by Malcolm Gladwell
Michael R. Rose began his quest to solve the problem of human
aging in 1976 with 200 garden-variety, fertilized female fruit
flies. He was then a graduate student in genetics at the University
of Sussex, testing a new idea known as the evolutionary theory
of aging, and he started out by putting his flies in milk
bottles with nutrients in the bottom. In the uncertain world
of the fruit fly drosophila, where predators and natural hazards
abound, the kinds of flies which survive are those which reproduce
the fastest, and these were no exception. They were, in Roses
words, trailer-park flies: quick to reach sexual maturity,
capable of laying a thousand eggs in their five-week period
of fertility, and for a few hours, just after they reach maturation,
possessed of almost dizzying sexual prowess. Left to their
own devices, they would have continued to reproduce at the
same breakneck pace. But Rose wasnt interested in the normal
rules of fruit-fly life. He wanted to reward not the flies
that reproduced the fastest but the ones that lived the longest;
and so, once his female flies came of age, he would wash away
their eggs and larvae every other day, destroying all the
progeny of his most precocious flies. The only eggs he saved
were those laid near the very end of the fruit flies five-week
fertility cycle in other words, those eggs born to the parent
flies who were healthy and sexually active latest in life.
Then, with these eggs in hand, he repeated the process. He
bred those specially selected fruit flies, and kept only those
offspring produced at the very end of the fruit-fly fertility
period, once more rewarding the hardiest and longest-lived
flies. He stayed in the lab sometimes for 21 hours at a stretch,
and when he went home he would see flies in his sleep. He
bred generation after generation, eventually conducting his
experiment on a scale that no other fruit-fly researcher had
ever attempted, and each time he measured the life span of
a new round he found that his drosophila offspring lived a
little longer than their forebears.
After getting his PhD from Sussex in 1979, Rose moved to the
University of Wisconsin, and then, two years later, to Dalhousie
University in Canada, shipping his flies with him each time
by express mail. In 1987, he and his flies moved again, this
time to the University of California at Irvine, and there
he expanded his research to more and more strains of flies,
painstakingly monitoring how his selected flies differed from
normal flies and, in the process, learning perhaps as much
as anyone has ever known about what it means to extend life
dramatically. Today, Roses operations occupy about 4,500 square
feet of laboratory space on the Irvine campus. He has more
than 50 people working for him. He has 170 separate populations
of drosophila, comprising somewhere between half a million
and a million flies, and on long benches in his laboratory
dozens of plastic fly cages are stacked up five and six high.
In the past 20 years, he has bred 500 successive generations
of flies, and in doing so he has doubled the fruit flys maximum
life span from about 60 days to about 120 days and counting.
He has created a race of fruit-fly Methuselahs.
Rose is a dark-haired man of 41, handsome in a boyish way,
with slow, deliberate movements. When he describes his flies,
he does not wave his hands or raise his voice excitedly. He
speaks in a steady, affectless monotone, and projects an air
of complete self-confidence. Among his peers, Rose is considered
a brilliantly innovative scientist, who has almost single-handedly
brought the evolutionary theory of aging from an abstract
notion to one of the more exciting topics in science. When
Rose started using evolutionary techniques to extend the life
of drosophila, no one else was trying it. Now that he has
proved that the method works, the field is growing, and Rose
isnt shy about stating and defending his accomplishments.
He is, in his own words, brash, blunt, and in-your-face. He
says things like In all my work, there is an eight- to ten-year
time lag before my colleagues start to realize what it is
all about, and he is unsparing in his scorn for some of his
fellow researchers on aging. The son of a Canadian Army officer,
he estimates that by the time he was 12 he had lived in 20
different places, and he still has the air of the new boy
about him the defensive aloofness of one who has never had
the opportunity to make friends and so has decided he doesnt
need them. Im known for being clear partly because Im not
diplomatic, he says, contrasting himself with many of his
peers, who, in his words, communicate with a great deal of
Peter Lorre shuffling of the feet. As Caleb Finch, who studies
aging at the University of Southern California, has put it,
If someone says something stupid, hell hit them between the
eyes with it.
Before I met Rose, I spent an afternoon in the laboratory
of Cynthia Kenyon, a young professor of biology at the University
of California at San Francisco, who is doing aging research
with the microscopic worms known as soil nematodes. Kenyon
says she works with nematodes in part because they have an
aesthetic appeal for her. The first time I saw them, I was
a graduate student at MIT, and another graduate student showed
me what they looked like, she said. Theyre transparent, and
I watched them eat. I watched the food move into the intestines,
and all the cells and the nuclei, and it was really beautiful.
When I asked Rose whether he finds his flies beautiful, he
looked at me sharply and said, Am I one of those people obsessed
with flies? No. The difference between Rose and Kenyon is
not that Kenyon cares about her work and Rose does not. It
is that, like many biologists, Kenyon brings to research a
trace of romanticism. This is the reason many researchers
can spend a lifetime behind a laboratory bench: they are able
to imagine a certain dignity and meaning in the narrow, microscopic
worlds they study. In the event that Kenyons nematode research
didnt yield any useful insight into how human beings age,
I dont think she would consider her work a failure. She has,
in some sense, made a beautiful organism more beautiful. Rose,
on the other hand, seems to view his work without any sentiment.
