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IN The Creeping Man by Arthur Conan Doyle, an ageing
professor attempts to rejuvenate his flagging libido with an injection of
ground-up monkey testicles. The remedy works but, unhappily, the professor turns
into an ape.

Research into ageing has often been the target of jibes about quacks peddling
bizarre elixirs based on the sexual parts of animals. But these days the joke is
wearing thin. Medicine’s ability to keep people alive in their old age is far
outstripping its ability to restore the vigour of their younger years. And that
grim reality is driving a new assault—minus the monkey glands—on the
underlying causes of ageing.

Brittle bones, grey hair, saggy skin, forgetfulness, loss of immunity,
cancer, strokes, these are the all too obvious hallmarks of ageing. But inside
cells, the landscape of old age looks very different. Chromosomes clock up
random mutations, and their ends fray. Molecular debris piles up. Membranes get
worn and ragged. And potentially most harmful of all, strange things happen to
the activities of specific genes: useful ones shut down for good while less
desirable ones mysteriously spring into life. These are the kinds of changes
that some gerontologists are trying to halt or reverse, convinced that ageing
need not be the inevitable consequence of a long life.

The high watermark of this new optimism can be seen in the glossy brochures
of Geron Corp., the world’s first biotechnology company devoted to developing
drugs and therapies to treat ageing. The company’s name and logo—an
hourglass inside a double helix of DNA—wouldn’t look out of place in a
fictional tale of scientists searching for a gene for eternal youth. But Geron’s
labs on the outskirts of San Francisco are real enough. As are the aspirations
of its scientists. “We hope to increase the lifespans of cells [using] compounds
that reverse the abnormal expression of genes that occurs in ageing,” Calvin
Harley, Geron’s scientific director, proudly told 91av last
year. As skin cells age, for example, their genes churn out more and more
collagenase, an enzyme that breaks down proteins needed to keep wrinkles at bay.
Other switches in gene activity afflict immune cells, making them “deaf” to
messenger molecules and infectious agents in old age. In Harley’s view, these
changes are as unacceptable as anything that happens in a disease—a vision
that many octogenarians share. Texan millionaire Miller Quarles is even offering
a prize of $100 000 for the person who discovers a “cure for the disease
of old age”.

At 81, however, Quarles might be better off blowing his cash elsewhere.
Despite their optimism, most experts on ageing say, when pushed, that there is a
world of difference between understanding what goes on in an ageing cell, and
doing anything about it.

Radical differences

And perhaps of even greater concern to Quarles is that they also
disagree—sometimes passionately—about the most likely route to
success. Some biologists believe that the clocking up of random damage to DNA,
proteins and cells is really all there is to ageing. This school sets great
store by developing novel ways of limiting the damage wreaked by oxygen free
radicals and other potentially hazardous by-products of fuel combustion in
cells. Others, however, argue that there is a further reason why we decay in old
age—our tissues lose the ability to produce new cells, and accumulate too
many old ones. This school includes researchers who think the overarching answer
to slower ageing lies in preventing the shortening of telomeres, non-coding
pieces of DNA that sit at the ends of chromosomes.

One thing is crystal clear: new insights into ageing are being thrown up at
an unprecedented rate. Take research into Werner’s syndrome. People affected by
this rare disease are cruelly wizened and grey by the time they reach their
late-20s. They can expect to die from prematurely clogged arteries and heart
disease in their late 40s or 50s. And all because they carry two copies of a
defective gene. For years, gerontologists could only speculate about how the
genetic defect behind Werner’s syndrome accelerates ageing. Then, in a
ground-breaking study in Science on 12 April this year, researchers led
by Gerard Schellenberg, a molecular geneticist at the University of Washington
in Seattle, showed that the Werner’s gene codes for a type of enzyme known as a
helicase.

Helicases split apart, or unwind, the two strands of the DNA double helix.
Their job is vital: DNA has to be unwound before genes can become active and
before dividing cells can pass on healthy copies of their chromosomes to new
cells. Either or both of these vital functions may be compromised in Werner’s
patients. But the leading theory on why they age so fast is that helicases
enable repair enzymes to weed out random mutations and breakages that constantly
threaten the integrity of genes and chromosomes.

Extra genes, extra years?

