Never say die.pdf

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er say die 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 ofred 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 his findings a “pharmacological dead end”. Now he

was toasting the curative qualities of pinot noir and raising a glass

to those colleagues who had stuck with him during 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. Ithought, ‘This is not worth it.’ But fortunately, I’m stubborn. And we

already had good results in the lab which 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 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.

Science

Today, Sinclair’s work on slowing the ageing process, and even

reversing some aspects of it, could lead to the most significant set ofmedical 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’sGlobal 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, meaning 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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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, 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.

Time

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 hisRasputin-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, enteredthe 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 $US70million 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 scientist 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 itfrom 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 toyour doctor. The US Department of Defence is funding his research

on helping soldiers wounded on the battlefield survive and recover.

included him in its list of the “100 Most Influential People” for

2014.

Time

In TED talks and lectures, his slides switch between diagrams of

molecular compounds, family snaps of his three young children andphotographs 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 onAgeing 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 sayshe 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 daughters 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 at is ignoring that fact. I have 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

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 have all the benefits of caloric

restriction without the starvation. magazine dubbed it the

$US40 billion drug.

Nature

Forbes

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 Sinclair.

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 apaper in claiming that neither

resveratrol nor several other compounds developed by Sirtris

The Journal of Biological Chemistry


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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 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.

Science

Nine months later, in the journal , 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.

Cell

“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 laboratoryat 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 , or for

short, because they live for 29 days, making them easy to study,

compared with lab mice, which live for about two years.

Caenorhabditis elegans C. elegans

By tweaking two genetic pathways in , 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.

C. elegans

“We often hear about breakthroughs, about new leads in

compounds or genes, but how are you going to replicate those


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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 mydoctor 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, trynot to fill myself up at any meals. I walk, I lift weights a couple of

times a week.”


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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 theother 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 achoice, 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 his93-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 Sinclair 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 agoal.”

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.”

John Zubrzycki

Marylouise Brammer

Nic Walker

WORDS

PRODUCTION/DESIGN

PHOTOGRAHY


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Photographed in the science labs at the UNSW Randwick Campus.


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