Everything he does seems contingent on a much more ambitious
even audacious conviction: that what he has learned about
extending life with drosophila can be applied to extending
life in human beings.
Rose wants his experiments to be repeated in mice, which are
close enough to human beings genetically to make them a useful
model. He hopes researchers will take those long-lived mice
and analyze them, in an attempt to identify all the ways in
which they differ genetically from normal mice. They may,
for example, make much more or much less use of certain hormones
or proteins. Certain genes may be more active in long-lived
mice than in normal mice, or vice versa. Living organisms
are like pianos, each of which has a different melody played
out on its genetic keys. Rose believes that if researchers
can find out what tune is being played by long-lived mice,
they can come up with a method of playing an equivalent tune
in human beings.
Were talking about thousands of mice, says Rose, who is a
consultant for a company preparing to perform these experiments.
Once we have those mice, we can get the basic knowledge we
need in order to tweak mammals to make them live longer. Well
run them through a variety of tests to see whats being up-regulated
or down-regulated, then find some way to mimic that in humans.
That can be done through several interventions, from supplying
substances in a pill to IV infusion.
Rose is not by nature a dreamer, and as he spoke, in his patient,
matter-of-fact manner, a Coke untouched in front of him, he
made it clear that none of what he proposed would be simple
or quick. Hes not talking about one pill but many, he said,
and not something you would take once but something you would
probably take day in and day out for years: Its going to be
like the deployment of electricity. Its going to take a long
time because its going to be a big, complicated technology.
Youll have a big, elaborate industry, like General Electric,
which will involve companies that turn out many products for
a considerable amount of money, so that people are going to
have to spend a very significant fraction of their disposable
income every year on products that will keep them young and
robust.
But Rose makes it clear that he expects those efforts to result
in fundamental increases in life span. At one point when we
were talking, he walked into the hallway outside his office,
where a research paper posted on the wall showed, in a bar
graph, how long Roses Methuselah flies were now living. Look
here, he said, pointing to the graph. This would correspond
to a human life span of 200 years.
Ten or fifteen years ago, scientists didnt talk like this.
The traditional scientific approach to the problem of aging
has been to accept our biological limits and try to rearrange
the lives and the care of the elderly to make old age more
manageable. Our efforts have been largely palliative to put
elevators in buildings, to make public spaces accessible to
wheelchairs, to devise better treatments for cataracts, to
perform coronary-bypass operations to cut down on chest pain,
and even, in the case of one of the more imaginative projects
sponsored by the Centers for Disease Control, to try to make
fluid-filled pads for elderly hips and thus protect against
the fractures that are such a common form of disability in
the old. The motto of the Gerontological Society of America
has been Add life to years, not years to life, which is a
statement not just of intention but of apparent fact. For
a long time, no one thought you could add years to life. Mice
were thought to live about two years, dogs about 15 years,
and human beings at most 100 years all according to some immutable
genetic clock and any scientists who made spectacular claims
of reversing the aging process were treated with skepticism.
Even the idea of treating aging with hormones like testosterone,
melatonin, and DHEA currently being celebrated as the fountain
of youth in one breathless magazine article after another
does not represent a dramatic departure from this way of thinking.
Hormone-replacement therapy is meant to give the aging body
a tune up, to delay or lessen certain problems associated
with old age. Yet even that modest goal comes with certain
caveats. DHEA for example, changes the color of rodent livers
from pink to brown; when 16 rats were fed DHEA for a year
and a half, in a recent study at Northwestern University,
14 developed liver cancer. Nor is melatonin likely to be any
better. Writing in the journal Cell late last year, Steven
Reppert and David Weaver, of Harvard Medical Schools Laboratory
of Developmental Chronobiology, pointed out that the animal
experiments that triggered the melatonin craze were conducted
on strains of mice with a genetic defect that made it impossible
for them to produce melatonin on their own. When the experiments
were done in mice that, like human beings, make the hormone
naturally, the authors noted dryly, The treatment actually
shortened survival by inducing reproductive tract tumors.
The new field of aging is quite different. It is not a tune-up
so much as an engine overhaul. There is Rose, with his Methuselah
flies, and behind him, in just the past decade, there has
arisen a whole field of scientists using evolutionary and
genetic techniques to create entirely new long-lived strains
of lower organisms. Last year, two researchers at Montreals
McGill University published a paper in the journal Science
showing how they genetically altered worms to live almost
seven times as long as is normal. Kenyon showed me one of
her mutant worms moving across a microscope slide as gracefully
and vigorously at 8 weeks as a normal worm moves at 2 weeks.
Over the past 5 years, too, an entirely separate field has
arisen that analyzes aging at the cellular level and looks
to treat and possibly cure many of the conditions and diseases
of old age by focussing on the mysterious role played by the
strips of DNA that cap the ends of our chromosomes. There
are now serious researchers not just science fiction writers
or crackpots who think that we are close to curing cancer
and other diseases of old age, and there are some who are
convinced that the day is not far off when science may be
able to extend the human life span by 20 or 50 or even 100
years. To this new crop of researchers on aging those who
look at the extension of life at a cellular or evolutionary
level growing old now seems less an immutable fact of human
existence than a chronic disease that can be delayed and treated
and manipulated as if it were diabetes or high cholesterol.
