Never Say Die.pdf

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http://www.smh.com.au/interactive/2015/never-say-die/

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n March 2013, a group of 40 scientists from Harvard Medical School were invited by biologist David Sinclair to the dining room of the upmarket Catalyst restaurant in Boston’s Kendall Square. Sinclair had deliberately chosen the location, and the alcohol being served. Kendall Square has the greatest concentration of biotechnology companies in the world and the restaurant’s name reflected the discovery they were celebrating – the age-extending qualities of a compound hidden in a glass of red wine. For the best part of a decade, the Sydney-born longevity researcher had battled sceptics in the scientific community who claimed his work was fundamentally flawed. The world’s largest drug company, Pfizer, had called h is findings a “pharmacological d ead end”. Now he was toasting the curative qualities of pinot noir and raising a glass to those colleagues who had stuck with him durin g what he calls a “David versus Goliath” battle for vindication.

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Scientist David Sinclair is confident anti-ageing research will revolutionise medicine and healthcare.

“You have a limited time to prove you’re right or your career is over, because you run out of money and good people,” says Sinclair, whose Australian accent is lightly brushed with an east coast American timbre, a result of the 20 years he has lived in Boston. “There were days when I just wanted to quit being a scientist. I thought, ‘This is not worth it.’ But fortunately, I’m stubborn. And we already had g ood results in the lab wh ich said I was right, but the

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results weren’t ready to publish. “We continued to keep working for another eight years after that. They were very painful years, knowing that you were right but the world didn’t believe you.” The gathering at Catalyst coincided with the publication in the journal Science of a study led by Sinclair showing that the compound resveratrol, and related substances, prolonged lifespan and improved health in animals as varied as worms, fruit flies and mice. Today, Sinclair’s work on slowing the ageing process, and even reversing some aspects of it, could lead to the most significant set of medical breakthroughs since the discovery of antibiotics nearly a century ago. At the heart of what motivates him is a deceptively simple notion: if the greatest driver of disease in old age is old age itself, then why not find a cure for ageing, which he describes as being “the greatest problem of our time”. Sinclair’s statement is borne out by the World Health Organisation’s Global Burden of Disease Project, which estimates that the number of years lost to premature death or compromised by disability in 2010 was 2.5 billion, meanin g that about a third of potential human life goes to waste. The toll from crime, wars and genocides does not come close to matching this. Yet, as Sinclair points out, just one per cent of medical research funding is spent on understanding why we age and even less on doing something about it. His goal is to find the “master control switch” that can regulate the pathways that contribute to ageing itself. “It could be one pill for 20 diseases at once,” says the boyish-looking 46-year-old, who divides his time between Boston’s Harvard Medical School, where he is a professor of genetics, and Sydney, where he heads a lab at University of NSW (UNSW) Medicine. “It would be the most profitable drug ever made.”

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Achieving everlasting life has obsessed mankind for millennia. In the Old Testament, Methuselah was said to have lived for 969 years. Herodotus, Alexander the Great and the 16th-century Spanish explorer Juan Ponce de León all probed the extremities of the known world in a search of the Fountain of Youth. While no serious scientist is talking immortality, at least one biologist has predicted we will eventually live to 5000 years of age. Sinclair is more modest in his projections: we’ll still be swinging golf balls at 90 and blowing out birthday candles at 120. So far only one person, Frenchwoman Jeanne Calment, has passed that milestone, reaching the age of 122 before she died in 1997. Sinclair says his discoveries could make 150 the new threshold.

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The “Prophet of Immortality” Aubrey de Grey.

Extending the generally accepted limits of human life is now being taken seriously by some of the world’s top scientists. Backed by wealthy philanthropists and tech giants such as Google, billions of dollars are being poured into longevity research. Press releases and PowerPoint presentations come laced with terms such as health-span, not lifespan. The elderly, we are told, will become the wellderly. There will be fewer bedridden geriatrics taxing our overstretched medical systems.

