Does a Real Anti-Aging Pill Already Exist?

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by Bill Gifford,

from Bloomberg Businessweek,

Inside Novartis’s push to produce the first legitimate anti-aging drug

One afternoon in the early 1980s, Suren Sehgal brought a strange package home from work and stashed it in his family’s freezer. Wedged beside the ice cream, it was wrapped in heavy plastic and marked, “DON’T EAT!” Inside were several small glass vials containing a white paste—all that remained of a rare bacterium that today is the foundation of the most promising anti-aging drug in decades. Sehgal had been studying it since 1972, when he’d first isolated it in a soil sample at Ayerst Laboratories, a pharmaceutical company in Montreal.

A Canadian medical expedition had collected the soil from beneath one of the mysterious stone heads on Easter Island, a speck in the middle of the Pacific Ocean. In the dirt, Sehgal had discovered Streptomyces hygroscopicus, a bacterium that secreted a potent antifungal compound. This intrigued him; he thought perhaps it could be made into a cream for athlete’s foot or other fungal conditions. He purified the stuff and named it rapamycin, after Easter Island’s native name, Rapa Nui.

When Wyeth, the global health-care company based in Pennsylvania, bought Ayerst in 1987, Sehgal persuaded his bosses to let him resume his work on the rare bacterium. Sehgal found that, besides its antifungal properties, rapamycin also suppressed the immune system. It tamps down the body’s natural reaction to a new kidney or other organ. Eventually, in 1999, the U.S. Food and Drug Administration approved rapamycin as a drug for transplant patients. Sehgal died a few years after the FDA approval, too soon to see his brainchild save the lives of thousands.

In the years since, rapamycin has been adapted for numerous uses. Like penicillin, it’s a biological agent, so it can’t be patented, although derivatives of it can. It’s now used routinely as a coating on cardiac stents to prevent scarring and blocking. Derivatives of rapamycin have been approved for use against certain kidney, lung, and breast cancers. That may be just the beginning. Over the past decade, it’s shown promise as a drug that not only can extend life by delaying the onset of aging-related diseases such as cancer, heart disease, and Alzheimer’s disease, but also postpone the effects of normal aging.

Pharmacological history is full of substances that have been purported to delay aging or lengthen life span, … Until rapamycin came along, however, nothing has actually worked in rigorously designed clinical studies.

The promise of rapamycin, he and others contend, is to treat aging as a contributing factor to the chronic diseases that kill people later in life, the way we now lower cholesterol to prevent heart disease. “I view it as the ultimate preventive medicine,” says Kaeberlein, who’s leading a rapamycin study on dogs.

Not everyone is convinced. “There are no interventions that have been documented to slow, stop, or reverse aging in humans,” says S. Jay Olshansky, a professor of public health at the University of Illinois … Olshansky welcomes the advent of therapies like rapamycin, but he doesn’t think we know enough yet: “My caution is always no, no, no: Let science do what it does and evaluate these interventions for safety and efficacy first,” he says.

Rapamycin works at a fundamental level of cell biology. In the early 1990s, scientists at Novartis’s predecessor, Sandoz, discovered that a rapamycin molecule inhibits a key cellular pathway regulating growth and metabolism. This pathway was eventually dubbed “target of rapamycin,” or TOR, and it’s found in everything from yeast to humans (it’s known as mTOR in mammals).

MTOR is like the circuit breaker in a factory: When it’s activated, the cell grows and divides, consuming nutrients and producing proteins. When mTOR is turned down, the “factory” switches into more of a conservation mode, as the cell cleans house and recycles old proteins via a process called autophagy. One reason caloric restriction extends life span in animals, researchers believe, is because it slows down this mTOR pathway and cranks up autophagy. Rapamycin does the same thing, only without the gnawing hunger.

There’s one catch: Rapamycin suppresses the immune system (that’s why it’s effective with transplants). That fact, many scientists and physicians believe, is its Achilles’ heel as a drug to treat aging. Giving such a drug to older patients, whose immune systems are often already diminished, would make them vulnerable to life-threatening infections, defeating the purpose.

… a breakthrough came on Christmas Eve 2014. That’s when a paper appeared in Science Translational Medicine, part of the Science family of journals. According to the study, conducted with volunteers in Australia and New Zealand, a derivative of rapamycin called everolimus had been shown to improve the immune response of elderly patients when administered in limited doses.

That doesn’t mean everyone should be asking their doctors for a prescription to an mTOR inhibitor.

The problem they’ll all face, though, is the same one that tripped up GSK: The FDA is unlikely to approve any drug intended to “treat” aging, because aging is not considered a disease. Another obstacle is the high safety standards required of any drug that would, in effect, be used to treat healthy people. “It would have to have fewer side effects than aspirin” …

n any case, one imagines Sehgal would be proud. After he was diagnosed with cancer in 1998, his son Ajai says, Sehgal began taking rapamycin, too—despite the drug not having been approved for anything yet. He had a hunch that it might help slow the spread of his cancer, which had metastasized to his liver and other organs. His doctors gave him two years to live, but he survived for much longer, as the tumors appeared to go dormant. The only side effect he suffered from was canker sores, a relatively small price to pay.

But in 2003, after five years, Sehgal, age 70, decided to stop taking the drug. Otherwise, he told his wife, he’d never know whether it was really holding back his cancer. The tumors came back quickly, and he died within months, says Ajai. “On his deathbed, he said to me, ‘The stupidest thing I’ve ever done is stop taking the drug.’ ”

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