This is what is so extraordinary about looking at Roses flies
and seeing them buzz about energetically in their plastic
cages weeks after normal flies would be dead. Its not that
they are imposing and impressive and bear the marks of some
dramatic scientific intervention. Quite the opposite: they
look just like normal flies and act like normal flies. Roses
flies, by their very ordinariness, make longer life seem eminently
possible.
But such research also raises all kinds of hard questions,
some of which may not be obvious at first. So far, extended
life has proven to be a healthier life, because better health
in itself prolongs life. Such is the case, certainly, with
most of the medical advances of the 20th century which have
so dramatically improved life expectancy. Because of modern
obstetrics, many fewer die in childbirth, and that, along
with the development of antibiotics and the effective eradication
of infectious diseases like tuberculosis, smallpox, and cholera,
means that people who used to die at 25 or 30 have been given
an extra few decades of healthy adulthood. More recently,
the push to exercise more and eat healthier foods seems to
have had a similar effect, because people who take care of
themselves suffer fewer problems in old age. Epidemiologists
call the idea that improvements in health will shrink illness
and disability the compression of morbidity hypothesis, and
it is what we all want. In fact, it is what we immediately
assume will happen when scientists talk about prolonging life.
There is another possibility, however: that advances in medicine
will lead people to live longer but without commensurate improvements
in health. In other words science may succeed in pushing the
average life expectancy from 75 years to 95, but the diseases
that used to leave us sick and disabled at 82 or 83 may still
hit at 82 or 83 the result being that we would live in a nursing
home for the last 12 years of our lives instead of the last
2 years. Epidemiologists call this possibility the expansion
of morbidity, and it has commanded more and more attention
in recent years. Today, many kinds of medical improvements
that we have devised are, after all, no longer aimed at saving
people from dying at 25 or 30 of tuberculosis or smallpox,
and so enabling them to enjoy another 40 or 50 years of healthy
life. Those diseases have been cured. Most attempts to improve
longevity today focus on the diseases that primarily afflict
the old cancer, heart disease, stroke, arthritis which means
it is now much more likely that saving people from one disease
may only result in their getting sicker and sicker with another.
Jonathan Swifts Gulliver, on the third of his famous voyages,
learns of a strange group of immortals known as the Struldbruggs.
The news fills Gulliver with inexpressible delight, for he
imagines lives rich with wisdom and experience. He automatically
assumes, as most of us do, that longer life means better life.
When he meets the Struldbruggs, however, Gulliver realizes
his error. What he is faced with instead is the expansion
of morbidity:
At Ninety they lose their Teeth and Hair; they have at that
Age no Distinction of Taste, but eat and drink whatever they
can get, without Relish or Appetite. The Diseases they were
subject to, still continue without Encreasing or diminishing.
In talking they forget the common Appellation of Things, and
the Names of Persons, even of those who are their nearest
Friends and Relations. For the same Reason they never can
amuse themselves with reading, because their Memory will not
serve to carry them from the Beginning of a Sentence to the
End; and by this Defect they are deprived of the only Entertainment
whereof they might otherwise be capable.
This is the difficult question raised by the new optimism
about fighting aging. If we are now on the verge of adding
new years to human life, what kind of years will we be adding?
Will we be compressing morbidity, or are we about to turn
ourselves into a race of Struldbruggs?
On a gray day in late June, 23 children from around the world
gathered for a picnic lunch at a campground in South Dakota.
The youngest was 2-1/2 and the oldest 15, and they all ate
hot dogs and wore baseball caps and ran around excitedly on
the grass. It looked at first like a standard summer picnic,
but then, on second glance, what had looked like running was
actually a kind of determined hobbling, and in almost every
instance the heads covered by those baseball caps were completely
bald.
The 23 children at the picnic had, in almost every case, neither
eyebrows nor eyelashes. Their eyes and ears stood out, because
their heads seemed to have shrunk. Few of the children were
much more than three feet tall or could have weighed more
than about 40 pounds. Their skin was thin and crinkly, like
old newsprint, and when one of the little boys took off his
cap I could see the veins bulging out from his scalp. Most
seemed to have hip problems and stiff joints this is what
gave them their wide-legged, shuffling gait and many had heart
problems so serious that they were taking 4 or 5 different
drugs every day, in combinations usually reserved for the
most enfeebled of 70 and 80 year-olds. These were children
who think and feel and talk like other young children, but
they had the frail and wizened appearance of the very old.
In fact, depending on your definition of what old is, they
really were old. One of the strange things about the genetic
mutation they share is that if you took a sample of their
cells and put it under a microscope side by side with cells
from an 80 year-old, you wouldnt be able to tell the difference.
