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The Longevity Seekers: Science, Business, and the Fountain of Youth – Ted Anton
Preface
Aging had been thought to be random decay, and no one wanted to study that. Yet all
biological processes are controlled by genes, so aging might be as well. This is the story of the
race to understand the genes of healthful human longevity. It looks at the story of a potential
science revolution and of the new money changing the way scientific ideas emerge. It
examines the idea that the quality of aging can be altered by tweaking single genes.
Part I. From Obscurity 1980-2005
1. “Greater Than the Double Helix Itself,” 1980-1990
The wish to overcome aging and death lies at the foundation of many founding myths.
The trade-off idea between youth and age: “antagonistic pleiotropy” – genes that trigger
youth hormones to keep us vigorous and attractive can later cause us to age more rapidly.
The discovery of such hormones led to a wave of early charlatans who transplanted goat and
monkey tecticles into patients. In the 1920’s it was thought that vasectomies would increase
male longevity.
Early theories of aging held that it was a random and chaotic process. It could be caused by
genetic mutation, build-up of cellular mistakes, free radicals, or the “Hayflick limit” that
human cells could only divide 52 times. One idea, which still exists, is that lowering caloric
intake can reduce aging.
The National Institute on Aging pushed academic science to take on the quest of improving
the quality of aging because of the increased percentage of older adults in the population.
This led to the hypothesis that genes timed the processes of life and death. The “gang of
cryptographers” studied the time-line of cell division in worms. At another lab, Tom Johnson
discovered that when mating a strain of long-lived worms with normal worms, exactly half of
the offspring were long-lived, which suggested that a single gene was responsible. This led to
the public popularity of what was later called the “age-1” gene, but other scientists were
skeptical.
2. The Grim Reaper, 1991-1993
Cynthia Kenyon was enthralled when she heard about Johnson’s work. She had had a
successful career in genetics but longed to do explore the unknown. She felt sure that genes
controlled the rate of aging, and changes in these genes during evolution were “responsible
for the different life spans of different animals,” but everyone tried to discourage her from
pursuing this idea. But the idea that one minor change in regulatory genes could make a
huge change in an animal appealed to her. She pushed one of her graduate students, Ramon
Tabtiang, to study aging.
There were 2 ways to learn about the gene regulation of aging: (1) identify changes in older
cells and ask if any of them actually caused aging and (2) Seek lab animals that had altered
life spans, to see if aging was regulated in a controlled or a haphazard way. Tabtiang used a
daf-2 hibernation gene mutant as a control group and discovered that it lived twice as long as
normal worms. Another gene, daf-16, superintended the process of lengthening life.
Although other researchers were still skeptical, once the results were published they had to
pay attention.
3. Sorcerer’s Apprentices, 1991-1996
MIT graduate students Brian Kennedy and Nic Austriaco wanted to pursue something big.
After much research, they decided to study aging in yeast. Rather than a previous approach
of inserting mammalian proteins into yeast, they would study yeast aging genes and see if
they existing in mammals. Yeast were simple and short-lived, so they hoped to answer these
questions quickly. They decided to measure life span by counting the number of times a
mother bud reproduces.
They found a long-lived mutant strain. The SIR (silent information regulator) gene had a
mutation that made yeast cells live 30 percent longer than normal. After graduating,
Kennedy went off to Switzerland to study Sir proteins. He found that the gene product was
acting in the nucleolus of the cell nucleus. Another MIT student, David Sinclair, discovered
that during aging, cell accumulation of ribosomal DNA circles caused a toxic effect.
California biotech company Geron figured out a way to inject into human cells more of the
enzyme telomerase, which repaired telomeres, the chromosome endings that shorten each
time a cell divided.
Back at MIT, it was discovered that starving cells produced a coenzyme, NAD, that stimulated
SIR2 to silence genes, which extended life. They thought that this was the key to why
reducing calories extended life. The search for longevity genes took off in multiple labs.
4. Race for a Master Switch, 1995-2000
After discovering that single gene mutations could extend the life span significantly with a
high quality of life, the biology of longevity was now considered a legitimate research area.
Unfortunately, no one knew the locations of the daf-2 or daf-16 genes, and with technology
of the early 1990s the work proceeded slowly.
Gary Ruvkun had been studying genetic material considered to be a clue to the origin of life.
He suspected Kenyon’s longevity claim as crossing the line from science into “snake oil.”
