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.
How do we reconcile such adverse effects with the drug’s unprecedented ability to boost healthy aging and longevity, at least in mice?
Some telling insights on this burning issue were recently published in two reports on rapamycin’s effect on insulin and blood sugar: a mouse study that revealed a probable mechanism behind the effect and a theory paper suggesting that the purported diabetes risk has been overblown.
The two papers make very interesting reading for those following the anti-aging quest—if rapamycin, or drugs like it (generically known as mTOR inhibitors), work in people as they do in mice, taking them as preventive medicines in midlife should delay virtually every bodily downside of aging, from senior moments and wrinkles to Alzheimer’s and cancer. That would buy us more quality time than any other foreseeable medical advance. But this promise may be only a mirage if mTOR inhibitors pose more risks than benefits.
I’m hopeful about mTOR inhibitors’ anti-aging promise despite rapamycin’s side effects. (But I have to add that little is known at this point about such drugs’ anti-aging potential in people, and in my view it would be premature to try personal experiments with them as aging retardants.) For one thing, 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.
Another reason for hope is that there’s considerable evidence that mTOR inhibitors’ power to delay diseases of aging in mice is indicative of similar benefits in humans. For instance, such drugs are FDA-approved to ward off certain cancers, several rodent studies suggest rapamycin can lower the risk of Alzheimer’s disease, and a number of rapamycin’s key metabolic effects in both people and animals closely resemble those of calorie restriction, which is known to slow aging in diverse species. These data aren’t surprising: The mTOR enzyme inhibited by rapamycin and its ilk lies at the heart of an evolutionarily ancient metabolic pathway that governs cell growth and other basic functions. Thus, it’s probable that the pathway’s molecular components, and what they do, are quite similar in rodents and people.
One indication of the similarity is the fact that rapamycin induces insulin resistance and impairs glucose tolerance in both rodents and humans. (Insulin, a hormone released into the bloodstream by the pancreas when we eat, causes cells in the liver, muscles and other tissues to take up sugar from the blood; insulin resistance sets in when cells’ sensitivity to the hormone’s signal wanes, which can make for damagingly high blood sugar and, eventually, full-blown diabetes.) The first of the two papers mentioned above, by researchers affiliated with MIT and the University of Pennsylvania, revealed molecular details of this effect. The researchers’ 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.
But Blagosklonny’s theory paper argues that such narrow-acting mTOR inhibitors may be superfluous. His case is based partly on the fact that, paradoxically, starvation induces insulin resistance and a diabetes-like condition. This effect is pretty shocking because type 2 diabetes has long been associated with overly rich diets and obesity.
First described in the 19th century, starvation diabetes occurs when the liver becomes resistant to insulin after food intake is cut off. As Blagosklonny notes, such resistance makes sense because the liver is called on during starvation to break down proteins and fats in order to provide fuel for sugar-hungry neurons and other cells. Insulin blocks this fuel-switching mechanism (sugar usually comes from ingested carbohydrates). Thus, the liver must dial back its response to the hormone’s signal in order to produce emergency fuel from non-carbohydrate reserves in the body, as well as to prevent itself from needlessly absorbing scarce glucose from the blood, potentially causing fatal hypoglycemia (very low blood sugar). This form of insulin resistance is accompanied by a drastic reduction in mTOR activity—mTOR promotes cell growth in response to nutrient intake, and it’s activity falls off when food intake drops.
In contrast, rich modern diets cause insulin resistance via a very different mechanism: They chronically overstimulate the mTOR pathway, which evolution has designed to turn down insulin sensitivity when cells have taken up adequate fuel.
Highlighting these completely opposite mechanisms (with regard to mTOR), Blagosklonny proposes that low-mTOR starvation diabetes “only superficially” resembles mTOR-revved-up type 2 diabetes and, in fact, the former is benevolent—a view contrary to the conventional wisdom that diabetes is always pathological. Supporting his idea, a 2010 study of people who had practiced stringent calorie restriction for an average of seven years showed that they exhibited “diabetic-like” glucose intolerance (perhaps a sign of incipient starvation diabetes) while also manifesting many signs of extraordinarily good health, such as low levels of inflammation-promoting molecules linked to many diseases of aging. Further support comes from studies showing that certain mutations that disrupt insulin signaling in mice—which induces a condition resembling profound insulin resistance—can extend the animals’ lifespans.
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.
Now all we need is a brilliant billionaire to step forward and fund the pursuit.