How
to live forever
Jan 3rd 2008
From The Economist print edition
It
looks unlikely that medical science will abolish the process of ageing. But it
no longer looks impossible
ÒIN
THE long run,Ó as John Maynard Keynes observed, Òwe are all dead.Ó True. But
can the short run be elongated in a way that makes the long run longer? And if
so, how, and at what cost? People have dreamt of immortality since time
immemorial. They have sought it since the first alchemist put an elixir of life
on the same shopping list as a way to turn lead into gold. They have written
about it in fiction, from Rider Haggard's ÒSheÓ to Frank Herbert's ÒDuneÓ. And
now, with the growth of biological knowledge that has marked the past few
decades, a few researchers believe it might be within reach.
To
think about the question, it is important to understand why
organisms—people included—age in the first place. People are like
machines: they wear out. That much is obvious. However a machine can always be
repaired. A good mechanic with a stock of spare parts can keep it going
indefinitely. Eventually, no part of the original may remain, but it still
carries on, like Lincoln's famous axe that had had three new handles and two
new blades.
The
question, of course, is whether the machine is worth repairing. It is here that
people and nature disagree. Or, to put it slightly differently, two bits of
nature disagree with each other. From the individual's point of view, survival
is an imperative. You cannot reproduce unless you are alive. A fear of death is
a sensible evolved response and, since ageing is a sure way of dying, it is no
surprise that people want to stop it in its tracks. Moreover, even the
appearance of ageing can be harmful. It reduces the range of potential sexual
partners who find you attractive—since it is a sign that you are not
going to be around all that long to help bring up baby—and thus, again,
curbs your reproduction.
The
paradox is that the individual's evolved desire not to age is opposed by
another evolutionary force: the disposable soma. The soma (the ancient Greek
word for body) is all of a body's cells apart from the sex cells. The soma's
role is to get those sex cells, and thus the organism's genes, into the next
generation. If the soma is a chicken, then it really is just an egg's way of
making another egg. And if evolutionary logic requires the soma to age and die
in order for this to happen, so be it. Which is a pity, for evolutionary logic
does, indeed, seem to require that.
The
argument is this. All organisms are going to die of something eventually. That
something may be an accident, a fight, a disease or an encounter with a hungry
predator. There is thus a premium on reproducing early rather than conserving
resources for a future that may never come. The reason why repairs are not
perfect is that they are costly and resources invested in them might be used
for reproduction instead. Often, therefore, the body's mechanics prefer
lash-ups to complete rebuilds—or simply do not bother with the job at
all. And if that is so, the place to start looking for longer life is in the
repair shop.
Seven
deadly things
One
man who has done just that is Aubrey de Grey. Dr de Grey, who is an independent
researcher working in Cambridge, England, is a man who provokes strong
opinions. He is undoubtedly a visionary, but many biologists think that his
visions are not so much insights as mischievous mirages, for he believes that
anti-ageing technology could come about in a future that many now alive might
live to see.
Vision
or mirage, Dr de Grey has defined the problem precisely. Unlike most workers in
the field, he has an engineering background, and is thus ideally placed to look
into the biological repair shop. As he sees things, ageing has seven
components; deal with all seven, and you stop the process in its tracks. He
refers to this approach as strategies for engineered negligible senescence
(SENS).
The
seven sisters that Dr de Grey wishes to slaughter with SENS are cell loss,
apoptosis-resistance (the tendency of cells to refuse to die when they are
supposed to), gene mutations in the cell nucleus, gene mutations in the
mitochondria (the cell's power-packs), the accumulation of junk inside cells,
the accumulation of junk outside cells and the accumulation of inappropriate
chemical links in the material that supports cells.
It
is quite a shopping list. But it does, at least, break the problem into
manageable parts. It also suggests that multiple approaches to the question may
be needed. Broadly, these are of two sorts: to manage the process of wear and
tear to slow it down and mask its consequences, or to accept its inevitability
and bring the body in for servicing at regular intervals to replace the
worn-out parts.