The children at the picnic were what are known as progerics
or, more technically, victims of Hutchinson-Gilford syndrome,
a rare, probably genetic disease that causes the interval
between childhood and old age to shrink from the normal 50
or 60 years to just over a decade. There are fewer than 30
children with progeria around the world, and every summer
a Philadelphia-based charity the Sunshine Foundation invites
all of them, free of charge, to a week-long reunion somewhere
in the United States. Last year, the reunion was near Lake
Wales, Florida, and this year it was just down the road from
Mt. Rushmore, on the western edge of South Dakota, where the
flat prairie of the east turns into rolling meadows and rocky
peaks. The main attraction of the picnic was two local motorcycle
clubs, whose members began driving the children around the
campground on the backs of their Harley-Davidsons wizened
11 and 12 year-olds clinging happily to beefy, leather-clad
bikers. Later, a cake was brought out to celebrate the birthday
of one of the children, a 15 year-old girl from Mexico. But,
since most progerics die of a heart attack or a stroke by
their late teens, birthdays at progeria gatherings are rather
like birthdays in nursing homes less about the anticipation
of the upcoming year than a moment of thanks for the year
that has passed. The cake didnt have any candles on it.
How can teenagers be as old as octogenarians? This question
has bedeviled scientists ever since progeria was first identified
in the 19th century. Over the past few years, however, at
least a partial answer may have been found and it goes a long
way toward explaining why some researchers are now so optimistic
about attacking the diseases of aging and extending human
life.
Consider the skin of progerics the most obvious and most puzzling
manifestation of their disease. Childrens skin is normally
thick and smooth and resilient, and when by the age of 60
or 70 the skin becomes crinkly and thin we attribute the change
to a lifetime of sun damage injury, and general wear and tear.
This is the way we think about aging in general that after
you walk enough miles, and your heart pumps enough blood,
and your brain performs enough work, your body starts to break
down, just as a car does when the odometer reaches 75,000
or 100,000 miles. But this analogy seems less apt if at the
age of 11 or 12 progerics already have skin every bit as thin
and papery as that of 80 year-old adults. What the progeric
children suggest is that, whatever processes make our skin
sag or, for that matter, make our joints go bad or our arteries
harden they run independently of the chronological clocks
we use to count the passing years. The progeric children suggest
that aging has its own mechanism, and here something known
as telomere theory offers an elegant and fascinating explanation.
Among the cells that make up human skin are the fibroblasts,
which float in a sea of collagen, the substance that makes
skin thick and resilient. Each fibroblast is a tiny repair
kit, which works to keep skin healthy. If you suffer sun damage
or a cut, your fibroblasts will make a substance called collagenase,
which breaks down the damaged collagen and clears it away.
If necessary, your fibroblasts will divide, to replace the
damaged cells, and then they will pump out new collagen, so
that what is known as the matrix can return to normal. This
is a remarkably efficient operation. But it comes with one
limitation. Inside a fibroblast, on the end of each of its
chromosomes, there is a telomere, which researchers propose
is a sort of timing device. Every time a fibroblast divides
and the chromosomes inside the cell split up in order to form
two new cells, the telomere gets a little shorter. The telomeres
of a 10 year-old, for example, are on average longer than
those of a 20 year-old, which in turn, are longer than those
of a 40 year-old. After a fibroblast has divided about 50
times which will take the average person into middle age the
telomere is shortened to a critical length, and the timer
goes off. A cell with a critically shortened telomere cannot
divide any further, and so the whole repair operation that
is used to keep skin thick and healthy is thrown out of whack.
Its not that skin cells die; rather, its as if they had become
senile.
The cell seems to undergo a kind of derangement, says Judith
Campisi, an expert on aging at the Berkeley National Labs,
in California. Instead of using collagenase selectively, to
clear away damage, and spending most of their time pumping
out collagen, the senescent cells start to pump out a large
amount of collagenase, which eats away at the healthy collagen,
and almost stop pumping out collagen altogether. Campisi has
done experiments in which she has pinpointed senescent cells
with a blue stain and then taken comparative photographs of
young and old skin under a microscope. The pictures are striking.
In the first case, there are healthy fibroblasts encased in
rich, red-stained collagen. In the second, the slide is spotted
with blue senescent cells, and in the matrix around them the
collagen has been reduced to a thin, wavy swirl.
How long your skin stays healthy, in other words, depends
in part on how long fibroblasts stay in their healthy, dividing
state or, as scientists now speculate, on how long your telomeres
are. That could be why a 50 year-old person who has spent
every summer in the sun looks a lot older than one who has
spent every summer in the shade: the fibroblasts of the sun
worshipper have had to divide many more times to repair damage
from ultraviolet rays. In this sense, the length of your telomeres
may be a better indicator of how old you are than is the number
of years you have lived a point neatly captured by a handmade
poster I saw in the office of a telomere researcher I visited.
Beneath a photograph of a grinning baby the child of one of
the researchers someone had written, Ha! My telomeres are
longer than yours. This is also why progerics seem so old:
by late childhood they have the telomeres of someone in a
nursing home. At an age when other children still have thick,
smooth skin, progerics fibroblasts have already started to
stop producing collagen. Progerics get heart disease, on this
theory, because the cells that line their arteries start running
out of telomeres and the arterial walls start to harden. Their
movements get creaky because the cartilage that lines their
joints begins to break down.
My Danny died in March, Bill Purcell, a friendly, white-haired
Englishman I talked to at the picnic, told me, speaking of
his son. He was adopted. He came to us when he was 11. About
6 months later, he had a massive stroke that left his left
side paralyzed. We thought we were going to lose him. He was
like a rag doll. He came back, although he was never as active
after that. Three years ago, he lost the sight in one eye
due to hypertension. He handled it well. That was in October.
