Staying out of the sun helps to keep that youthful glow as the years go by. Certain foods, including avocado and fatty, oily omega-rich fish such as salmon and mackerel, also help. Carbohydrates, on the other hand, are unlikely to, as they turn to sugar in the bloodstream, and an excess of sugar is fingered in research as a poison for health on the inside as well as the outside.
Popping a pill to fight age-related disease and premature wrinkling of the skin would be a win all round. It’s the holy grail of anti-ageing research. It may have been here all along, if we’d all known where to look for it – a bacterium in the beneath one of the ‘mysterious stone heads on Easter Island, a speck in the middle of the Pacific Ocean’. This is a long read on it, but well worth it if you’re interested in quality as well as quantity of years on this earth. – MS
By Bill Gifford
Picture: emi iemai / Foter / CC BY-NC-SA
Bloomberg – One afternoon in the early 1980s in Canada, biochemist 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-ageing drug in decades.
Sehgal had been studying it since 1972, when he 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, who immigrated to Canada from a tiny village in what’s now Pakistan, became convinced he’d stumbled upon something special. Before he could develop it 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, New Jersey. 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 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 US 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 lives of thousands of transplant patients, and go on to make Wyeth hundreds of millions of dollars.
The promise
In the years since, rapamycin has been adapted for numerous uses. Like penicillin, it’s a biological agent, so can’t be patented, although derivatives can. It’s used routinely as a coating on cardiac stents to prevent scarring and blocking. Derivatives of rapamycin are approved for use against certain kidney, lung, and breast cancers. That may be just the beginning.
Over the past decade, it has shown promise as a drug that not only can extend life by delaying the onset of ageing-related diseases such as cancer, heart disease, and Alzheimer’s disease, but also postpone the effects of normal ageing.
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-ageing drug.
Pharmacological history is full of substances purported to delay ageing 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-ageing properties). Until rapamycin came along, nothing has actually worked in rigorously designed clinical studies.
“People have shown that rapamycin extends life span again and again and again,” says Dr Matt Kaeberlein, a scientist at the University of Washington and a leading researcher in the biology of ageing.
So far it has 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 ageing process”.
Ultimate medicine
The promise of rapamycin, he and others contend, is to treat ageing as a contributing factor to chronic diseases that kill people later in life.
“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 Dr 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 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 ageing,” 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 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.
One of the most passionate advocates for rapamycin is Russian scientist 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 realised the same qualities that made rapamycin effective at slowing tumour growth might also slow the ageing process. He became so convinced of rapamycin’s potential and safety, he tried it himself.
The dangers
“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 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 changed 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 – late middle age in mouse terms (mice typically live two to three years). Male mice on rapamycin lived 9% longer. The females’ life span was extended by 14% – 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 an anti-ageing drug. In older patients, whose immune systems are often already diminished, it would make them vulnerable to life-threatening infections, defeating the purpose.
For believers like Blagosklonny, a breakthrough came on Christmas Eve 2014, when a paper appeared in Science Translational Medicine, part of the Science family of journals. The study, conducted with volunteers in Australia and New Zealand, showed that a derivative of rapamycin called everolimus improved 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 ageing, it was big.
“A watershed,” says Nir Barzilai, director of ageing 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 ageing, which conventional wisdom deemed 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.
French paradox explained
It was said to be responsible for the “French paradox”: Although the French eat fatty foods, they remain healthy. A highly publicised 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 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 ageing in normal mice — it appeared to work only in fat mice.
Rapamycin has been found to reduce age-related bone loss, reverse cardiac ageing and reduce chronic inflammation in mice. It is even 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.
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 too fundamental to normal cellular function to be used as a drug in healthy people until we have more safety data,” says Valter Longo, a professor at the University of Southern California who discovered key pathways related to TOR. He says 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 low doses for a defined period. They found its benefits persisted long after the drug was discontinued.
But the Novartis study is far from definitive, says Janko Nikolich-Zugich, chair of the department of immunobiology at the University of Arizona and co-director of the Arizona Centre on Ageing.
Innovative trial
The study measured response to a vaccine, not an infectious agent. Nikolich-Zugich fears that rapamycin would stop immune cells from multiplying quickly enough to fight off an army of invading pathogens.
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 ageing-related parameters, such as arterial stiffness and cardiac function. If successful, rapamycin and its derivatives could end up as the first anti-ageing 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.”
In September, Novartis Chairman Joerg Reinhardt announced the company’s new commitment to ageing research.
Ageing represents a fertile field of discovery: identifying the pathways and proteins associated with ageing 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: Last fall, Chicago-based AbbVie announced a $500 million partnership with Calico, an ageing-research venture founded by Google.
Rapamycin isn’t the only widely used medication with possible anti-aging properties. Millions of diabetics take 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 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% lower mortality rate than nondiabetic patients in the same doctors’ offices.
“That suggests t’s actually targeting ageing,” says Kennedy.
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” ageing, because ageing is not considered a disease. Another obstacle is 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 Centre 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, Massachusetts, 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.
Rare condition
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-ageing 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 favourable 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 tumours 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 tumours 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.’ ” – Bloomberg
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