Eat
up your greens
Managing
wear and tear may not be as complicated as it looks, for the last five items on
Dr de Grey's list seem to be linked by a single word: oxidation. Regular
visitors to the Òhealth and beautyÓ sections of high-street pharmacies will, no
doubt, have come across creams, pills and potions bearing the word antioxidant
on their labels and hinting—though never, of course, explicitly
saying—that they might possibly have rejuvenating effects. These products
are the bastard children of a respectable idea about one of the chief causes of
ageing: that one big source of bodily wear and tear, at least at the chemical
level, is the activity of the mitochondria.
Mitochondria
are the places where sugar is broken down and reacted with oxygen to release
the energy needed to power a cell. In a warm-blooded creature such as man, a
lot of oxygen is involved in this process, and some of it goes absent without
leave. Instead of reacting with carbon from the sugar to form carbon dioxide,
it forms highly reactive molecules called free radicals. These go around
oxidising—and thus damaging—other molecules, such as DNA and
proteins, which causes all sorts of trouble. Clear up free radicals and their
kin, and you will slow down the process of ageing. And the chemicals you use to
do that are antioxidants.
This
idea goes back to one of the founders of scientific gerontology, Bruce Ames of
the University of California, Berkeley. Dr Ames began his career studying
cancer. He found that damage to certain genes was a cause of cancer. These
genes evolved to keep tumours at bay by stopping cells dividing too readily,
and the damage was often done by oxidation. Gradually, his focus shifted to the
more general damage that oxidation can do—and what might, in turn, be
done about it.
Some
vitamins, such as vitamin C, are antioxidants in their own right. This is the
basis of the high-street propaganda, though there is no evidence that consuming
such antioxidants in large quantities brings any benefit. A few years ago,
however, Dr Ames found he could pep up the activity of the mitochondria of
elderly rats—with positive effects on the animals' memories and general
vigour—by feeding them two other molecules: acetyl carnitine and lipoic
acid. These help a mitochondrial enzyme called carnitine acetyltransferase to
do its job. Boosting their levels seems to compensate for oxidative damage to
this enzyme. He also reviewed the work of other people and found about 50
genetic diseases caused by the failure of one enzyme or another to link up with
an appropriate helper molecule. Such helpers are often B vitamins, and the
diseases were often treatable with large doses of the appropriate vitamin.
The
enzyme damage in these diseases is similar to that induced by oxidation, so Dr
Ames suspects that its effects, too, can be ameliorated by high doses of
vitamins. He has gathered evidence from mice to support this idea, but whether
it is the case in people has yet to be tested. Nor is it easy to believe it
ever will be. The necessary clinical trials would be long-winded. They would
also be expensive—and there is no reason for vitamin companies to pay for
them since sales are already buoyant and the products could not be patented.
Nor is Dr Ames claiming vitamins will make you live longer than a natural human
lifespan, even if he thinks they might prolong many individual lives. For that,
other technologies will need to be invoked.
Stemming
time's tide
One
way that might let people outlive the limit imposed by disposable somas is to
accept the machine analogy literally. When you take your car to be serviced or
repaired, you expect the mechanic to replace any worn or damaged parts with new
ones. That, roughly, is what those proposing an idea called partial
immortalisation are suggesting. And they will make the new parts with stem
cells.
The
world has heard much of stem cells recently. They come in several varieties,
from those found in embryos, which can turn into any sort of body cell, to
those whose destiny is constrained to becoming just one or a few sorts of cell.
The thing about stem cells of all types, which makes them different from
ordinary body cells, is that they have special permission to multiply
indefinitely.
For
a soma to work, most of its component cells have to accept they are the end of
the line—which, given that that line in question stretches back unbroken
to the first living organisms more than 3 billion years ago, is a hard thing to
do. There are, therefore, all sorts of genetic locks on such cells to stop them
reproducing once they have arrived at their physiological destination. If these
locks are picked (for example by oxidative damage to the genes that control
them, as discovered by Dr Ames), the result is unconstrained growth—in
other words, cancer. One lock is called the Hayflick limit after its
discoverer, Leonard Hayflick. This mechanism counts the number of times a cell
divides and when a particular value (which differs from species to species) is
reached, it stops any further division. Unless the cell is a stem cell. Every
time a stem cell divides, at least one daughter remains a stem cell, even though
the other may set off on a Hayflick-limited path of specialisation.
Some
partial immortalisers seek to abolish the Hayflick limit altogether in the hope
that tissue that has become senescent will start to renew itself once more.