Then, in August of 1994, another eye went and that left him
totally blind. His world was black. He was very frail. His
features had caved in, and his movements were slow and painful.
He had all the problems associated with a very, very old man.
Purcell added, Danny died of old age. He was 22.
At this point, the idea that telomeres regulate the aging
of cells is only a theory. Although there is plenty of highly
suggestive evidence in its favor, it hasnt been definitively
proved. If or once it is, however, it is not hard to see how
revolutionary it will be.
The original wear-and-tear idea of aging was essentially defeatist:
it suggested that aging was inevitable, because it seemed
so clearly linked to the passage of time. But telomeres suggest
quite the opposite. In fact, telomeres make it much easier
to believe people like Michael Rose when they say that by
tinkering with the bodys machinery we can substantially prolong
life, for if there are genetic changes capable of shortening
telomeres in progerics, then shouldnt there also be changes
capable of making them longer in the rest of us?
Two of the principal architects of telomere theory are Carol
Greider, a molecular biologist at the Cold Spring Harbor Laboratory
on Long Island, and Calvin Harley, who is chief scientific
officer at the Geron Corporation, a California-based biotechnology
firm primarily devoted to applications of telomere theory.
When Greider was in graduate school at Berkeley, in the early
80s she did ground-breaking work with telomeres, but it did
not occur to her at the time that they might play a role in
cell senescence. Harley, then at McMaster University in Canada
was interested in cell senescence but wasnt yet a telomere
expert. Their fields were so distinct that ordinarily the
two might never have met. But in one of those serendipitous
events that often lead to scientific breakthroughs, Greider
began dating a biologist who shared lab space with Harley
at McMaster. I would go and chat with Cal when I was visiting,
she recalls. It was basically just a pleasant, scientific
interaction. They kicked around the idea that their fields
might somehow be related. By the end of the decade, they were
collaborating sending research materials back and forth through
the mail. In 1990 and again in 1992, they jointly published
landmark papers laying out the idea of telomeres as cellular
clocks papers that spawned what is today one of the hottest
fields in molecular biology.
I like to think of Cal and myself as like that old television
commercial for Reeses peanut-butter cups, where the chocolate
and the peanut butter run into each other, Greider told me.
She didnt specify who was which ingredient, but she didnt
really have to. When I met her, she was 8 months pregnant
but was still charging around her laboratory, a petite and
dynamic woman with frizzy brown hair and a beautiful smile.
Shes the chocolate. And Harley 40ish, trim, and with thinning
hair, soft-spoken and precise is the peanut butter.
Harley, a Canadian, studied science at the University of Waterloo
in Ontario a fact not without sociological significance. Waterloo
is a school for science nerds, much like MIT, which is to
say that, like MIT, it attracts and nurtures a certain kind
of stubborn and prickly intellectual idiosyncrasy. But it
is a Canadian nerd school, and so all those stubborn and prickly
idiosyncrasies appear only through the filter of Canadian
conformity and self-effacement. Had Albert Einstein taught
at Waterloo, he would have had a brush cut and worn Haggar
slacks, and that is the impression Harley gives as well, that
his bland demeanor is less a matter of character than of presentation.
Harley came to Geron in 1993, and works out of a small office
in the firms cluttered, maze-like headquarters in Menlo Park.
Over the past few years, he has been steadily exploring the
implications of telomere theory, gathering many of the countrys
leading telomere experts and setting up collaborations with
others like Greider who remain in academe. As a result, Geron
is at this point exploring projects in an astonishing number
of fields.
The telomere hypothesis suggests, for one thing, that AIDS
is a disease at least in part of cellular aging. According
to the theory, the AIDS virus does its damage by taking on
and eventually defeating the human immune system. Among other
things, it overwhelms the white blood cells known as CD8s,
which the body uses to fight HIV. Why are CD8s overwhelmed?
Well, it turns out that the telomeres of certain CD8 cells
in AIDS patients are, in Harleys words, as short as the telomeres
we saw in centenarians. The cells are so busy trying to fight
HIV, dividing and redividing in order to keep the virus in
check, that in a decade or so they run through telomeres that
would otherwise last them a normal lifetime. What we want
to do, Harley says, after stressing that this idea is only
in the earliest of stages, is to find some way of increasing
the life span of those cells. For example, it might be possible
to remove the CD8 cells of someone in the earliest phase of
HIV infection, lengthen their telomeres in a test tube, and
put them back in, giving the patient a rejuvenated immune
system.
The same thing could be done again, in theory for heart disease.
According to this idea, arteries clog because as the cells
that line arterial walls get injured by high blood pressure
and cholesterol and smoking, they have to divide and redivide
much more than they would normally, and thus run through their
telomeres early. Once senescent, the cells that line the arterial
walls start to misbehave just as senescent fibroblasts do:
they stop producing critical factors that keep blood vessels
healthy, and instead hasten the process of hardening, the
buildup of cholesterol that foreshadows heart disease. The
theoretical solution is the same as for CD8 cells: find some
way to lengthen their telomeres, so they can withstand the
onslaught of cholesterol and high blood pressure much longer.
