The pathologist makes do with red wine until an effective drug is available, the
biochemist discards the bread from her sandwiches, and the mathematician indulges in
designer chocolate with a clear conscience. The demographer sticks to vitamin supplements,
and while the evolutionary biologist calculates the compensations of celibacy, the
population biologist transplants gonads, but so far only those of his laboratory mice.
Their common cause is to control and extend the healthy lifespan of humans. They want to
cure ageing and the diseases that come with it.
“I would take resveratrol if it were feasible,” notes David Sinclair, assistant
professor of pathology at Harvard Medical School in Boston, Massachusetts. In the meantime,
he adds, “I do enjoy a glass of red wine about once a day.” It was Sinclair's laboratory,
in association with a commercial partner, that revealed last August how the team had
identified for the first time a group of simple organic molecules capable of extending
lifespan. The most proficient of the group is resveratrol, the plant polyphenol found in
red wine, and its discovery as a potential elixir to combat ageing represents another
extraordinary advance in a decade of discoveries that have revolutionised the field.
“These molecules will be useful for treating diseases associated with
ageing, like diabetes and Alzheimer's.”
Extending Life
Although the life-enhancing effects of Sinclair's polyphenols are so far confined to the
baker's yeast
Saccharomyces cerevisiae , the work suggests that researchers
are only one small step from making a giant leap for humankind. “People imagined that it
might have been possible, but few people thought that it was going to be possible so
quickly to find such things,” says Sinclair. The field of ageing research is buzzing.
Resveratrol stimulated a known activator of increased longevity in yeast, the enzyme
Sir-2, and thereby extended the organism's lifespan by 70% (Box 1). Sir-2 belongs to a
family of proteins with members in higher organisms, including SIR-2.1, an enzyme that
regulates lifespan in worms, and SIRT-1, the human enzyme that promotes cell survival
(Figure 1). Though researchers still do not know whether SIRT-1, or “Sir-2 in humans,” as
Sinclair puts it, has anything to do with longevity, there is a good chance that it does,
judging by its pedigree. In any event, resveratrol proved to be a potent activator of the
human enzyme. This might not be altogether surprising, at least not now, given that the
polyphenol is already associated with health benefits in humans, notably the mitigation of
such age-related defects as neurodegeneration, carcinogenesis, and atherosclerosis.
“The study came out from a pretty big gamble,” recalls Sinclair, who used the human
enzyme to screen and identify molecules that he expected would also stimulate those related
enzymes in lower organisms. Unlike SIRT-1, these related enzymes are known to increase
longevity when activated, usually by restricting the organism's calorie intake. Not only
did they find “a whole collection of related polyphenols that activate ‘Sir-2 from humans,’
… but we put them onto yeast, justbeing the simplest model, and amazingly [they] did what
we were hoping [they] would do,” recalls Sinclair. “But it was a real long shot.”
Now there's great eagerness in the Sinclair laboratory to complete and publish related
research, notably by replicating the yeast work in higher organisms. “We have very
promising results in
Drosophila , which is a huge jump from a yeast cell,” says
Sinclair. “So we're very encouraged by that.” Publication of these results is imminent. The
team has also quickly broadened its horizons and is already testing the polyphenols on
mouse disease models. “We think we may have tapped into a cell survival and defence
programme [and] that these molecules will be useful for treating diseases associated with
ageing, like diabetes and Alzheimer's,” says Sinclair. He hopes to publish the diabetes
results by mid-2004 and those for Alzheimer's by the end of the year. Harvard and BIOMOL
Research Laboratories, its commercial partner based in Pennsylvania, have already filed a
patent application for the use of “synthetic related molecules” to combat diseases of
ageing—an application, Sinclair adds, “very much linked to the [polyphenols] paper.”
There's been a radical shift in attitude towards ageing, says Sinclair. Before the
1990s, “people thought that we were a lot like cars, that we would just rust and
breakdown—nothing we could do about it. The new idea is that there are pathways that can
boost our defences against ageing—the ‘ageing-can-be-regulated’ discovery … that genes can
control ageing [and] that there are pathways that [we can use to] slow down the process,”
he says. “If that's true—and it really seems to be true for a lot of organisms—if it's true
for us, it really means that there is hope that we will be able, one day, to find small
molecules that can alter these pathways.”
How Long Could We Live?
