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.
It
soon proved its potential. When a neighbor’s wife developed a stubborn
fungal skin condition, Sehgal mixed up a rapamycin ointment for her. “It
was probably illegal,” says his son Ajai Sehgal, but the infection
cleared up quickly. Suren, a biochemist who’d immigrated to Canada from a
tiny village in what’s now Pakistan, became convinced that he’d
stumbled upon something special. Before he could develop it any further,
however, Ayerst abruptly closed its Montreal lab, and his bosses
ordered all “nonviable” compounds destroyed—including the rapamycin.
Sehgal couldn’t bring himself to do it and instead squirreled a few
vials of Streptomyces hygroscopicus into his freezer at home.
Most of the staff was fired, but Sehgal was transferred to the company’s
lab in Princeton, N.J. The plastic package made the move packed in dry
ice.
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 of transplant
patients and go on to make Wyeth hundreds of millions of dollars.
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. With an eye
toward changing the way millions grow older, Novartis, the $260 billion
Swiss pharmaceutical giant, has begun taking the first steps to position
a version of rapamycin as the first true anti-aging drug.
Pharmacological
history is full of substances that have been purported to delay aging
or lengthen life span, from resveratrol (the “red wine pill”) in the
2000s to testicular implants in the 1920s, all the way back to medieval
alchemists (gold was thought to possess anti-aging properties). Until
rapamycin came along, however, nothing has actually worked in rigorously
designed clinical studies.
“People
have shown that rapamycin extends life span again and again and again,”
says Matt Kaeberlein, a scientist at the University of Washington and a
leading researcher in the biology of aging. So far it’s demonstrated it
can lengthen the lives of mice, not men, but what’s particularly
exciting is how it did so, Kaeberlein says. The drug appears to delay
“age-related decline in multiple different organ systems, which is
something we would expect if we were fundamentally slowing the aging
process.”
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 at
Chicago and a leading critic of purported life-extending supplements
and treatments. “The batting average is zero.”
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. Such admonitions are justified. And yet the enthusiasm
of scientists such as Kaeberlein is hard to resist. “We have the
potential to delay the onset of all of these diseases at the same time
by understanding and intervening in the molecular processes that drive
aging,” he says. “We now know that that is possible.”
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.
“Really
what rapamycin is doing is tapping into the body’s systems for dealing
with reduced nutrition,” says Brian Kennedy, chief executive officer of
the Buck Institute for Research on Aging in Novato, Calif. “We’ve
evolved over billions of years to be really good at that. When things
are good, we’re going to grow and make babies. And when things are not
so good, we go into a more stress-resistant mode, so we survive until
the next hunt. And it just so happens that stress resistance is good for
aging.”
One of the most passionate advocates for rapamycin as an
anti-aging drug is a Russian scientist named Mikhail Blagosklonny, who
now works at the Roswell Park Cancer Institute in Buffalo. A native of
St. Petersburg, he was working on cancer treatments in the early 2000s
when he realized the same qualities that made rapamycin effective at
slowing tumor growth might also help it slow the aging process. He
became so convinced of rapamycin’s potential, and its safety, that he
tried it himself. “Some people ask me, is it dangerous to take
rapamycin?” Blagosklonny says. “It’s more dangerous to
not take rapamycin than to overeat, smoke, and drive without belt, taken together.”
Many
colleagues have regarded his advocacy as a bit over-the-top. When
Blagosklonny submitted papers to major journals making these arguments,
they were brutally rejected. “Sometimes, the reviewers would call me
names,” he says. That started to change in 2009, when a large National
Institutes of Health-funded study established that rapamycin and its
derivatives helped mice live longer. The NIH scientists started mice on
the drug at 20 months, or late middle age in mouse terms (mice typically
live two to three years). Male mice on rapamycin lived 9 percent
longer. The females’ life span was extended by 14 percent. This is
roughly the equivalent of giving 60-year-old women a pill that would
enable them to see their 95th birthday.
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.
