Unformatted text preview: [ Medicine ] why can’t
we live forever?
As we grow old, our own cells begin to betray us.
By unraveling the mysteries of aging, scientists
may be able to make our lives longer and healthier
<< By ThoMAs KirKwood >
> if you were given a free hand to plan how your ■ ■ The average life span of
humans continues to
lengthen, and some scien tists have begun to ponder
w hether this trend will
Not every species ages, and
some research suggests that
drugs or changes in diet
may slow metabolism or
alter basic aging processes
so that we can live longer.
A ll proposed longevity
strategies remain unproved,
—The 42 Editors Scientific AmericAn life will end—your last weeks, days, hours and minutes—what would you choose? Would you, for example, want to remain in great shape right up until the
last minute and then go quickly? Many people say
they would choose that option, but I see an important catch. If you
are feeling fine one moment, the very last thing you would want is to
drop dead the next. And for your loving family and friends, who
would suffer instant bereavement, your sudden death would be a cruel loss. On the other hand, coping with a long, drawn-out terminal
illness is not great either, nor is the nightmare of losing a loved one
into the dark wastes of dementia.
We all prefer to avoid thinking about the end of life. Yet it
is healthy to ask such questions, at least sometimes, for ourselves
and to correctly define the goals of medical policy and research. It is © 2010 Scientific American jon krause [ K ey ConCepts ] S e p t e m b e r 2 0 10 w w w. S c i e n t i f i c A m e r i c a n . c o m © 2010 Scientific American Scientific AmericAn 43 also important to ask just how far science can help in efforts
to cheat death. W e’re Living Longer
that our ancestors had an easier relationship
with death, if only because they saw it so much more often. Just
100 years ago life expectancy was shorter by around 25 years in
the West. This literal fact of life resulted because so many children and young adults perished prematurely from a whole variety of causes. A quarter of children died of infection before their
fifth birthday; young women frequently succumbed to complications of childbirth; and even a young gardener, scratching his
hand on a thorn, might be lost to fatal blood poisoning.
Over the course of the past century sanitation and medical care
so dramatically reduced death rates in the early and middle years
of life that most people now pass away much later, and the population as a whole is older than ever before. Life expectancy is still
increasing worldwide. In the richer countries around the world it
lengthens five hours or more every day, and in many developing
countries that are catching up the rate quickens still faster. Today
it is often said the dominant cause of death is the aging process itself and the various diseases to which it gives rise — whether cancer, which drives
cells to proliferate out of control, or Alzheimer’s, at the opposite
pole, which causes premature death of brain cells.
Until as recently as 1990, demographers predicted confidently that the historical trend of increasing life expectancy would
soon cease. Aging, many researchers believed, was fixed— a process programmed into our biology that resulted in a built-in time
No one foresaw the continued increase in life expectancy. It
has taken our politicians and planners by surprise. Scientists are
still coming to terms with the notion that aging is not fixed, that
average life spans have not reached a limit. They change and continue to change, stretched for reasons that we do not fully understand. The declining death rates of the very old are now driving
human life expectancy into uncharted territory. If the prevailing
certainties about human aging have crumbled, what is left? What
does science actually know about the aging process?
Accepting new ideas is not always easy, because scientists are
humans, too, and we have all grown up with fairly rigid precon- [ longevity Meter ] How MucH MoRE can LifE span incREasE?
Human life expectancy, or average life span, has been rising for
more than 100 years in the U.S. and globally ( graph). Evidence
suggests, however, that biological constraints keep most species from surpassing age limits specific to that species (below).