Right now, Schellenberg and David Galas, chief scientist with Darwin
Molecular, the biotechnology company that helped to trace the Werner’s gene, are
looking for the counterpart of the gene in mice so that they can make transgenic
animals carrying mutant helicase genes. Such animals may well be prone to the
kinds of cancers and heart diseases that afflict Werner’s patients. If they are,
Darwin Molecular will swiftly market the animals as “research tools” for
studying the diseases of old age.

Gerontologists, however, are keen to learn the answer to another question
altogether. If a lack of helicase accelerates ageing, will lab animals that are
engineered to carry extra copies of the helicase gene live longer? If the answer
turns out to be yes, that will suggest that boosting helicases could also extend
lifespan in humans. But most researchers are sceptical. Galas points out that
boosting helicase in bacteria kills them. And Tom Kirkwood, professor of
biological gerontology at the University of Manchester, counsels against viewing
helicase as the be-all and end-all of human ageing. “The gene may be just one
component of a rather larger complex network of genes that keep our bodies in
good shape,” he says. Underscoring that view, some tissues, notably brain cells,
are unscathed by the Werner’s gene and age as normal.

Besides, when it comes to preventing ageing due to damaged DNA and proteins,
strengthening the repair systems is just one approach. Another is to curb the
rate at which the damage happens in the first place. For example, only last
month, Jeff Poulin, Marguerite Kay and their colleagues at the University of
Arizona in Tucson reported that the brain and immune cells of mice fed high
doses of vitamin E clock up damage to proteins more slowly than mice on normal
diets. This confirms a long line of studies suggesting that antioxidant vitamins
neutralise reactive free radicals, and—in theory at least—slow
cellular ageing. The question researchers must now answer is whether swallowing
antioxidants can also slow the ageing of whole organisms.

Meanwhile, health zealots are taking to heart a different approach to
combating the hazardous by-products of food combustion in cells. For
decades, biologists have known that rats and mice reared on draconian diet live
30 to 40 per cent longer than normal. Now, a research team led by George Roth at
the National Institute on Aging in Maryland is looking to see if the same thing
happens to our primate cousins. For the past nine years, they have been
monitoring the progress of some 200 captive squirrel and rhesus monkeys kept on
a variety of diets.

Lean burn

This year, Roth and his colleagues reported that slashing monkeys’ food
intake by 30 per cent for several months leads to a roughly 1 °C drop in
their body temperature—a sign, says Roth, that restricting calories
triggers a fundamental change in the way cells use energy, at least in the short
term.

Captive rhesus monkeys normally live for 30 to 40 years, so it will be a long
time before Roth and his colleagues know if minimalist diets increase primate
longevity. But so far the monkeys’ metabolic response to the drastic slash in
calories mimics that seen in mice and rats. If it continues, Roth says, the
monkeys could end up living ten or more years longer than normal.

Roth says he is swamped with requests for information from humans who would
like to ape his lean and hungry monkeys. Indeed, some Methuselah wannabes are
already eating less in the name of longevity. Roy Walford, a biologist at the
University of California at Los Angeles, for example, consumes a meagre 1800
calories a day (most people eat 3000) in the hope of attaining the magic age of
120 years old. But persuading most humans to do likewise may not be so easy.

That’s why Roth is keen to uncover the molecular mechanisms underlying the
life-extending effects of caloric restriction. Finding these, he says, would
open the way to designing drugs that trick cells into thinking they are being
deprived of energy when in fact they get a normal supply. That way, suggests
Roth, we could all have our cake, eat it, and live a long time.

The bad news is that the research is at a very early stage. One theory is
that ageing in cells is caused by sugar molecules gumming up the body’s works by
forming complexes with proteins and other vital molecules. Cutting
calories—and hence the rate at which sugars are released inside
cells—may slow this down. But depriving cells of energy may not just make
the wheels of metabolism turn more slowly, argues Roth. It may also boost the
activities of specific genes and enzymes that help to protect DNA and proteins
from damage by free radicals and other poisons. Still, it could be years before
biologists know enough to develop drugs that could trigger similar molecular
changes. Meanwhile, say critics, we don’t yet know what the full biological and
psychological implications of caloric restriction would be. Energy deprived
rats, mice and monkeys cannot tell you how they feel, although cold and hungry
is probably a good guess.

A more radical approach to the problem of ageing is to slow the whole
biological timetable from the cradle to the grave. At McGill University in
Montreal, Siegfried Hekimi and his colleagues have created mutant nematode worms
which prove this can be done in simple organisms. Movement, defecation, ageing,
you name it, these worms do it all more slowly or less frequently. Whatever the
identity of the genes affected, Hekimi suspects that the worms age more slowly
because their cells burn less food and hence produce fewer free radicals.