Sinclair expects to see such developments within his lifetime, but he ridicules the
notion that humans will experience anything like the 70% extension to lifespan of his
cultured yeast. “It'll be great if we can just give people an extra five years and have
less disease in their old age and make it less painful,” he says. “We won't be seeing any
Methuselahs around,” he insists.
On his side are James Vaupel, one of Europe's leading demographers, and Marc Mangel, a
mathematical modeller at the University of California at Santa Cruz. “Since 1840, life
expectancy has been going up at 2.5 years per decade and will continue at this rate, maybe
a little faster,” says Vaupel, head of the Laboratory of Survival and Longevity at the Max
Planck Institute for Demographic Research in Rostock, Germany. Women in Japan currently
have the highest average life expectancy of 85, he notes: “So the figure could be 100 in
six decades, but not 500.” There's remarkably little people can do even if they want to
live as long as possible, he says. “Give up smoking, lose weight, don't drive when drunk,
install a smoke detector, take regular exercise,” suggests Vaupel, who insists he does them
all, as well as taking vitamin supplements.
“You look at these worms and think, ‘Oh my God, these worms should be
dead.’ But they're not. They're moving around.”
Mangel sees the problem of assessing the limitations of ageing research as fairly
straightforward. Mathematical models, he says, could solve it by linking demographic
properties and physiological developments. “We've had a separation of the biology of ageing
and the demography of ageing, and they need to come together again,” notes Mangel, whose
personal anti-ageing regime involves taking “a dose of anti-oxidant chocolate with a good
feeling.”
But Cythnia Kenyon, whose laboratory reported in October that it had generated a 6-fold
increase in the lifespan of its nematodes, is not so sure about the limitations. “You look
at these worms and think, ‘Oh my God, these worms should be dead.’ But they're not. They're
moving around…. Once you get your brain wrapped around that … then you start thinking, oh
my goodness, so lifespan is something you can change—it's plastic. Then who knows what the
limit is?” (Cynthia Kenyon has recorded video clips of the superstars of her lab,
Caenorhabditis elegans , to show how long-lived mutant nematodes
are as vigorous as normal young adults [Videos 1–4].)
Warming to the theme, Kenyon hypothesises: “If you'd asked me many generations ago, when
we were actually common precursors of worms and flies, ‘Cynthia, you have a two-week
lifespan, do you think that you could [live longer]?’ And if I'd told you, ‘Well, I think
our descendants will live 1,000 times longer,’ you'd have said, ‘Oh, come on!’ But we do.
It happened,” she notes.
“Who knows what you could do in people?” Kenyon muses. “I don't want to go on record
saying that it's not possible in people because I don't see why it wouldn't be…. I'm
certainly not imagining that my company in the next few years is going to come up with a
compound that can make people live to be 500. That seems just preposterous.” So the
timescale is millions of years? “No, not necessarily,” she insists, “because once we
understand the mechanism, then we can intervene and see what we can accomplish.”
Signalling Life and Sweet 16
Kenyon, professor of biochemistry and biophysics at the University of California at San
Francisco, is among the key contributors responsible for showing that a single gene, and
subsequently many genes, can change an organism's lifespan.
“It is inconceivable … that a life-extending therapy will ever be developed that is
able to extend life independent of every other change.”
In a seminal paper published a decade ago, Kenyon's laboratory showed that mutations in
the
daf-2 gene doubled the lifespan of the nematode
C. elegans .
daf-2 encodes a receptor that is similar to those for insulin and
insulin-like growth factor-1 (IGF-1) in humans; this hormone receptor normally speeds up
ageing in worms, but the mutations inhibit its action and enable the organisms to live
longer. Before the results appeared, there was a “very negative attitude” towards ageing
research, recalls Kenyon. Since then, and especially over the past few years in response to
later findings, graduate students have been scrambling for a chance to work in her
laboratory. “You can't believe the difference—there was such resistance to it,” she says. “
daf-2 made a huge difference.” But then so did her subsequent research in
the field.
Among her most significant findings is the identification of many more longevity genes;
the results, published in July, derive directly from her early work on
daf-2 . “We discovered that in order for long-lived worms to live so
long, they need another gene called
daf-16 ,” recalls Kenyon. “
daf-16 is kind of the opposite of
daf-2 , in the sense that it promotes longevity and youthfulness … so we
call it ‘sweet 16.’”
daf-16 encodes a transcription factor that controls the expression of
more than 100 genes. “They don't do just one thing, they do many things,” says Kenyon. They
can act as anti-oxidants (to prevent damage from oxygen radicals), as chaperones (to
prevent misfolded proteins from forming aggregates), as antimicrobials (to protect against
bacteria and fungi), and as metabolic agents.