Perhaps the most important potential application of telomere
theory and the subject most telomere researchers are concentrating
their energies on is in the treatment of cancer, and it is
a concept of such extraordinary elegance that when Greider
(who must have explained telomere theory hundreds of times)
described it to me it was almost as if she were talking about
a painting she had just seen in the Louvre. The idea starts
with the most puzzling of the many questions raised by cancer:
how is it that a cell escapes its normal growth limits? A
cancerous cell, after all, is a cell that will not stop dividing.
There are, in fact, cancer cells that have been grown continuously
in laboratories for decades, filling petri dish after petri
dish. The puzzle is that this kind of immortality would seem
to be impossible, since any cell that keeps dividing will
eventually run out of telomeres. So how do cancer cells get
around the telomere problem? The answer is thought to be the
presence of an enzyme known as telomerase, which, for reasons
that no one quite knows, is present in cancer cells but not
in most normal cells. Telomerase has the extraordinary ability
to stabilize telomeres, automatically replacing every bit
of telomere lost during cell division. Normal cells know how
to make the enzyme, but they dont: in a normal cell, the telomerase
switch is turned off. One of the ways in which a cell becomes
cancerous, however, is that through some random mutation or
mistake it finds a way to turn the telomerase switch on, so
that the cell has the ability to divide indefinitely without
ever tripping the telomere timer.
Greider discovered telomerase in the winter of 1984, when
she was working with a single-cell pond-dwelling organism
known as tetrahymena. But she didnt grasp its significance
until almost 8 years later, when she and Harley began finding
telomerase in human tumor cells. Then they realized they might
have stumbled on a beautiful and straightforward strategy
for fighting cancer to find the telomerase switch in tumor
cells and turn it off.
Blocking telomerase is actually much easier than the reverse
trying to lengthen telomeres. Harley says of the suppression
of telomerase in normal cells, You have something that has
evolved for a specific function over millions of years roughly
six hundred million years, Its harder to turn that on than
to turn it off, just as there are many more ways to make a
car stop running than to make it run better. Suppressing telomerase
is also, at least in theory, a hugely attractive way of fighting
cancer. Right now, standard cancer-fighting techniques dont
do a good job of finding and killing cancer cells that have
escaped to other parts of the body those metastatic tumor
cells which lodge in the lungs or the liver and usually end
up killing the patient. Standard cancer drugs also have the
problem of being unable to distinguish between healthy cells
and cancerous cells. They attack every dividing cell they
meet, and therefore the treatment of cancer is sometimes as
dangerous as the disease itself. But if Geron develops as
it hopes to do a pill that turns off telomerase, it should
sidestep that problem. With a few, minor exceptions, tumor
cells are the only cells in the body that produce telomerase,
and therefore the therapy should be able to zero in, like
a guided missile, on cancer cells, wherever they might be,
blocking the enzyme that makes them immortal. The idea is
that, with a few months, or perhaps a year, of continuous
telomerase therapy, cancer tumors would simply divide themselves
out of existence.
Two years ago, at the American Association for Cancer Research,
which is the major yearly meeting on cancer, there were two
posters which advertise research papers on this topic, Jerry
Shay, a cell biologist at the University of Texas Southwestern
Medical Center in Dallas told me. A year ago, there was one
symposium and maybe 12 posters. This year, there were two
symposiums and about 70 posters. My guess is that next year
the numbers will be even higher.
The theory has one important limitation. Telomere shortening
seems to be involved in the aging of a whole range of cells
throughout the body, from skin to arteries and to various
organs, but telomere shortening is not the only factor that
causes cells to age. In the course of a human lifetime, cells
are also frequently damaged by the task of breaking down oxygen,
and, as we get older, they often fail to correct mistakes
in DNA, which means that if you extend telomeres you dont
solve every one of a cells problems. Perhaps more important,
there are vast numbers of human cells that don't run through
their telomeres in the way that skin cells and the cells of
our livers and lungs do. Neurons, the electrical wires of
the brain, for example, dont divide at all, dont lose their
telomeres, and dont undergo senescence. Neither, for that
matter, does heart tissue. For this reason, Harley and Greider
make a point of saying that telomere theory is a useful way
of attacking certain diseases of aging but is not a solution
to the overall problem of aging. In the future, Geron may
be able to treat arteriosclerosis and make our skin beautiful
again. But telomere therapy wont be able to prevent us from
losing our memory or to stop our hearts from wearing out.
Perhaps the best way to think about this is to imagine what
would happen if telomere therapy ends up being the cure for
cancer, which is likely to be the first disease that Geron
would address. Curing cancer would represent an incalculable
contribution to modern society. But would taking out just
one disease even a disease that ranks as the second-leading
cause of death in America behind heart disease really make
that much difference? For one thing, most types of cancer
are diagnosed in patients over the age of 50, since its usually
not until middle age that the body becomes vulnerable to cancerous
mutations, and consequently for most people ending cancer
isnt going to buy them a great deal more time. On average,
eliminating cancer gives the average American only about 3
extra years of life expectancy. And thats only half of it.