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The ever-growing list of billionaires funding research into longevity includes PayPal co-founder Peter Thiel, who has set up Breakout Labs, a non-profit organisation that supports early-stage companies, and Oracle founder Larry Ellison, who has donated more than $US430 million ($600 million) to anti-ageing research. In September 2013, Time magazine asked: “Can Google Solve Death?” after the search giant announced its latest “moonshot”, Calico, short for California Life Company. The company has snared some of the biggest names in the field, including geneticist Cynthia Kenyon, and plans to build a $1.5 billion life-extension research centre in San Francisco. The facility will be run by Art Levinson, Steve Jobs’ successor at Apple. Scientists promising a race of Methuselahs include Aubrey de Grey, a self-taught biologist, who calls ageing a “barbaric phenomenon that shouldn’t really be tolerated in polite society”. It was de Grey who, in 2004, posited the 5000-year lifespan, earning him the moniker, the “Prophet of Immortality”, an apt label given his Rasputin-style beard and dagger-like eyes. As chief scientist at the California-based SENS Research Foundation, de Grey argues ageing can be “cured” using tissue engineering and regenerative medicine. Probably the most audacious attempt to crack the code of life is taking place at the laboratories of maverick American scientist Craig Venter. In the 1990s Venter’s company, Celera Genomics, entered the race to be first to sequence a human genome – a race that formally ended in a tie in 2000 – and five years ago made headlines by creating synthetic life using computer-generated DNA inserted into a living bacterium. Venter’s search for the wellness gene combines biology with big data. He set up Human Longevity, Inc in March 2014 with $US70 million in start-up capital and two DNA sequencing machines that will map 40,000 human genomes a year, including those from

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supercentenarians (those who’ve lived past their 110th birthday). Rafael de Cabo, a senior scientist at the National Institute on Aging (NIA) in Maryland, credits recent advances in science with driving the interest in longevity research. “This change is due to the accumulating evidence that manipulations in environment, genes and nutrition in model organisms are able to consistently alter ageing processes and the outcomes in health and survival,” he says. “There are now a handful of compounds and dozens of genes identified that hold the promise to be translatable to humans.”

Maverick American s cientist Craig Venter.

Sinclair is decidedly reticent when it comes to passing judgment on the work of scientists such as Venter and Kenyon: “I think it’s going to take a lot of resources to find the needle in the haystack, but it’s helpful that more people are getting involved in ageing research. If Craig and his associates tackle it from the sequencing side and we tackle it from the fundamental biology side and Google attacks it from bio informatics side, then there’s more chance of finding the right medicines.”

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Circumspection is embedded in Sinclair’s DNA. He speaks slowly and deliberately, giving his audiences time to absorb both the complex science behind his discoveries and to underline what motivates him. “How sad would it be if we, after 10,000 generations, we were the last ones to live a normal lifespan?” he ponders. “Imagine if we were born one generation too early to reap the benefits of this technology.” Sinclair is confident those benefits might be just a few years away. He is the co-founder of several biotechnology companies turning out everything from new in-vitro fertilisation techniques to a health app that will use an implant to send real-time health information to your doctor. The US Department of Defence is funding his research on helping soldiers wounded on the battlefield survive and recover. Time included him in its list of the “100 Most Influential People” for

2014. In TED talks and lectures, his slides switch between diagrams of molecular compounds, family snaps of his three young children and photographs of his grandmother, Vera, who saved people from the horrors of the Nazis during World War II, then fled her native Hungary after the Soviet invasion in 1956 for Australia, never to return home again. “In my life I’ve been taught to head in the other direction,” he says. “That was the philosophy my grandmother taught me, to be unique. Whatever you do, just don’t be boring.” Sinclair’s colleagues say he is passionate and driven. “He is always demanding new ideas, insisting that you think outside the box, always pushing you to do more,” says Dr Abhirup Das, who is working with Sinclair at UNSW on a molecule that will change the number of capillaries in muscles and increase blood flow. Professor Brian Kennedy, of the Buck Institute for Research on Ageing in California, a vocal critic of Sinclair’s earlier work on resveratrol, now concedes he may be on the right track: “We have

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not tried to repeat the findings, but they are plausible. While there was controversy in the early days, this is how science often works. Scientific groups had conflicting results and the answer turned out to be between the two positions.”

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For someone whose work may change human destiny, Sinclair says he grew up feeling more empathy towards animals and plants than people. “When I was four I remember realising my pet cat would not live forever. Then I made the leap to, ‘If my cat’s going to die, what about everyone else I love and need for survival?’ I asked my mother would she be around forever and she said no. That was devastating.”

David Le Couteur, scientific director of the Sydney-based Ageing and Alzheimers Institute.

As a father, he has watched his son and two d aughters go through the same process. “Our instincts tell us to bury thoughts about our mortality because otherwise we could not function,” he says. “What I’m not good a t is ignoring that fact. I ha ve that philosophy that every day is precious. I need to try to make the most of my time on the planet and make the world a better place. The theme in my