Investigators hope interventions aimed at relaxing such constraints will extend today’s maximum achievable life span or
will at least help people stay healthy longer than they do now. LIves get Longer:
Advances in medicine
and sanitation have
extended life spans
in the U.S. and
around the world. Average life expectancy (years)
90 2050 2010 1950 70 U.S. 1900
50 World average 30 Predicted But LImIts exIst: T he maximum age a species, including humans, can reach depends on both biology
(simpler organisms can reach Methuselean ages that more complex creatures cannot) and environment
(dangerous surroundings lead to evolution of rapid reproduction, fast aging and early death). m axImum recorded LIfe spans (years, In wILd) Horse (62) Bat (30)
Mountain lion (15) Great horned owl (20+)
Condor (75) Dragonfly (4 months) House mouse (4) Mayfly (1 day) Dog (29) Jackrabbit (13) 10 years 44 Scientific AmericAn Chimp (59) Cat (36) 20 30 © 2010 Scientific American Queen termite (50) 40 50 60
S e p t e m b e r 2 0 10 jason lee ( animals); lucy reading-ikkanda, s ource: “THe World econoMy in Millennial PersPecTiVe,” By angus Maddison, oecd, 2001
(world, 1900–1950 ); “World PoPulaTion ageing, 2009,” By THe uniTed naTions, deceMBer 2009 (world, 1950–2050 ); WWW.gaPMinder.org
(U.S., 1800–2010 ); u.s. census Bureau, inTernaTional daTa Base and cenTers For disease conTrol and PreVenTion (U.S., 1950–2050 ) ( graph) ceptions about how the body ages. Some years ago, while driving
with my family in Africa, a goat ran under the wheels of our vehicle and was killed instantly. When I explained to my six-yearold daughter what just happened, she asked, “Was it a young goat
or an old goat?” I was curious why she wanted to know. “If it was
old, it’s not as sad, because it wouldn’t have had so long to live
anyway,” came her answer. I was impressed. If such sophisticated
attitudes to death form this early, small wonder that modern science struggles to come to terms with the reality that most of what
we thought we knew about aging is wrong.
To explore current thinking about what controls aging, let us
begin by imagining a body at the very end of life. The last breath
is taken, death takes hold and life is over. At this moment, most
of the body’s cells are still alive. Unaware of what just happened,
they carry out, to the best of their abilities, the metabolic functions that support life — procuring oxygen and nutrients from the
surrounding environment and using them to generate the energy
needed to make and power the activities of proteins (the main
working parts of cells) and other cellular components.
In a short while, starved of oxygen, the cells will die. With their
death, something of immense antiquity will come to its own quiet end. Each and every one of the cells in the body that just died
could, if the records were available, trace its ancestry through an
unbroken chain of cell divisions backward in time through an almost unimaginable four billion years to the emergence of the earliest forms of cellular life on this planet.
Death is assured. But some of your cells, at least, have this astonishing property: they are endowed with something as near to
immortality as can be attained on earth. When your death occurs,
only a tiny number of your cells will continue this immortal lineage into the future — and then only if you have children. Only one
cell of your body escapes extinction— a sperm or an egg— for each surviving child. Babies are born, grow, mature and reproduce,
and so it continues.
The scenario we have just imagined reveals not only the fate of
our mortal body, or “soma,” made up of all the nonreproductive
cells, but also the almost miraculous immortality of the cellular
lineage to which we belong. The central puzzle in aging science,
from which all else follows, is, Why do most creatures have a mortal soma? Why is it that evolution has not led all our cells to enjoy
the apparent immortality of the reproductive lineage, or germ
line, as represented by the sperm and the egg? This puzzle was first
recognized by 19th-century German naturalist August Weismann, and a solution occurred to me in the bath one winter night
in early 1977. I believe that the answer, now called the disposable
soma theory, goes a long way toward explaining why different
species age as they do. W hy We Age As We Do
is best understood by considering the challenges
cells and complex organisms face as they try to survive. Cells are
damaged all the time — DNA gets mutated, proteins get damaged,
highly reactive molecules called free radicals disrupt membranes,
and the list goes on. Life depends on the continual copying and
t ranslation of genetic data, and we know that the molecular
machinery handling all these things, excellent as it may be, is not
perfect. Considering all these challenges, the immortality of the
germ line is actually remarkable.
