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
“IN THE long run,” as John Maynard Keynes observed, “we are all
dead.” 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 “She” to Frank Herbert's
“Dune”. 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.
The question, of course, is whether the machine is worth
repairing. 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.
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.
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.
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.
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
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.
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.
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
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..
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.
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.
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 “longevity escape velocity”.
The chances are that it will not work. But hope springs eternal.
To end with another quote, this time from Woody Allen, “I don't want to achieve
immortality through my work. I want to achieve immortality through not dying.”
If any researcher manages to beat evolutionary history and achieve his goal, he
might get to do both.