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house is ‘carpe diem’. No one is allowed to waste a moment.” After finishing school at St Ives, in Sydney’s north, Sinclair toyed with the idea of becoming a vet before enrolling in medical science at UNSW. In 1996, while completing his PhD, he met Dr Leonard Guarente, one of the world’s leading genetic researchers. Guarente asked Sinclair to join his team at the Massachusetts Institute of Technology. In 1997 they made their first breakthrough – by studying yeast cells, they pinpointed for the first time the genetic causes for ageing in an organism. Two years later they identified a group of enzymes called sirtuins, which they found conferred the longevity and health benefits of kilojoule restriction. (The anti-ageing magic of kilojoule restriction has been known for more than 80 years. In the 1930s, researchers at Cornell discovered that mice fed 40 per cent fewer kilojoules while being provided the same level of nutrition lived up to 50 per cent longer than their peers, looked younger, were more energetic, and staved off age-related disease.) Sinclair believes sirtuins are the master regulators that divert energy into cellular preservation in times of famine in order to preserve the organism for reproduction when times are better. “They are the body’s natural defence against disease,” he says. In 2003 Sinclair, who by then had set up his own lab at Harvard, and biochemist Konrad Howitz, published a paper in the journal Nature reporting that resveratrol, a compound found in red wine, could activate one of the sirtuin enzymes known as SIRT1. When Sinclair fed resveratrol to yeast cells, lab worms and fruit flies, they lived longer. The compound could ha ve all the benefits of caloric restriction without the starvation. Forbes magazine dubbed it the $US40 billion drug. Sinclair patented his discovery, co-founded Sirtris Pharmaceuticals

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and floated the company on the US sharemarket in 2007 with a $US69 million initial public offering. A year later Sirtris was bought by GlaxoSmithKline for a staggering $US720 million.

Australian anti-ageing scientist David Sinclai r.

It was not just the price tag that raised eyebrows in the scientific community – some labs were reporting that Sinclair’s conclusions were incorrect. In 2010, a team of Pfizer researchers published a paper in The Journal of Biological Chemistry claiming that neither resveratrol nor several other compounds developed by Sirtris

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affected the SIRT1 enzyme at all. They also presented evidence that the compounds were inhibiting other proteins and that some of the mice taking high doses of the drugs had died. The paper concluded that the Sirtris compounds and resveratrol were pharmacological dead ends owing to “their highly promiscuous profiles”. “At the personal level it was hard to get out of bed, it was hard to get money for research, hard to recruit students and post-docs to come to the lab,” recalls Sinclair of the controversy. “I crashed. It was hard and it was depressing, but I didn’t want to give up because I knew this discovery was important for the world.” The study published in Science in 2013 presented convincing evidence that Sinclair’s earlier conclusions about how resveratrol activates SIRT1 were correct and that hundreds of other, more powerful, compounds developed by Sirtris worked in the same way. Nine months later, in the journal Cell, Sinclair announced another breakthrough – he’d reversed the ageing process using a molecule, naturally produced in humans, known as nicotinamide adenine dinucleotide (NAD). After being fed NAD for a week, mice that were the equivalent of a human aged 60, saw an improvement in their metabolism that turned them into the equivalent of 20 year olds. “Exercising and dieting can boost NAD levels, but as we age, our body makes less and less NAD,” says Sinclair. “Resveratrol works on just one [the Sirtuin enzyme], whereas NAD works on all seven. NAD is the fuel for these enzymes. Think of it as the petrol and resveratrol as the accelerator pedal. You need the petrol but you also need the accelerator, so if you have both it’s even better.”

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Slithering around on a glass slide under a microscope in a laboratory at UNSW, a worm no thicker than an eyelash and found in every backyard compost heap seems an unlikely ally in the quest for longevity. Scientists love Caenorhabditis elegans , or C. elegans for short, because they live for 29 days, making them easy to study, compared with lab mice, which live for about two years.

By tweaking two genetic pathways in C. elegans, researchers at the Buck Institute recently increased the worm’s lifespan by a factor of five – which, if translated into human terms, could see us living for half a millennium. But, like so many discoveries, what works on worms won’t necessarily work on humans. “We often hear about breakthroughs, about new leads in compounds or genes, but how are you going to replicate those

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results?” asks University of Queensland scientist Brad Partridge. “It’s a problem not confined to those researching ageing. It faces all scientists, particularly those working in the field of drug development.”

Clinical trials on humans are lengthy and costly. In the US, the Food and Drug Administration’s refusal to recognise ageing as a disease is holding up the testing of drugs already on the market that have been shown to increase lifespan, such as the immunosuppressant rapamycin and diabetes treatment metformin. Mice given rapamycin have lower rates of cancer, show improvements in physical fitness, cognition and cardiovascular health, and live about 15 per cent longer than normal mice. A recent study of 180,000 people found that people with type-2 diabetes taking metformin also lived, on average, 15 per cent longer, supporting findings that metformin can curb some cancers and heart disease. But since it isn’t prescribed for these conditions, the FDA will not allo w clinical trials.