Living cells operate constantly under threat of disruption, and
the germ line is not immune. The reason that the germ line does
not die out in a catastrophe of errors has to do, on the one hand,
with its highly sophisticated mechanisms for cellular self-maintenance and repair and, on the other hand, with its ability to get rid
of its more serious mistakes through continual rounds of compethe t heory Bowhead whale (211) Jellyfish, Turritopsis
nutricula (immortal) Human (122) Asian elephant (86) Red sea urchin (200+) Galápagos tortoise (150) Barrel cactus (65) Lobster (170) Eastern box turtle (80) 70 80
w w w. S c i e n t i f i c A m e r i c a n . c o m Yelloweye rockfish (120) 90 100 © 2010 Scientific American Bristlecone pine (1,000s) Koi fish (200) Hydra (immortal) 200+
Scientific AmericAn 45 [ A t heory of Aging ] How aging stEMs
Aging occurs because our body must make a trade-off between reproducing
and staying in good repair, according to the author’s “disposable soma” the ory. Given a limited supply of energy, the amount that goes to making and
protecting sperm and eggs tips the scale away from ensuring that “somatic”
cells— skin, bone, muscle, and so on — remain in good condition. As a result,
cells accumulate damage over time, which ultimately causes some organ or
another to become diseased. If bodily functioning is sufficiently compro mised, death ensues. H ow energy Is aLLocated In tHe Body fLaggIng ceLL repaIr
Leads to a graduaL decLIne BraIn
Memory and reaction time may begin
to decline around age 70.
Difficulty focusing on close objects begins
in 40s; ability to see fine detail decreases
in 70s; from age 50, susceptibility to glare
increases, and ability to see in dim light and
to detect moving targets decreases.
Maximum breathing capacity diminishes
by 40 percent between ages 20 and 80.
Heart rate during maximal exercise falls
by 25 percent between ages 20 and 75. Short
life span spInaL dIsKs
Years of pressure on the spongy disks
that separate the vertebrae can cause
them to slip, rupture or bulge; then
they, or the vertebrae themselves, can
press painfully on nerves. Life span Bones
Bone mineral loss begins to outstrip
replacement around age 35; loss speeds
up in women at menopause.
Veins in the legs become enlarged and twisted
w hen small valves that should snap shut
between heartbeats (to keep blood moving
up toward the heart) malfunction, causing
blood to pool. Severe varicosities can lead to
swelling and pain and, on rare occasions,
to life-threatening blood clots. Long
life span Cellular energy generated from nutrients tition. Sperm are produced in vast excess; usually only a good one
can fertilize the egg. Egg-forming cells are produced in much
greater numbers than can ovulate; stringent quality control eliminates the ones that fail to make the grade. And finally, if errors
slip past all these checks, natural selection provides the final arbiter of which individuals are the fittest to transmit their germ line
to future generations.
After the seemingly miraculous feat of growing a complex
body from a single cell— the fertilized egg— it should be relatively
straightforward merely to keep a body going indefinitely— as
A merican evolutionist George Williams has pointed out. Indeed,
for some multicelled organisms, an absence of aging appears to
be the rule. The freshwater hydra, for example, shows an extraordinary power of survival. Not only does the hydra apparently not
age, in the sense that as it gets older it shows no increase in death 46 Scientific AmericAn rate or decline in fertility, it also appears capable of regrowing a
whole new body from even a tiny fragment, if by chance it is cut
into pieces. The secret of the hydra’s eternal youth: quite simply,
germ cells permeate its body. If the immortal germ line is everywhere, it actually comes as no surprise that an individual hydra
can survive without any foreseeable end, presuming it does not
succumb to injury or predators.
In most multicelled animals, however, the germ line is found
only in the tissue of the gonads, where the sperm and eggs form.
This arrangement provides great advantages. During the long history of evolution, it freed other cell types to become specialists —
nerve, muscle and liver cells, among others, that are required for
the development of any complex organism, whether a Triceratops
or a human.
This division of labor had far-reaching consequences for how © 2010 Scientific American S e p t e m b e r 2 0 10 j on krause ( scales); jason lee, source: BalTiMore longiTudinal sTudy oF aging ( human body ) JoInts
Repetitive motions through the years thin
the slippery protective coverings over joints,
c ausing bones to grind against each other.
T he resulting pain may be exacerbated by
osteoarthritis and other disorders. courTesy oF daVid glen Walker organisms age and how long they can live. As soon as the specialist cells surrendered the role of continuing the species, they also
abandoned any need for immortality; they could die after the
body had passed on its genetic legacy through the germ line to the
next generation. gene that the researchers aptly named age-1 produced a 40 percent increase in average life span. Since then, investigators in
many laboratories have found numerous other genes capable of
increasing nematode life span, and similar mutations have turned
up in other animals, from fruit flies to mice.