For believers like Blagosklonny, 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. It wasn’t the sort of thing
that makes CNN, but in the world of scientists who work on human aging,
it was big. “A watershed,” says Nir Barzilai, director of aging
research at New York’s Albert Einstein College of Medicine.
“People
have shown that rapamycin extends life span again and again and again.
... I view it as the ultimate preventative medicine”
For
the first time, the study showed, rapamycin appeared to enhance aspects
of the immune response, boosting the efficacy of a flu vaccination in
the study population, who were all 65 or older. “It seems to modulate
the immune response, not suppress it,” says Barzilai. “It’s very
exciting.” The study was noteworthy also because Novartis paid for it.
For the most part, Big Pharma has shied away from aging, which
conventional wisdom had deemed to be a quackery-ridden money pit. In
2008, GlaxoSmithKline paid $720 million to buy Sirtris Pharmaceuticals, a
biotech startup founded by Harvard professor David Sinclair that was
developing drugs based on resveratrol, the antifungal compound found in
the skins of red-wine grapes. Resveratrol received a tremendous amount
of coverage in the media, including 60 Minutes, the New York Times,
and Barbara Walters. It was said to be responsible for the “French
paradox”: Although the French eat fatty foods, they remain healthy. A
highly publicized Nature paper had shown that mice on a
high-fat diet had lived longer with resveratrol. After the study
appeared, sales of resveratrol supplements rocketed from basically zero
to about $100 million a year. But the drugs all flopped in human trials,
and in 2013 GSK shuttered its Sirtris division and fired all but a
handful of staffers.
“The
difference between rapamycin and resveratrol is that rapamycin really
works as advertised and resveratrol doesn’t,” says the University of
Washington’s Kaeberlein. “If you look at the data, you have to agree.”
Kaeberlein, who went to graduate school with Sinclair at MIT, was an
early critic of resveratrol, which he points out has actually never
extended life span or otherwise slowed aging in normal mice—it appeared
to work only in fat mice.
Rapamycin
has been found to reduce age-related bone loss, reverse cardiac aging,
and reduce chronic inflammation in mice. It’s even been shown to reverse
Alzheimer’s disease in them. The Novartis study was the first to
examine rapamycin’s effect on aging-related parameters in healthy older
people. “It’s a landmark study,” says the Buck Institute’s Kennedy.
“It’s the kind of study we need more of.”
That doesn’t mean
everyone should be asking their doctors for a prescription to an mTOR
inhibitor. Critics say it may be too risky for people who are otherwise
fine. Besides the possibility of immune suppression, rapamycin’s side
effects can include canker sores and impaired wound healing. “Rapamycin
works on pathways that are too fundamental to normal cellular function
to be used as a drug in healthy people until we have much more safety
data,” says Valter Longo, a professor at the University of Southern
California who discovered key pathways related to TOR. He points out
that periodic fasting also shuts down the same pathways, without the
side effects.
The Novartis researchers tried to get around the
immune-suppression side effect by giving the drug in very low doses and
for a defined period. They found its benefits persisted long after the
drug was discontinued. But the Novartis study is far from definitive on
the issue, says Janko Nikolich-Zugich, chair of the department of
immunobiology at the University of Arizona and co-director of the
Arizona Center on Aging.
The
study measured response to a vaccine, not to an infectious agent.
Nikolich-Zugich fears that rapamycin would stop immune cells from
multiplying quickly enough to fight off an army of invading pathogens.
“I don’t think this in any way, shape, or form settles concerns about
what mTOR inhibitors would do in cases of infection,” he says.
An
innovative clinical trial set to begin in March may resolve some of
these issues. Kaeberlein and his University of Washington colleague
Daniel Promislow plan to test the drug in small doses in middle-aged pet
dogs. Rather than looking at life span, which would take years, they
will look for signs that the drug is affecting key aging-related
parameters, such as arterial stiffness and cardiac function. If
successful, rapamycin and its derivatives could end up as the first
anti-aging drug—for dogs. Kaeberlein wouldn’t mind: “I love my dogs,” he
says. “If there’s anything we can do to make them live longer,
healthier lives, we have to do it. I feel like I personally have to do
this.”
