The Anti-Aging Drug for Everyone

The soil bacteria from Easter Island did not make rapamycin to slow aging, but to inhibit the growth of their natural enemies, soil fungi—much like fungi produce penicillin to wipe out competing bacteria. Fungi, starting with yeasts and up, have genes corresponding to mTOR, as do all plants and animals. mTor is the universal growth regulator of advanced life forms. So while rapamycin originally drew attention as an antifungal agent, we soon realized that it has many other effects.

The Anti-Aging Drug for Everyone

Dozens of published studies showed that rapamycin extends both the average and the maximum lifespan in laboratory mice by slowing mTOR. But what about if you’re not a rodent? Rapamycin appears to be a universal anti-aging compound that extends life expectancy in all animals and other organisms tested so far—and it is the only one. It even works when you don’t start until middle age.

The original experiment, conducted by the Intervention Testing Program of the National Institute on Aging and published in 2009, was delayed because the researchers had trouble keeping the rapamycin stable in the mice’s food pellets. (It can’t simply be dissolved in the drinking water, because it is fat-soluble.) By the time the experiment could begin, the mice were 600 days old, which corresponds to 60 human years. Even though the mice received the drug so late in life, their lifespan increased by about 12 percent, which would mean more than seven additional years of life for humans.

At first there was debate about whether rapamycin is a genuine anti-aging intervention or “just” a powerful anticancer drug that extends lifespan simply by preventing cancer. In up to 80 percent of human cancers, in which it plays a central role in tumor growth, mTOR sends hyperactive signals. When rapamycin was used clinically to prevent rejection of transplanted organs (by suppressing the proliferation of immune cells that attack the new organ), an odd side effect was noticed: It made cancer disappear. In a group of 15 patients in whom Kaposi sarcoma had been diagnosed by biopsy—a cancer that often affects the skin—all skin lesions disappeared in all subjects after three months of rapamycin therapy. Since mTOR is the master regulator of cell growth, it is not surprising that it inhibits tumor cells from growing, but follow-up studies showed that rapamycin can do much more.

In animal models it also extends health span. Rapamycin mitigates the age-related decline in mental and physical function, builds up the periodontal bone that holds the teeth in place, and prevents hearing loss, arterial dysfunction, and tendon stiffening. It can even rejuvenate the hearts of old mice. Remarkably, health and life expectancy improved with both intermittent and short-term dosing—for example, administered every five days or only for a few months in middle age.

As a dog owner, I was eager to read about the Dog Aging Project, in which owners enrolled their middle-aged dogs for a ten-week trial during which the animals were randomized to receive either a low or high dose of rapamycin or a placebo. As in the mouse studies, rapamycin in the dogs appeared to at least partially reverse some cardiac dysfunctions without undesirable side effects. Interestingly, most dog owners whose animals had received rapamycin without the owners’ knowledge described how active and energetic the dogs suddenly were. Only a few could say the same about the dogs in the placebo group. It was time to try rapamycin in humans. At see.nf/rapamycin I report on all rapamycin trials to date. The bottom line? For the first time, there will be no headline about rapamycin as an anti-aging drug. Can we suppress mTOR without medications?

Calorie Restriction

For an organism to reach reproductive age as quickly as possible, it makes sense to go full speed ahead, but sometimes you have to hit the brakes. Over the course of evolution we didn’t have the luxury of delivery services and pizza taxis. Regular periods of hunger were normal. Anyone who didn’t slow his (cell-growth) pace in lean times might not live long enough to pass on his genes. For this reason, we have a braking mechanism in the body that is triggered when calories are restricted.

Do you remember AMPK, our enzyme that functions like a fuel gauge? When the tank is empty, AMPK puts us into energy-saving mode and, among other things, turns off mTOR via two different mechanisms to keep us from continuing to throw money around even though we have only cents left in the account. AMPK and mTOR are, in a sense, the yin and yang of nutrient sensing and growth regulation. When one rises, the other falls, depending on how many nutrients are available.

Food restriction extends life, and a central factor in that may be the suppression of mTOR. mTOR also explains why anorexic women in the hospital were found to have only half the risk of breast cancer as others. The disorder-driven severe calorie reduction could have halted the mTOR expression found in breast tumors, which is associated with a more aggressive course of the disease as well as a lower survival rate among breast cancer patients. Of course, life-threatening anorexia nervosa is one of the most dangerous mental disorders, but long-term strict calorie restriction is no picnic either.

Calorie restriction, hyped by some as a fountain of youth, sometimes has side effects such as dangerously low blood pressure, infertility, slower wound healing, irregular menstruation, sensitivity to cold, loss of strength, bone loss, loss of libido, and “psychological problems such as depression, emotional blunting, and irritability.” And you walk around hungry all the time. In the notorious Minnesota Starvation Study, which used volunteers as guinea pigs during World War II, many of the conscientious objectors suffered from obsessive thoughts about food, constant hunger, binge eating, and many emotional and psychological problems. Even scientists who study calorie restriction rarely practice it. There has to be a better way to suppress mTOR.

Protein Restriction

The breakthrough came when scientists discovered that the benefits of eating less might not lie in calorie restriction, but rather in protein restriction. A comprehensive comparative meta-analysis of dietary restriction in animal models found that the ratio of protein intake was more important for extending life expectancy than the degree of calorie restriction. In some cases it turned out that restricting protein intake alone, without changing calories at all, sometimes produced results similar to calorie restriction. Rats that get about 8 percent protein in their diet live almost 40 percent longer than rats that eat about 20 percent protein.