When his lab discovered that the worm’s gene resembled the human gene for insulin, the
possibility of extending this research to humans seemed more real. When food is plentiful,
the insulin receptors promote energy storage and growth. When food is scarce, the lowered
insulin levels shift cells to a state of maintenance, repair and long life. At the International
Worm Meeting in Madison, Wisconsin, the Ruvkun lab divulged too much of their discoveries
and gave an advantage to the Kenyon lab. Both rushed to publish papers.
“An explosion of analysis” ensued. Kenyon returned to the question of sex and life span: a
trade-off between reproduction and longevity. Molecular geneticists of aging thought this
was too deterministic. Having problems finding someone to perform the experiments,
Kenyon allowed Honor Hsin, an enthusiastic home-schooled 12-year-old girl to help. They
discovered that while removing entire gonads did not extend the life span of normal worms,
just removing the precursor seed cells did.
Now “angel investors” became interested in the biotechnology industry. Arch Ventures
teamed up MIT’s Guarente with Kenyon. On June 26, 2000, the sequence of the human was
announced. While few noticed that it had depended on the original research done on worms,
venture investors were watching closely.
5. Money to Burn, 2000-2003
In 2000, it became cheaper to process genetic data than to understand it. Kenyon and
Guarente had formed the company Elixir. A new term, “genotech,” described the gold rush of
science rivals, each with their own longevity gene approach, suddenly competing for
investors. More than $100 million was raised among them. Gene patents and new tools of
automated genetics sequencing made this possible. The companies offered similar business
plans: find a promising pathway, seek compounds to tweak the pathway, test the
compounds, identify people who know how to make drugs, and find a specific disease to
treat in order to obtain FDA approval. But not everyone liked the new relationship between
business and academic science.
In Paris, researcher Martin Holzenberger studied the insulin gene pathway in mice. In Illinois,
biologist Andrzej Bartke studied growth hormone receptors in dwarf mice. Kenyon’s lab
discovered that the insulin pathway increased life span only when tweaked in adulthood.
Researchers clashed with evolutionary theorists who claimed that if a gene prolonged life, it
would do other things that were deleterious. There was also the problem of how to prescribe
a drug to “those at risk” when everyone is a risk for aging! The ethics of longevity research
was discussed in Washington DC.
6. Longevity Noir, 2003-2004
Elixir, after scanning almost 400,000 artificial compounds, found no single intervention with a
clear profit potential At Harvard, David Sinclair was trying to find a plant compound to
trigger an enzyme expressed by a human gene. He teamed up with Konrad Howitz who found
two polyphenols, which were known antioxidants. They discovered reversatrol, found in red
wines and already available over the counter in health food stores. Although there were still
potential issues, much media hype followed. Eventually Christoph Westphal of Polaris
Venture Partners incorporated the company Sirtris with the idea of attacking diseases of
aging. Other labs were unable to reproduce the results.
Kenyon continued to study insulin and published papers that attracted attention. Elixir
discovered the enzyme AMP-kinase, a master metabolic regulator.
7. Betting the Trifecta, 2005-2006
By 2005, at least 15 major longevity genes had emerged. Lab experiments fused disparate
theories of aging – free radicals, limited calories, inflammation and DNA repair. A lifetime
could be divided into 3 phases:
Growth, where gene networks increase in strength and fidelity, the maintenance phase of
Healthy Adulthood, and Decline, when cell functions are destabilized as the forces of natural
selection wane. Many molecular mechanisms preserve or shorten life; some inhibit repair
mechanisms, some assist; some kill diseased cells and others kill off healthy cells. All this had
to be taken into consideration.
Daf and SIR became “celebrity genes” and the two pathways resulted in “almost like a
religious cult.” A new field developed called the computational biology of aging. By 2005,
four intertwined genetic pathways came to the forefront: insulin, sirtuins, the anticancer
gene TOR, and the energy regulator AMP-kinase. The key was to find which worked best in
humans. One early surprise was that only a small number of genes actually changed in their
activity as animals aged. Cosmetics companies entered, providing funding and developed skin
creams based on these compounds.
Biotechnology companies were accused of overselling their claims because of the money on
the line. A number of issues with procedures and evaluation of results were pointed out.
Replication of results was problematic. Top science journals were accused of having
“devolved into information laundering operations for the pharmaceutical industry.” Several
critics argued that the whole idea was over-simplified and wrong and that the interventions
only worked on lab animals. Research companies struggled for funding.
Then an old gene reappeared. Rapamycin, found on Rapa Nui (Easter Island), had been
licensed as an immunosuppressant drug. The gene affected in yeast also appeared in worms
and flies, TOR, turned out to be an essential component of the nutrient-sensing pathway. The
same gene in mice, mTOR, proved to be a longevity gene. The attention was shifted to the
effect of reversatrol on mitochondria, the cell’s energy factories. Companies were betting on
compounds that could hit several longevity pathways, leading to speculation about a “trifecta
of aging.”
