sizable doses were taken by sickly people, many of whom were on potent immunosuppressants such as cyclosporin (chiefly organ transplant patients). These data aren’t necessarily indicative of rapamycin’s side effects when taken in smallish amounts by healthy adults as a broad-spectrum reducer of degenerative disease risks (which is one way to describe an anti-aging drug). Most, if not all, of rapamycin’s side effects are dose-dependent—smaller doses pose less risk. Thus, it seems possible that a dosing regimen could be found that confers preventive gains with little risk. One expert on mTOR and aging, Mikhail Blagosklonny at Roswell Park Cancer Institute in Buffalo, N.Y., has proposed that intermittent doses of rapamycin might do the trick. Not coincidentally, Blagosklonny authored the recent theory paper downplaying the drug’s reported diabetes risk
.

A recent paper suggests that the diabetes risk is overblown.



ABSTRACT - Calorie restriction (CR), which deactivates the nutrient-sensing mTOR pathway, slows down aging and prevents age-related diseases such as type II diabetes. Compared with CR, rapamycin more efficiently inhibits mTOR. Noteworthy, severe CR and starvation cause a reversible condition known as "starvation diabetes." As was already discussed, chronic administration of rapamycin can cause a similar condition in some animal models. A recent paper published in Science reported that chronic treatment with rapamycin causes a diabetes-like condition in mice by indirectly inhibiting mTOR complex 2. Here I introduce the notion of benevolent diabetes and discuss whether starvation-like effects of chronic high dose treatment with rapamycin are an obstacle for its use as an anti-aging drug.

Mouse Study

A mouse study showed that rapamycin inhibits two protein “complexes” in mammals, called mTORC1 and mTORC2, that have very different effects on longevity and insulin: The drug’s suppression of mTORC1 appears largely responsible for its calorie-restriction-like boosting of healthy lifespan, while its suppression of mTORC2 reduces insulin sensitivity. The scientists concluded that drugs targeting mTORC1 alone may slow aging without blood-sugar discombobulation.

ABSTRACT - Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend life span independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended life span but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo.

In sum, writes Blagosklonny, insulin resistance can be good or bad—it’s bad when mTOR is amped up by overeating, and good when mTOR is inhibited by calorie restriction or by taking drugs like rapamycin. Such context-dependent assessments are common in biomedicine—for instance, weight loss due to calorie restriction promotes healthy aging, but it’s a bad thing when caused by terminal cancer. The bottom line, he concludes, is that the diabetes-like side effects induced by rapamycin shouldn’t be regarded as an obstacle to pursuing it as an anti-aging drug for humans.


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