The genes that extend life span mostly alter an organism’s meULtimAte trADe-offs
tabolism, the way it uses energy for bodily functions. Often invesso how long can those specialist cells survive? In other words,
tigators find these genes play a role in the insulin-signaling pathhow long can we and other complex organisms live? The answer way, pivotal in metabolic regulation. The cascades of molecular
for any given species has a lot to do with the environmental threats interactions constituting this pathway shift the overall level of acits ancestors faced as they evolved and with the energy costs of tivity of literally hundreds of other genes responsible for controlmaintaining the body in good operating order.
ling all the intricate processes that carry out cellular maintenance
By far the majority of natural organisms die at reland repair. In effect, it seems that lengthening life
atively young ages because of accidents, predation,
span requires changing exactly those processes we
[ t HE autHoR ]
infection or starvation. Wild mice, for example, are
know protect the body against buildup of damage.
at the mercy of a very dangerous environment. They
The amount of food available also ratchets metabare killed rather quickly— it is rare for a wild mouse
olism up or down. As long ago as the 1930s, researchto see its first birthday. Bats on the other hand are safers discovered, rather surprisingly, that underfeeding
er because they can fly.
laboratory rodents extends their lives. Once again,
Meanwhile maintenance of the body is expensive,
modulating metabolism seems to have an effect on
and resources are usually limited. Out of the daily inthe rate of damage accumulation, because mice subtake of energy, some might go to growth, some to
jected to dietary restriction increase the activity of a
physical work and movement, some to reproduction.
range of maintenance and repair systems. At first
is professor of medicine
Some energy, instead, might be stored as fat to protect
glance, it might seem strange that an animal short of
and director of the
against famine, but much gets burned just to fix the
food should spend more, not less, energy on bodily
institute for ageing and
innumerable faults that arise every second the organmaintenance. A period of famine is, however, a bad
Health at newcastle
ism is alive. Another increment of these scarce retime to reproduce, and some evidence suggests that
university in england. His
sources goes to proofread the genetic code involved in
during famines certain animals will do better to
books include the awardwinning Time of Our
the continual synthesis of new proteins and other esswitch off their fertility, thereby diverting a large
Lives: The Science of
sential molecules. And still another allocation powers
f raction of their remaining energy budget to cell
Human Aging, w ritten for
the energy-hungry garbage disposal mechanisms that
a general readership, and
clear molecular debris out of the way.
Here is where the disposable soma theory comes
of mice AnD men
and Aging (with caleb e.
Finch) mapping out how
in. The theory posits that, like the human manufacthis notion of caloric restriction— and its purportintrinsic chance,
turer of an everyday product— a car or a coat, for exed ability to extend longevity— has captured the
as well as genes and
ample — evolving species have to make trade-offs. It
attention of people who wish to live longer. Humans
environment, shapes the
does not pay to invest in allowing indefinite survival
who go hungry in the hope of a longer life should take
way the body grows,
if the environment is likely to bring death within a
note, though, that such a mechanism is much less
develops and ages.
fairly predictable time frame. For the species to surlikely to work for us because our slow-paced metabvive, a genome basically needs to keep an organism
olism differs greatly from that of organisms in which
in good shape and enable it to reproduce successfully within that this strategy has already been tested.
Dramatic extension of life span has indeed been achieved in
At all stages of life, even to its very end, the body does its ut- worms, flies and mice. These animals, with their short-lived, fastmost to stay alive — in other words, it is programmed not for ag- burn biology, have an urgent need to manage their metabolism in
ing and death but for survival. But under the intense pressure of a way that adapts rapidly to changing circumstances. In nematode
natural selection, species end up placing higher priority on invest- worms, for example, most of the more spectacular effects on life
ing in growth and reproduction— in the perpetuation of the spe- span result from mutations that evolved to allow the worms to
cies— than on building a body that might last forever. So aging is switch their development to a stress-resistant form whenever they
driven by the gradual lifelong accumulation of diverse forms of find themselves in a bad environment and potentially required to
unrepaired molecular and cellular damage.