Because most people who get cancer are already sick with a
number of other diseases, those 3 extra years of life may
leave them even sicker. If you make some great stride in preventing
cancer, well, then were left with all the illnesses that have
not had much attention varicose veins, migraines, arthritis,
sensory impairments, hearing and vision impairments, and a
variety of orthopedic impairments, Lois Verbrugge, a social
demographer at the University of Michigan and WESTAT, Inc.,
says. You will have people creaking around for a lot longer,
and all these other diseases are going to ascend. If the fatal
diseases move out, then the nonfatal diseases are going to
move in. Curing cancer would be an example of the expansion
of morbidity, not the compression of morbidity.
In a fascinating recent paper, three demographers Mark Hayward
of Penn State; Eileen Crimmins of the University of Southern
California; and Yasuhiko Saito of Nihon University in Japan
showed how changes in cause of death would affect morbidity.
The three researchers broke down the life expectancy of men
and women at the ages of 70, 80 and 90 into two categories:
active years, which are the years when people can still take
care of themselves, and inactive years, which are the years
when those people need assistance in everyday living or are
bedridden. By this measure, the average 70 year-old American
woman can today expect to live until she is almost 85, of
which 12 of those remaining 15 years are active, and 3 years
are inactive. Now, assume that we cure cancer. By the groups
estimate, that woman will now live until shes 86. But of those
extra 14 months of life only about half will be active. For
the rest of that time, the woman will be battling the problems
that she might otherwise have avoided by dying sooner diabetes,
arthritis, Alzheimers, Parkinsons, and osteoporosis, for instance.
I suppose that there are some 70 year-old women who might
still want those extra 14 months, even if the last half of
them were spent in a nursing home. But I think it fair to
say that most 70 year-old women would gladly give up the extra
14 months if there were some way of shrinking the 3 years
of inactive life they now face to 2 years or 1 year or, best
of all, zero. In other words, in old age we really dont want
to get rid of the diseases that kill us before weve gotten
rid of the diseases that slow us down, that rob us of our
independence, that put us at the mercy of someone else.
Another way to look at this matter is from the standpoint
of cost. If we were to cure cancer, and give 6 months of inactive
life to the average 70 year-old woman, thats 6 months with
a nurse or in a home that society is going to have to pay
for. The financial implications of this are huge. Joshua Wiener
of the Urban Institute in Washington, estimates that under
assumptions of low disability that is, if changes in medical
care and in the health of the elderly have the effect of compressing
morbidity in the 4-year period between 2016 and 2020 America
will spend $134 billion (in constant dollars) on long-term
care of the elderly. Under assumptions of high disability,
however that is, if we do something like cure cancer and give
several months of inactive life to the elderly that same figure
will nearly double, to $215 billion. Even if every 70 year-old
woman wants those extra 14 months, can society afford to give
them to her?
This is not to say, of course, that Grieder and Harley and
everyone else studying the telomere questions should abandon
the effort. Thirty-five percent of all American cancer patients
are under 65, and any remedy for this disease would represent
an incalculable medical advance. Nor is it to say that telomere
theory doesnt represent a critical contribution to our understanding
of why certain cells in our bodies age, and why certain diseases
arise as a result. It is simply to say that a partial solution
to the aging problem is in some ways worse than no solution
at all. We might only be creating a new race of Struldbruggs.
What, then, about Michael Roses fruit flies? Do they have
a Struldbruggian problem? The answer seems at first glance
to be no. They dont crawl around the cages in their dotage.
They are stronger and fly as much as five times as long as
the average fly. Because they are fertile for a much longer
time, they have not 1,000 offspring, like normal flies, but
up to 2,000. They can weather hardship and deprivation and
other conditions that would make other flies drop dead. We
have created flies that can survive for 10 days under conditions
of starvation, Rose told me. A normal fly dies after a day
or two. As we were talking in Roses sprawling laboratory,
we walked by a giant refrigerator where Roses Methuselah flies
meet their maker, marked in the sarcastic manner of graduate
students, Fruit Fly Heaven. In the fly world, Roses drosophila
are the blessed.
They are not, however, superior to normal flies in every way.
Trailer-park flies may live only 50 days, but they are very
good at producing lots of offspring very quickly under adverse
circumstances. That trait is critical in the wild. In fact,
for all the alleged superiority of Roses Methuselah flies
which he calls welfare-state flies they could never compete
with trailer-park flies outside the friendly confines of their
plastic cages. In the period of peak fruit-fly fertility the
few giddy hours after puberty that Rose calls prom night trailer-park
flies are something like 6 times as fecund as welfare-state
flies. They reproduce so quickly that in the real world their
offspring would quickly overwhelm the offspring of Roses Methuselah
flies. In other words, you cannot have it all. Many of the
same genetic traits that make a trailer-park fly a sexual
juggernaut also serve to shorten its life. This is true not
only of flies, in fact, but for a wide range of organisms.
The surge of hormones that accompanies the mating season of
marsupial mice and Pacific salmon also seems to be the reason
that those species undergo aging and death soon after reproduction.
Some researchers have hypothesized that prostate cancer in
human beings is a consequence of genes that are involved with
the production of seminal fluid in other words, with fertility
earlier in life. A study of institutionalized mental patients
at the turn of the century found that castrated men lived
longer than uncastrated ones. To live longer involves a tradeoff,
and that means that if Rose ever develops his line of anti-aging
products it is quite possible that they would require us to
make the same kind of sacrifice that Methuselah flies do.
Ill tell you what the tradeoff will be, Rose told me. No question.
