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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
Bostons 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 restaurants 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 worlds 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 youre 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, Im stubborn. And we
already had good results in the lab which said I was right, but the

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results werent 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 didnt 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, Sinclairs 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.
Sinclairs statement is borne out by the World Health Organisations
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, 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 Bostons 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 Len 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: well 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 worlds 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 shouldnt 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 Venters 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.
Venters 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 whove 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 its going
to take a lot of resources to find the needle in the haystack, but its
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 theres more chance of finding the
right medicines.

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Circumspection is embedded in Sinclairs 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 Ive 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 dont be boring.
Sinclairs 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 Sinclairs 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 cats 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
Im 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 Sydneys 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 worlds 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
bodys 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 have 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 Sinclair.

It was not just the price tag that raised eyebrows in the scientific
community some labs were reporting that Sinclairs 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 didnt 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 Sinclairs 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 hed 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 its 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 worms 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 wont 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. Its

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 Administrations 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 isnt prescribed for these conditions, the FDA will
not allow 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 NIAs 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 didnt tell him about the resveratrol. He did a blood test and
said: This is fantastic, have you changed your lifestyle? Whatever it
is youre 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 Institutes 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. Its 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. Its 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 its 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 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 didnt know how to treat her because
they had never seen anyone live that long.
Sinclairs 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 youve extended the
lifespan of a mouse by 30 per cent, theyll go, So, whats new?
Whats 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 hes playing God, Sinclair pauses. Im
assisting God. Like all doctors, we see it as our mission to prolong
life. Its a noble pursuit. The only difference is that if we are
successful, well 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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