make a long trek to find better living conditions. We humans, in
No biological software program, then, dictates precisely when any case, may not have the same flexibility in altering our own
it is time to die, but growing evidence suggests that certain genes metabolic control. Immediate metabolic effects, of course, occur
can nonetheless influence how long we live. Tom Johnson and Mi- in humans who undergo voluntary dietary restriction, but only
chael Klass, working with tiny nematode worms, discovered a time — and many hungry years —will tell if these have any benefigene with such an effect on longevity in the 1980s. Mutation of a cial impact on the aging process and, in particular, on longevity.
w w w. S c i e n t i f i c A m e r i c a n . c o m © 2010 Scientific American Scientific AmericAn 47 [ hintS for new DrugS ] can wE sLow aging?
No one yet knows how to slow human aging. But basic research into the process
might eventually yield longevity drugs. Some compounds might tinker with cell
metabolism (energy use) to mimic benefits seen in animals (below); others might
change the way damaged cells behave (opposite page). Short
life span Lean and Long-LIved: Certain therapies might redirect cell metabolism, tilting the scale toward maintenance and repair functions and away from reproduction, thereby keeping bodily organs healthy longer. Calorie restriction lengthens the
median life span of flies, worms and mice over that of animals eating a normal diet
( graph). It is unclear yet whether caloric restriction can work in humans. Previous
life span r estrIctIng caLorIes enHances LIfe span In anImaLs Growth and
reproduction Median life span
enhances longevity Too little food
decreases life span
life span Diet restriction
i normal i t k )
DECLINING CALORIE INTAKE Starvation
d ti ) r estrIctIng caLorIes affects energy aLLocatIon The goal of gerontology research in humans, however, is always
improving health at the end of life, rather than achieving Methuselean life spans.
One other thing is also very clear: the longer-lived worms, flies
and mice still undergo the aging process. Aging happens because
damage still accumulates and in time leads to the breakdown of
healthy functions of the body. Therefore, if we want our end to be
actually better, we need to look elsewhere. In particular, we need
to focus on figuring out how to safely limit or reverse the buildup
of damage that leads eventually to age-related frailty, disability and
disease. This goal represents a huge challenge and calls for some
of the most demanding of today’s interdisciplinary research. no simpLe AnsWers
aging is complicated. It affects the body at all levels, from mol- ecules to cells to organs. It also involves multiple kinds of molecular and cellular damage. And although it is true that, in general,
this damage accumulates with age and occurs slower in some cell
types than in others (depending on the efficiency of the repair systems), injury to any given cell occurs randomly, and the extent can
differ even in two cells of the same type in an individual. Thus, all
individuals age and die, but the process varies considerably— more
confirmation that aging does not stem from a genetic program
that specifies how quickly we become frail and die. To understand
aging in enough detail to intervene in a suitably targeted fashion
that stops or slows the death of selected kinds of cells, we need to
know the nature of the molecular defects that drive the aging process at the cellular level. How many of these flaws must accrue 48 Scientific AmericAn before the cell can no longer function? How many defective cells
need to accumulate in a given organ before it shows signs of disease? And if we agree that some organs are more important to target than others, how do we deliver the necessary precision?
It may be possible to combat aging by altering important mechanisms that cells use to counteract the buildup of damage. One
way that a cell responds to too much wear and tear is simply to
kill itself. At one time, scientists viewed this cellular suicide pro cess, technically called apoptosis, as evidence that aging adheres
to a genetic program. In aged tissues the frequency of cells killing themselves increases, and this process does indeed contribute
to aging. But we now know that apoptosis acts chiefly as a survival mechanism that protects the larger body from injured cells
that could potentially cause trouble, notably, ones that have become malignant.
Apoptosis happens more in old organs because their cells have
suffered more insults. Remember, though, that in nature animals
rarely live long enough to grow old. Apoptosis evolved to deal
with damaged cells in younger organs, when many fewer would
need to be eliminated. If too many cells die, an organ fails or becomes debilitated. So apoptosis is good and bad— good when it
deletes potentially dangerous cells, bad when it deletes too many.