Randy teenagers will be a thing of the past. James Dean, Kurt
Cobain. All those people. Well lose that. He snapped his fingers.
Well lose the high-testosterone surge of insanity that so
much of American culture is based on.
This is a critical point. When most of us think about the
meaning of immortality or, at least, a radical extension of
life we think about endless youth, about being 20 forever.
And under those circumstances being given an opportunity to
experience the thrill and vigor and insanity of youth over
and over again the idea of immortality is highly seductive.
But immortality and youth are not necessarily the same thing,
and Rose is talking about endless middle age about always
being 50 and never being 20, which is a very different prospect.
The idea appeals to Rose, because he is a scientist, a man
consumed by his own thoughts and intellectual endeavors. The
one moment I saw Rose lose his customary detachment and grow
passionate was when he spoke of what he felt was one of the
most poignant tragedies of human existence, which is that
you spend all your life learning how to do things, learning
what it all means, and then you die. Rose, immersed in the
life of the mind, may not object to the idea of trading in
his callow 20 year-old self for a permanent authoritative
middle age. But Im not sure that all of us feel the same way.
Isnt the surge of insanity of youth part of what makes the
rest of life livable? To put it more bluntly, there is a real
possibility that for many of us a life undifferentiated by
the contrasts of young and old a life removed from the variety
and novelty that physical change brings might well be boring,
which is surely as serious a Struldbruggian problem as physical
impairment.
At the end of our discussion of the implications of longer
life, Rose told me that the best thing hed read on this question
was Robert Heinleins Methuselahs Children, a science-fiction
novel from the 50s. The book is about a group of human beings
who have been selected because of a family history of longevity
and induced to marry among themselves, producing, in the course
of several hundred years, descendants capable of living two
and three times the normal human life span. It is the human
equivalent of Roses work with fruit flies, and that may be
why it appeals to him so much. It deals with the social questions,
Rose told me. But Methuselahs Children deals with the social
questions raised by longevity in a way that could seem satisfactory
only to people who were not actually interested in the social
questions to begin with. Heinleins approach to the questions
raised by radically extending life is simply to have his very
old people act exactly like normal people, with the one exception
that they say things like I havent thought of that in centuries
instead of I havent thought for that in years. Here is the
books sole moment of philosophical reflection, a conversation
between its 183 year-old heroine, Mary Sperling, and its 213
year-old hero, Lazarus Long:
There was silence. At last she said, Lazarus, I dont want
to die. But what is the purpose of our long lives? We dont
seem to grow wiser as we grow older. Are we simply hanging
on after our time has passed, loitering in the kindergarten
when we should be moving on? Must we die and be born again?
I dont know, said Lazarus, and I dont have any way to find
out and Im damned if I see any sense in my worrying about
it. Or you either. I propose to hang onto this life as long
as I can and learn as much as I can. Maybe wisdom and understanding
are reserved for a later existence and maybe they arent for
us at all, ever. Either way, Im satisfied to be living and
enjoying it. Mary my sweet, carpe that old diem! its the only
game in town.
Carpe that old diem?
When Jonathan Swift wrote Gullivers Travels, in the early
18th century, a series of apparent scientific and medical
breakthroughs had created a new optimism about the prospects
of extending life. The Venetian architect Luigi Cornaros work
on how to live long, Discourses on the Temperate Life, was
reprinted in 50 editions in England through the 18th and 19th
centuries. The English philosopher Francis Bacon laid out,
to great acclaim, his theories for improving longevity, calling
it medicines most noble objective. The pioneering British
doctor William Harvey autopsied a poor farmer named Thomas
Parr in 1635 and announced that he was 152 years and 9 months
old at death a finding (later discredited) that lent Parr
such celebrity that he was buried in Westminster Abbey, close
to where Charles Darwin was later buried. This was the attitude
that Swift was satirizing when he had Gulliver, upon first
hearing of the Struldbruggs, rhapsodize over the possibility
of immortality. Swifts concern was not just that people seemed
to want to live forever; it was that they still desired to
live longer, even in the face of evidence that longer life
only brought increased infirmity. What Swift recognized was
that this desire was basically irrational: that men were so
afraid of death that they constructed an unreasonable fantasy
of what living longer would mean unreasonable because it supposed
a perpetuity of Youth, Health and Vigour when the real question
was not whether a Man would chuse to be always in the Prime
of Youth, attended with Prosperity and Health, but how he
would pass a perpetual Life under all the usual Disadvantages
which old Age brings along with it.
There are ways around the problem that Swift outlined, of
course. Telomere therapy combined with medical interventions
that address some of the other mechanisms of aging might be
a good start toward extending life without extending disability.
In the case of the evolutionary approach, Rose says that people
who wanted to take his pill regime later in life might still
be able to achieve an appreciable if much less dramatic increase
in life span without giving up their youth. But this is all
very speculative and all very far off. For the moment, the
battle against aging is characterized by an unrestrained enthusiasm
that sounds an awful lot like Gulliver when he first heard
about the Struldbruggs. Then he actually met the Struldbruggs,
the living exemplars of what longer life really was, and his
fantasies about defeating death were laid to rest. He looked
immortality in the eye and turned away: They were the most
mortifying sight I had ever beheld.