(The clock that controls it is understood, so this is possible in principle.)
Most, though, fear that this would simply open the door to cancer. Instead,
they propose what is known as regenerative medicine—using stem cells to
grow replacements for tissues and organs that have worn out. The most visionary
of them contemplate the routine renewal of the body's organs in a Lincoln's
axish sort of way.
In
theory, only the brain could not plausibly be replaced this way (any
replacement would have to replicate the pattern of its nerve cells precisely in
order to preserve an individual's memory and personality). Even here, though,
stem-cell therapists talk openly of treating brain diseases such as Parkinson's
with specially grown nerve cells, so some form of partial immortalisation might
be on the cards. But it is a long way away—further, certainly, than Dr
Ames's vitamin therapy, if that is shown to work.
Neither
prevention, nor repair, is truly ready to roll out. But there is one other
approach, and this is based on the one way of living longer that has been
shown, again and again, in animal experiments, to be effective. That is to eat
less.
From
threadworms to mice, putting an animal on a diet that is near, but not quite
at, starvation point prolongs life—sometimes dramatically. No one has done
the experiment on people, and no one knows for sure why it works. But it does
provide a way of studying the problem with the reasonable hope of finding an
answer.
Gluttons
for punishment
You
would, of course, have to wish a lot for a long life to choose to starve
yourself to achieve it. Extrapolating from the mouse data, you would need to
keep your calorie intake to three-quarters of the amount recommended by
dieticians. That means about 1,800 for sedentary men and 1,500 for sedentary
women. But several people are trying to understand the underlying biology, in
order to develop short cuts.
One
such is David Sinclair of Harvard University. Unlike those trying to fight the
causes of ageing or to repair the damage done, Dr Sinclair thinks he has found,
in caloric restriction as the technique is known, a specifically evolved
natural anti-ageing mechanism that is quite compatible with disposable-soma
theory.
The
reason for believing that prolonged life is an evolutionary response to
starvation rather than just a weird accident is that when an animal is starving
the evolutionary calculus changes. An individual that has starved to death is
not one that can reproduce. Even if it does not die, the chance of it giving
birth to healthy offspring is low. In this case, prolongation of life should
trump reproduction. And that is what happens, even among people. Women who are
starving stop ovulating. The billion-dollar trick would be to persuade the body
it is starving when it is not. That way people could live longer while eating
normally. They might even, if the mechanism can truly be understood, be able to
reproduce, as well.
In
Dr Sinclair's view, the way caloric restriction prolongs life revolves around
genes for proteins called sirtuins. Certainly, these genes are involved in life
extension in simple species such as threadworms and yeast. Add extra copies of
them to these organisms' chromosomes, or force the existing copies to produce
more protein than normal, and life is prolonged. This seems to be because
sirtuins control the abundance of a regulatory molecule called nicotinamide
adenine diphosphate which, in turn, controls the release of energy in the
mitochondria.
The
most intriguing connection in this story is with the French paradox. This is
the fact that the French tend to eat fatty diets rich in red meat but to have
the survival characteristics of those whose diets are lean and vegetarian. Some
researchers link this with their consumption of red wine—and, in
particular, of a molecule called resveratrol that is found in such wine.
Resveratrol activates sirtuins, and some similar molecules activate them much
more. It is these sirtuin super-stimulators that interest Dr Sinclair.
Not
everyone is convinced, but Dr Sinclair has done experiments on mice that look
promising, and has started a company called Sirtris Pharmaceuticals to follow
it up. The fact that he is (at least in his own eyes) working with nature
rather than against it argues that this is the most promising approach of all.
That
said, the logic of the disposable-soma theory is profound. Even working with
its grain may do no more than buy a few extra years of healthy living. Dr de
Grey's reason for thinking that some people now alive may see their lives
extended indefinitely is based on the hope that those few extra years will see
further discoveries and improved life-extension technologies based on
them—a process he describes as achieving Òlongevity escape velocityÓ.
The
chances are that it will not work. But hope springs eternal. To end with
another quote, this time from Woody Allen, ÒI don't want to achieve immortality
through my work. I want to achieve immortality through not dying.Ó If any
researcher manages to beat evolutionary history and achieve his goal, he might
get to do both.