Nature cares more about survival of the young than managing
decline in old age, so not all apoptosis might be strictly necessary
in our later years. In some diseases, such as stroke, researchers
hope that by suppressing apoptosis in the less damaged tissue, the
resulting loss of cells may be reduced, thereby aiding recovery.
Instead of dying, hurt cells that are normally able to reproduce © 2010 Scientific American S e p t e m b e r 2 0 10 j on krause ( scales a nd cells); lucy reading-ikkanda; source: “eXTending HealTHy liFe sPan–FroM yeasT To HuMans,”
By luigi FonTana eT al. in SCIENCE, Vol. 328; aPril 16, 2010 ( graph) LIFE SPAN
FE SPAN Long
life span Healthy cell Cell rescued from
apoptosis Cell suicide program
is activated Damaged cell destroys itself,
contributing to organ aging Damaged cell
occurs Uncontrolled division;
more damage accumulates Abnormal cells multiply
uncontrollably and can
become cancerous Typical aging sequence
Pathway induced by therapy HeaLIng tHe aILIng ceLL: New ways of slowing aging will come f rom learning how to manipulate damaged cells. Such cells often commit
suicide, a process called apoptosis. Or, failing that, they may begin to
replicate uncontrollably and become cancerous or enter a senescent state
in which they function but do not replicate ( black paths). In theory, rescu ing damaged cells from apoptosis or from senescence and inducing their
rejuvenation (orange paths) could protect organs from the unwanted
effects of injured cells. Investigators are in the earliest stages of testing
these possibilities, which they hope will lead to new drug treatments. may take a less extreme course and simply stop dividing, a fate
known as replicative senescence. Fifty years ago Leonard Hayflick,
now at the University of California, San Francisco, discovered that
cells tend to divide a set number of times— now called the Hayflick
limit— and then stop. Later work showed that they often stop dividing when the caps, or telomeres, that protect the ends of chromosomes erode too much. But other details of how cell senescence
sets in remained obscure.
Recently, though, my colleagues and I have made an exciting
discovery. We found that each cell has highly sophisticated molecular circuitry that monitors the level of damage both in its DNA
and in its energy-forming units known as mitochondria. When the
amount of damage passes some threshold, the cell locks itself into
a state where it can still perform useful functions in the body but
can never divide again. As with apoptosis, nature’s bias toward the
survival of the young probably means that not all these lockdowns
are strictly necessary. But if we are to unpick the locks and so restore some division capacity to aged cells, without unleashing the
threat of cancer, we need to understand very thoroughly just how
cell senescence works.
The demanding science needed to make this discovery required
a multidisciplinary team, including molecular biologists, biochemists, mathematicians and computer scientists, as well as state-ofthe-art instruments for imaging the damage in living cells. Where
such discoveries might lead we do not yet know, but it is through
studies of this kind that we can hope to identify novel drugs able
to combat age-related diseases in completely new ways and thereby
shorten the period of chronic illness experienced at the end of life.
w w w. S c i e n t i f i c A m e r i c a n . c o m Cell
senescence Healed cell ready
to divide again The difficulty of this type of basic research means that many years,
perhaps decades, may pass before these drugs come to market.
Using the science of aging to improve the end of life represents
a challenge, perhaps the greatest yet to face medical science. Solutions will not come easily, despite the claims made by the merchants of immortality who assert that caloric restriction or dietary supplements, such as resveratrol, may allow us to live longer. The greatest human ingenuity will be needed to meet this
challenge. I believe we can and will develop treatments targeted
at easing our final years. But when the end arrives, each of us—
alone— will need to come to terms with our own mortality. All the
more reason then to focus on living— on making the most of the
time of our lives, because no magic elixir will save us.
■ more to expLore
How and why we age. Leonard Hayflick. Ballantine Books, 1994.
understanding ageing. Robin Holliday. Cambridge University Press, 1995.
why we age: what science Is discovering about the Body’s Journey
through Life. Steven N. Austad. John Wiley and Sons, 1999.
understanding ageing from an evolutionary perspective. T. B. Kirkwood
in Journal of Internal Medicine, Vol. 263, No. 2, pages 117–127; February 2008.
the end of age. Thomas Kirkwood. BBC Reith Lectures. w ww.bbc.co.uk/radio4/reith2001
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