Part 2. Defying Gravity: The Battle to find a Drug for Extending Health, 2005-2013
8. Sex, Power and the Wild: The Evolution of Aging, 2001-2008
For 4 years, David Reznick studied the effect of environment on guppy life spans. He found
that life span could lengthen or shorten significantly in a short time, that lengthened span
could be inherited, and that the longest-lived wild guppies came from the most hostile
environments. This meant that genetic mechanisms had to drive it. Researchers of wild
animals discovered many evolutionary adaptations to live longer. Many sea creatures can live
a century or two. The secret seemed to be stress resistance. For a long time, researchers in
the wild and in the lab did not communicate.
Labs continued to experiment, and scientists continued to disagree on results. In 2007, Sirtris
applied for approval for human clinical trials of artificial reversatrol and attracted
GalaxoSmithKline. Elixir prepared to go public with a glucose-lowering drug.
9. The Rush and Crisis, 2008-2010
In 2009, the Nobel Committee recognized the biology of aging as a science by awarding its
Prize for Medicine for the discovery that the enzyme telomerase protects chromosome
endings. Several biotech and cosmetics companies sprang up to market telomerelengthening products.
By the fall of 2009 the sirtuin and reversatrol claims had accumulated significant challenges.
Yet the controversy did little to slow the public hunger for reversatrol.
Money and experiments continued.
10. Live Long and Prosper, 2009-2011
In 2010, a new generation of researchers competed to understand the ways in which a gene
discovery might lead to the treatment of disease. The focus changed from why we age, to
why we remain healthy. Protein shape, cell defenses and repair mechanisms, patterns of
healthy gene expression, telomere lengthening, isolating damaged tissues, and utilizing the
insulin receptor or the SIR gene pathway all seemed promising. Twenty years of research had
produced very little of therapeutic value, yet 247 known or suspected longevity genes in
humans had been claimed!
GSK/Sirtris dominated the field. New ideas developed about how to make drugs. Historically,
some of the most successful drugs had been found by serendipity.
Epigenetics entered the picture and provided further areas to research.
11. Centarians in the Making, 2011-2013
Nir Barzilai established the Albert Einstein College of Medicine’s Institute of Aging Research.
Genes of long-lived humans were analyzed. Many teams rushed to investigate this approach.
FOX genes were discovered to provide a potential bridge between insulin signaling, free
radicals, and human longevity. The next step was to find uniquely human gene mechanisms
of longevity. Researchers looked at DNA repair, mitochondrial health, and human CETP. In
2011 several claims by human longevity gene researchers had to be retracted due to falsepositives. The press to find human drugs continued.
12. Fountains of Youth, 2013We live in a world that celebrates youth, yet the world’s fastest-growing demographic group
is those 80 and above. People worry that the general trend toward lengthened human lives
will exacerbate generational conflict. Living longer, healthier lives may provide a boost to the
world economy. Yet attempts to align retirement income to the new life span expectancies
globally meet with strong resistance. Developed countries may be forced to choose between
funding entitlements or investing in education and infrastructure. Research to improve the
overall quality of late-life health is more necessary now than ever.
The right answer to the question of global aging is living healthier, longer lives, along with
equality and the rising wealth and knowledge of human civilization. Improved social policy,
greater social equality, and some health-care overhaul are necessary.
In the labs, researchers continue to make new discoveries even as these issues are being
discussed. Mitochondria remains one promising area of research.
13. Reimagining Age
Most science proceeds quietly, yet there never has been a science like this for its sudden
media and money infusion. The quest has turned to a new unifying theory of longevity. One
emerging model is that genes behave a bit like investors, picking and choosing the traits that
would maximize their return, yet susceptible to mistakes and faulty communication.
Research has sought to move from the lab to the clinic. Acceleration in molecular genetics
tools has had considerable influence.
So what has been accomplished? Our understanding of molecular genetics of longevity has
deepened. We have moved from description to cause and effect. Many believe that there will
be a longevity pill developed. According to Brian Kennedy, “The next decade is going to be
amazing.”
Epilogue
As we glimpse the possibilities of a productive later life, we can glimpse what healthful
longevity may mean for the individual, society, and the human experience. The scientists of
longevity genes took risks. They struggled to make sense of their discoveries. Their journeys
went to the core of what it means to be human, the transmutation of nature into something
akin to art. It is the beginning of a new science, not the end.