So far, no one has suggested that similar genetic mutations should ever be
introduced in to humans. For a start, such genes may not even exist in humans.
What is more, not every biologist sees ageing in humans as a straightforward
tussle between molecular repair and damage. Some think cell division, which
doesn’t hppen in adult worms, might be an important piece in the puzzle of
ageing in our own species.

Unless they are doctored to make them immortal, cells in lab cultures run out
of steam after a limited number of divisions. The cells “senesce”. They don’t
die, but they do stop dividing, and they can no longer produce new DNA. In
culture at least, cells from short-lived species tend to senesce after fewer
divisions than cells from long-lived species, and skin cells from an 80-year-old
person will run out of steam quicker than those from a fetus.

The key question is does the same state of exhaustion afflict cells in living
tissues? If it does, argue some gerontologists, this could explain ageing
in tissues with high rates of cell division, such as the skin and immune system.
In the past, many biologists were doubtful. They argued that such tissues have a
huge surplus capacity for replacing worn-out or damaged cells, and that crucial
evidence that senescent cells build up in tissues like skin was missing. Now,
Judith Campisi, a molecular biologist at the University of California at
Berkeley, and other researchers are reviving the theory.

Last year, Campisi and her team discovered a molecular marker for senescent
cells—an abnormal form of the enzyme galactosidase. Using this marker, the
researchers found that thirty-somethings have almost no senescent cells in
their skin, while folk in their 70s and 80s have “multiple clusters” of the
cells in both the dermis and epidermis. The study helped to dispel Campisi’s own
doubts. “A couple of years ago I was not at all convinced that cell senescence
had much to do with ageing,” she says. “But I’ve changed my mind.”

Unruly pensioners

And the rethink doesn’t end there. When dividing cells run out of steam in
the body, one might naively expect them to turn into kindly “pensioner” cells
whose only crime is to occupy house room that might be better filled by more
active cells.

This is no benign old age, however. Campisi’s team has shown “that a number
of proteins, genes and enzymatic processes are altered in these senescent
cells”. And altered, mind you, in ways that could make the cells harmful to
healthy tissue. Senescent skin cells produce that wrinkle-inducing collagenase,
for example, while the endothelial cells that line the arteries, the gut and
other organs pump out interleukin 1, which can trigger tissue-damaging
inflammation.

In theory, then, preventing cells from senescing might help to slow down
ageing. But how to do it? Back at Geron, Harley and his colleagues are racing to
find the gene that they believe will help to provide the answer, and seal the
company’s fortunes in the process.

The gene carries the code for an enzyme called telomerase that prevents the
telomeres, the end of the chromosomes, shortening. All human cells carry this
gene, yet few bother to switch it on and produce any telomerase. The cells of
virulent tumours do, however. Over the past 18 months, telomerase’s fame has
spread, fuelled by evidence suggesting that it helps tumour cells achieve their
dangerous immortality. This alone would make the gene for telomerase hot
property. New tests for diagnosing and monitoring cancers, transgenic animals
for testing anticancer drugs targeting telomerase, all would become possible
once the gene was found. And the gene’s value— commercial as well as
scientific—will be higher still if Harley and his colleagues are right
about something else. The researchers believe that what makes cancer cells
deadly might also be used to keep healthy cells youthful. The reason for this
ironic twist lies in the details of how telomerase works.

When cells divide repeatedly the telomeres gradually wear away. Eventually
they are snipped to the quick, leaving chromosomes unable to replicate properly
and putting DNA at risk of being damaged or lost. Cells with shrunken telomeres
must stop dividing or risk turning cancerous. In short, claim Harley and his
colleagues, the wearing away of telomeres is like a time bomb ticking away
inside cells. And when it explodes, the damaged cells senesce to contain the
damage.

In some cells, however, the telomerase enzyme can dampen the fuse, and put a
stop to telomere shortening. Take sperm. No matter how many times these cells
divide in the testes, their telomeres never shrink because telomerase is always
active. And findings just published by Jerry Shay, a cancer biologist at the
Southwestern Medical Center in Dallas, and his colleagues, show that the enzyme
is also switched on in embryo cells, explaining how embryo cells can divide so
furiously in the womb. Now, it turns out, it may be possible to artificially
elongate telomeres to keep adult cells young too.