In September, Novartis Chairman Joerg Reinhardt announced
the company’s new commitment to aging research. “Over the long term, one
could argue that R&D productivity has relentlessly declined,” he
said in a keynote at a drug development conference in Basel,
Switzerland. Aging represents a fertile field of discovery: Identifying
the pathways and proteins associated with aging could yield promising
drug targets, he said. By tweaking the right pathways, researchers could
theoretically prevent a host of age-related diseases. Novartis is not
alone in this: Last fall, Chicago-based AbbVie announced a $500 million
partnership with Calico, an aging-research venture founded by Google.
Rapamycin
isn’t the only widely used medication that’s turning out to have
possible anti-aging properties. Millions of diabetics take a drug called
metformin, which has been around for decades. Like rapamycin, metformin
extended the life of federally funded mice in a clinical trial. And
there is evidence that it might do the same for people. Diabetes
typically shaves about five years off a person’s life. But a large
retrospective analysis found that diabetics on metformin had a 15
percent lower mortality rate than nondiabetic patients in the same
doctors’ offices. “To me that suggests that it’s actually targeting
aging,” says Kennedy.
“I remain skeptical that there will be one
magic bullet,” says Novartis’s Fishman. But the 2014 study “is a good
proof-of-concept”
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,” says Randy Strong, a
pharmacologist at the University of Texas Health Science Center at San
Antonio who worked on the 2009 NIH study.
This
may explain why Novartis is taking an incremental approach with
therapies aimed at specific conditions, says Dr. Mark Fishman, head of
the Novartis Institutes for BioMedical Research in Cambridge, Mass., and
a member of the company’s executive committee. “We’re therapeutically
oriented, rather than looking for the pill that will make everybody live
to 120,” he says.
The
company’s age-related drug pipeline includes a novel drug aimed at
treating heart failure, which the European Union recently fast-tracked
for approval. Another, bimagrumab, is meant to reverse muscle loss.
Designated a “breakthrough” by the FDA, it’s soon set to enter Phase III
clinical trials for a rare condition called sporadic inclusion body
myositis, but it could have wider application for muscle wasting and
frailty in older people. “This whole frailty business is right up there
with Alzheimer’s as a cause of incapacitation and sadness for the
elderly,” Fishman says.
Also
in the works are a drug that could potentially restore cartilage in
aging joints and, most interestingly, a radical gene therapy meant to
reverse the loss of “hair cells” in the ear canal that are crucial for
good hearing, but which are knocked out by things like antibiotics,
chemotherapy, and “too much Lady Gaga,” Fishman says.
He’s
cautious about the anti-aging potential of rapamycin, which the company
sells under the Afinitor brand name for cancer treatments and as
Zortress for transplants, with 2012 sales of just more than $1 billion.
(Pfizer, which purchased Wyeth in 2009, also sells a version under the
brand name Rapamune.) “I remain skeptical that there will be one magic
bullet,” Fishman says, “but [the 2014 study] is a good proof-of-concept,
and it’s provocative enough that we’ll at least think of how and
whether we should proceed.”
Blagosklonny isn’t so measured or
patient. In his view, rapamycin has been approved for use for more than
15 years, with no serious problems reported. “I have read all papers
about side effects,” he says, “and there are less side effects than with
aspirin.” When he took it, he says, it made him feel better, “like with
exercising.”
Novartis strongly discourages such off-label use. In
an e-mail, spokeswoman Mariellen Gallagher wrote: “It is far too early
to tell whether low-dose rapamycin will lengthen human life span. A
favorable risk/benefit ratio needs to be demonstrated in clinic trials
to be sure that mTOR inhibitors such as rapamycin have acceptable safety
and efficacy in aging-related conditions in humans.”
In 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.’ ”
(Corrects the caption for Mark Fishman and his role on Novartis's executive committee.)
*The Critical Need to Promote Research of Aging and Aging-related
Diseases to Improve Health and Longevity of the Elderly Population*