“So the picture that emerges is that the way the insulin/IGF-1 hormone system produces
these enormous effects on lifespan is by coordinating the expression of many genes that do
different things to affect lifespan, each of which on its own has only a small effect,”
notes Kenyon. “It's as though
daf-2 and
daf-16 , the regulators, would be the conductors of an orchestra. They
bring together the flutes and the violins and the French horns, each of which do different
things, and they make them all work together in concert.”
Kenyon is unequivocal about the bottom line: “Now we have a whole set of genes whose
biochemical functions we can be working on to understand more about the actual mechanisms
of ageing.” Complementary results in flies and mammals persuade her to be more explicit.
“The common ancestor of worms, flies, and mice must have had an insulin/IGF-1-like hormone
system that controlled ageing. And that ability has been maintained. So the question is,
has [that ability] been lost in humans? I think it's quite likely that it will also
function in humans, but there isn't a direct demonstration yet that that's the case.”
Nevertheless, the discoveries about the role of the insulin/IGF-1 pathway in ageing have
had a profound impact on her own lifestyle, which includes a tendency to discard the bread
from sandwiches and eat only the toppings of pizzas (Box 2). “I'm on a low-carb diet. I
gave my worms glucose, and it shortened their lifespan. [The diet] makes sense because it
keeps your insulin levels down,” she says.
“Caloric restriction extends lifespan of mice, and so does the insulin/IGF-1 pathway,”
she notes. Indeed, starting a low-calorie diet at any point in adulthood appears to help
fruit flies live longer, according to research in Britain published last September. “What
we don't know for sure in mice,” Kenyon continues, “is whether the two pathways are
different or the same.”
While much ageing research focuses on these two influences, she says that there are
another two areas of investigation. Her laboratory reported in December 2002 that
inhibiting the respiration of mitochondria in developing worms increased longevity, but
that it had no effect in adult worms, for reasons still unexplained, she says. Further
microarray analysis is underway to pinpoint whether the cause simply lies downstream of the
insulin/IGF-1 pathway or whether it is something different altogether.
The Price of Life
Then there's research looking at the effects on lifespan of changes to an organism's
reproductive system. For Kenyon, such work often involves a battle to convince sceptics
that longevity is not a trade-off with fertility. Four years ago, her laboratory reported
that killing germ cells increases the lifespan of worms by 60%, but only because, she
stresses, it affects endocrine signalling and not because it prevents reproduction. Further
research, published last year, showed quite clearly, she says, that ageing and reproduction
are controlled independently of one another. And as for her recent work on infertile worms,
which lived six times as long as normal following the removal of their entire reproductive
systems, she says: “If we could intervene in the hormone signalling pathways directly, we
think the animals would still live six times as long as normal, but would be fertile as
well.”
Jim Carey is one of those “trade-off” sceptics. He is a population biologist at the
University of California at Davis and his research, on the effect on life expectancy of
replacing the ovaries of old mice with ovaries from younger mice, is intended to complement
Kenyon's work. But he insists that “an honest discussion of lifespan extension must include
consideration of tradeoffs.” Many manipulations that extend lifespan in model systems,
whether genetic or dietary, for example, ignore or gloss over the side effects, such as
permanent sterility, huge weight loss, distorted organ-to-body ratios, or major behavioural
aberrations, he notes. “It is inconceivable to me that a life-extending therapy will ever
be developed that is able to extend life independent of every other change,” he concludes.
“All life systems are interlinked and hierarchically integrated at all levels, so to talk
about life extension using analogies with a car warranty concept is wrong-headed.”
Another “trade-off” sceptic takes a different tack. As Armand Leroi puts it: “During
occasional periods of involuntary celibacy I have thought, well, I may not be getting laid,
but at least I shall live to a miserable and solitary old age.” Leroi, an evolutionary
biologist at Imperial College of Science, Technology, and Medicine in London, offers an
optimistic appraisal of the chances of finding a cure for ageing in his new book about the
effects of genetic variety on the human body. He sees ageing simply as a collection of
curable diseases: “There is no obvious impediment to that advance, nothing to make us think
that human beings have a fixed lifespan.”