Three months ago, Shay and his Dallas colleague Woodring Wright, produced the
first, tentative evidence that cells with artificially lengthened telomeres live
longer in lab cultures. Looking for ways to shorten telomeres in cancer cells,
the researchers inadvertently stumbled on a class of DNA-like molecules that
make cancer cells grow even longer telomeres. Fusing these cells with normal
cells produced non-cancerous “hybrid” cells with elongated telomeres-and
lifespans about double those of normal hybrid cells.

In Wright’s view, this is “strong evidence that telomere length is the clock
that counts cell divisions” in ageing. But many biologists are reserving
judgement until the telomerase gene has been found and researchers have done
what everyone acknowledges to be the key experiment—genetically
manipulating lab mice to see if longer telomeres mean longer lifespans for the
whole organism.

Forever young

Not that the absence of that crucial experiment has stopped some telomere
fans from getting wild-eyed. In Reversing Human Aging, a feverishly
optimistic book published in the US earlier this year, American doctor and
neuroscientist Michael Fossel speculates about a future world full of people
living for hundreds of years thanks to what he calls “telomere therapy”.
Telomerase, says Fossel, is every pension fund manager’s nightmare. Scientists,
he says, are on the eve of discovering how to manipulate the enzyme to
reset the telomere clocks that determine cell lifespan. And the result will be a
generation of Methuselahs. “Before 2015,” writes Fossel, “telomere therapy will
be available to us all . . . the most remarkable change in all human history
will have begun.”

Gerontologists’ reactions to Fossel’s extravagant claims range from the
amused to the outraged. Discovering drugs or gene therapies to switch on
telomerase inside specific cells and tissues in the human body won’t be easy,
they say. Nor is it clear it would be safe to do so in cells that normally lack
the enzyme. After all, cancer cells have high levels of the enzyme. Some even
question whether the loss of telomeres in dividing cells really is that
important to ageing, pointing to the awkward fact that mice have very long
telomeres but very short lifespans.

But telomere enthusiasts continue to hit back. For example, Harley and his
colleagues have uncovered evidence of abnormally fast telomere shortening in
tissues where the demand for cell replacement is often high, such as the inside
walls of middle-aged arteries that are subjected to onslaughts from cholesterol
plaques and other stresses.

And Shay says that two teams will soon publish evidence showing that T cells
from AIDS patients not only divide fewer times in culture than similar cells
from healthy people of the same age, but that the cells have shorter telomeres
as well. This suggests that HIV infection accelerates ageing of the immune
system by keeping it perpetually on full throttle.

One way to slow down the immune system’s ageing, suggests Shay, might be to
remove T cells from patients at an early stage in the infection and regrow the
telomeres with telomerase. Later on, when the patients get sick, these
rejuvenated T cells could be given back to them. “You’d be running a risk,” says
Shay. “Turn telomerase on and you might get cancer, but on the other hand the
cells would keep proliferating. You’d be on the fine edge of a sword.”

Sting in the tail

But for some, the knife edge of telomerase therapy, whether it be applied to
AIDS or to ageing, is just too sharp. Campisi and others believe it’s no
accident that dividing cells are preprogrammed to run out of steam. Cell
senescence may be one of the body’s many mechanisms for preventing tumour growth
early in life. Scientists’ attempts to reverse cell senscence to prevent ageing
may therefore carry a nasty sting in the tail—an increased risk of
youthful cancers. The challenge for scientists in future, says Campisi, is to
find ways of “reversing the unsavoury effects of replicative senescence without
causing runaway cellular proliferation”.

In the meantime, the spectre of Conan Doyle’s ape-professor lives on. For
when it comes to extending lifespan, there invariably seems to be a biological
cost waiting in the wings. Sometimes an unacceptable one. History shows, for
example, that castratos and eunuchs lived longer than their sexually active
brethren; but castration has yet to catch on as a method of prolonging male
life. Even something as simple as eating less in the name of longevity carries a
risk of reduced fertility and increased sensitivity to the cold, not to mention
rake-like thinness.

Conan Doyle would have suffered no such problems. A great bear of a man who
enjoyed a life of literary lunches, he died of a heart attack at the age of 71,
secure in the knowledge that he had found a foolproof yet completely safe way to
achieve immortality. Invent the world’s most famous fictional sleuth.