How
to live for ever
Feb 23rd 2006
From The Economist print edition
The
latest from the wacky world of anti-senescence therapy
DEATH
is a fact of life—at least it has been so far. Humans grow old. From
early adulthood, performance starts to wane. Muscles become progressively
weaker, cognition fails. But the point at which age turns to ill health and,
ultimately, death is shifting—that is, people are remaining healthier for
longer. And that raises the question of how death might be postponed, and
whether it might be postponed indefinitely.
Humans
are certainly living longer. An American child born in 1970 could expect to
live 70.8 years. By 2000, that had increased to 77 years. Moreover, an adult
still alive at the age of 75 in 2002 could expect a further 11.5 years of life.
Much
of this change has been the result of improved nutrition and better medicine.
But to experience a healthy old age also involves maintaining physical and
mental function. Age-related non-pathological changes in the brain, muscles,
joints, immune system, lungs and heart must be minimised. These changes are
called ÒsenescenceÓ.
Research
shows that exercise can help to maintain physical function late in life and
that exercising one's brain can limit the progression of senescence. Other
work—on the effects of caloric restriction, consuming red wine and
altering genes in yeast, mice and nematodes—has shown promise in slowing
senescence.
The
approach advocated by Aubrey de Grey of the University of Cambridge, in
England, and presented at last week's meeting of the American Association for
the Advancement of Science, is rather more radical. As an engineer, he favours
intervening directly to repair the changes in the body that are caused by
ageing. This is an approach he dubs Òstrategies for engineered negligible
senescenceÓ. In other words, if ageing humans can be patched up for 30 years,
he argues, science will have developed sufficiently to make further repairs
more effective, postponing death indefinitely.
Dr
de Grey's ideas, which are informed by literature surveys rather than
experimental work, have been greeted with scorn by those working at developing
such repair kits. Steven Austad, a gerontologist based at the University of
Texas, warns that such therapies are many years away and may never arrive at all.
There are also the side effects to consider. While mice kept on low-calorie
diets live longer than their fatter friends, the skinny mice are less fertile
and are sometimes sterile. Humans wishing both to prolong their lives and to
procreate might thus wish to wait until their child-bearing years were behind
them before embarking on such a diet, although, by then, relatively more
age-related damage will have accumulated.
No
one knows exactly why a low-calorie diet extends the life of mice, but some
researchers think it is linked to the rate at which cells divide. There is a
maximum number of times that a human cell can divide (roughly 50) before it
dies. This is because the ends of chromosomes, structures called telomeres,
shorten each time the cell divides. Eventually, there is not enough left for
any further division.
Cell
biologists led by Judith Campisi at the Lawrence Berkeley National Laboratory
in California doubt that every cell has this dividing limit, and believe that
it could be only those cells that have stopped dividing that cause ageing. They
are devising an experiment to create a mouse in which senescent
cells—those that no longer divide—are prevented from accumulating.
They plan to activate a gene in the mouse that will selectively eliminate senescent
cells. Such a mouse could demonstrate whether it is possible to avoid growing
old.
But
successful ageing is being promoted here and now. Older people who engage in a
lot of social interactions stay young for their chronological age, argues John
Rowe, a professor of medicine and geriatrics at the Mount Sinai School of
Medicine in New York. Research has shown that people who receive emotional
support not only have higher physical performance than their isolated
counterparts, but also that they show lower levels of hormones that are
associated with stress.
Other
work, led by Teresa Seeman of the University of California, Los Angeles, shows
that Òallostatic loadÓ—the cumulative physiological toll exacted on the
body—predicts life expectancy well. It is measured using variables
including blood pressure and levels of stress hormones.
Dr
Seeman found that elderly people with high degrees of social engagement had
lower allostatic loads. They were also more likely to be well educated and to
have a high socio-economic status. It would thus appear that death can be
postponed by various means and healthy ageing extended by others. Whether death
will remain the ultimate consequence of growing old remains to be seen.
http://www.ted.com/index.php/talks/view/id/39?gclid=CK_J3_TG15ACFQFZQgodNTn4Wg
http://en.wikipedia.org/wiki/Aubrey_de_Grey
http://mfoundation.org/index.php?pagename=research_adgbio
http://www.bruceames.org/bnamedia.html
http://sinclairfs.med.harvard.edu/