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“Scientists are working hard to find solutions to this problem and the FDA is starting to listen,” says the NIA’s de Cabo. “I think there will be pathways to test whether drugs extend human health-span.” According to David Le Couteur, scientific director of the Sydney-based Ageing and Alzheimers Institute, scientists in Australia face the same hurdles with the Therapeutic Goods Administration. “As far as our regulatory bodies are concerned, a drug that would act on the ageing process is not even on the horizon. Even if we found a drug that had dramatic results, we would have to start from ground zero when it came to testing.”

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For Sinclair, waiting for a green light from the medical bureaucracy is not an option. He has been self-experimenting by taking resveratrol and other anti-ageing compounds for the past decade and has started giving them to his wife and friends. “I went to my doctor because I was nervous something terrible might happen,” he says. “I didn’t tell him about the resveratrol. He did a blood test and said: ‘This is fantastic, have you changed your lifestyle? Whatever it is you’re doing, just keep doing it.’” Sinclair looks fit, but so do many people in middle age who take care of their diet and exercise regularly. “I cut out desserts at age 40, try not to fill myself up at any meals. I walk, I lift weights a couple of times a week.”

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Not everyone is lining up for longevity pills. Writing in The Atlantic magazine last October, oncologist and bioethicist Ezekiel Emanuel declared he wanted to die at 75. “Living too long is

…

a loss,” he

wrote. “It renders many of us, if not disabled, then faltering and declining, a state that may not be worse than death but is nonetheless deprived. It robs us of our creativity and ability to contribute to work, society, the world.” The World Health Organisation estimates that, by 2050, the number of people aged 60 years and older will increase from 841 million to about two billion. According to American bioethicist Daniel Callahan, longer lives have run exactly parallel to the increase in chronic illness and the explosion in healthcare costs. “Can we possibly afford to live even longer – much less radically longer?” he asked in a recent New York Times article.

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The Buck Institute’s Kennedy says that sceptics such as Callahan are ignoring the facts. “Every nation that has increased lifespan and health has become a richer nation,” he says. “It’s pure economics. The healthier your population, the wealthier is your nation, not the other way around. Chronic diseases and healthcare costs have exploded because there are more people reaching old age. But the key difference are the costs associated with healthy ageing and unhealthy ageing.” Sinclair compares the debate with the reaction to the life-saving effects of antibiotics when they were first introduced. “If given a choice, no one would want to go back to the 1920s, when people could die from a splinter or an infection. Society will adapt. It’s going to be gradual. The first thing that will happen is for the retirement age to go up, unfortunately, but that allows for people to have a different career. The savings you get from having people healthy and productive in society … are in the order of trillions of dollars and that money can be poured back into things such as education and infrastructure.”

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The public, however, is sceptical. A 2011 survey found that while 65 per cent of Australians supported research that would slow ageing, only 35 per cent said they would use a life-extension technology if one became available. Nearly half of those polled (47.8 per cent) believed that developing life-extension technologies would do more harm than good to society overall. “People were concerned about what was going to be the effect if everybody lived longer,” says Brad Partridge, who led the survey. “If presented with the genuine article, people would probably change their minds, but for now the perception is that it’s not on the near horizon.”

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In August, Sinclair flew to Australia to attend the funeral of his 93-year-old grandmother, Vera, whom he describes as the greatest role model in his life. A year earlier, it was the death of his mother that brought him back to Sydney. “I felt like I could have worked harder and done better,” he says. “My goal is to keep people alive, and when my mother passed away I felt like I had failed in my mission.”

David Sincla ir with his grandmother, Vera, in 1991.

Sinclair credits the anti-ageing compounds he gave his mother for extending her life. After losing one lung to cancer, she lived for another 20 years. “The doctors didn’t know how to treat her because they had never seen anyone live that long.” Sinclair’s quiet confidence is contagious. But the scientific world is

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divided. In 2014, the Longevity Science Panel in Britain said the lack of consensus regarding which mechanisms of ageing were dominant in humans presented challenges. “Many potential anti-ageing interventions have been explored but their effectiveness on humans is unclear and their side effects are potentially unacceptable,” the panel concluded. Sinclair sees things differently. “It is surprisingly easy to extend the lifespan of lab animals. If you tell someone you’ve extended the lifespan of a mouse by 30 per cent, they’ll go, ‘So, what’s new?’ What’s important now is to do that for humans. And what was considered crazy talk by me 15 years ago is now well accepted as a goal.” Asked whether he feels as if he’s playing God, Sinclair pauses. “I’m assisting God. Like all doctors, we see it as our mission to prolong life. It’s a noble pursuit. The only difference is that if we are successful, we’ll have an even bigger impact than current medicines.” WORDS John Zubrzycki PRODUCTION/DESIGN Marylouise Brammer PHOTOGRAHY Nic Walker

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Photographed in the science labs at the UNSW Randwick Campus.

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