WHY do we have to die? We are not like machines—our bodies constantly
repair and renew themselves. And unlike a brand new car, which starts to wear
out the moment it leaves the showroom, a newborn baby’s immunity, coordination,
heart and circulation will actually “improve” during its first decade. True, the
chances of dying—mortality—are high around birth, but they steadily
decline until around 10 years of age. Mortality only starts to increase again at
puberty, when ageing begins in earnest. From then on it’s a gentle but slippery
slope all the way to the grave.
Down the ages, countless sages and magicians have discovered “elixirs of
life”, but none has survived to pass on the recipe. There may be some
consolation in knowing that one of the cell lines in our bodies is potentially
immortal, namely germ cells—sperm or eggs. These cells, and the DNA they
carry, trace their ancestry right back in an unbroken line to the first
organisms that swarmed over the Earth more than 4 billion years ago. The other
cells in our bodies, the somatic cells, are merely the disposable slaves of this
immortal DNA. Only in recent years has medical science found a way for somatic
cells to achieve immortality, but the price is high. Henrietta Lacks, a young
woman from Baltimore in the US who died in 1951, lives on in cell cultures
around the world. She was terminally ill when some of her cancerous cells were
removed and, long after her death, they’re still going strong. Normally, it is
very difficult to culture human cells for long periods, so HeLa cells have made
a huge contribution to our understanding of cell biology.
The immortality of germ cells and some cancerous cells suggests that ageing
is not inevitable. For us mere mortals, however, the story is rather different.
And though the annual mortality figures seem to show that we are successfully
tackling ageing, the truth is that falling mortality in the industrial world is
largely due to improved health care and infant survival. While average life
expectancy in Britain has increased over the past century from 49 to 74 years
for men and from 52 to 79 years for women, maximum life span has improved only
modestly. When Jeanne Louise Calment died in 1997, she was the first human to
have lived to a verified age of 122. But at the turn of the 20th century, Thomas
Emley Young, a former president of the Institute of Actuaries in Britain,
verified the case of a person who had lived to 113 years of age. So while we
have boosted average life span substantially, with the help of antibiotics and
improved hygiene and sanitation, strictly speaking the ageing process has
scarcely been challenged.
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Average life expectancy is a poor indicator of the rate of ageing because it
lumps together all the many causes of death, from infant mortality to road
accidents. An alternative measure is the mortality rate doubling time (MRDT),
the time it takes for the probability of dying to double. The beauty of this
measure is that it eliminates the effects of accidental death, such as fatal
infections, predation or being run over by a bus. It only measures the rate of
physical decay associated with ageing. Fruit flies have an MRDT of about 10
days, mice 3 months, and humans 8 years.
Caleb Finch, a neurobiologist at the University of Southern California, Los
Angeles, has found the same 8-year mortality-doubling period in American women
in 1980, Australian civilians during the Second World War and Australians in
Japanese prisoner-of-war camps in Java. Steven Austad of the University of Idaho
has even estimated that people living in the Stone Age, despite being 150 times
as likely to die in any given year, had the same rate of ageing as we do
today.
So what exactly does ageing do to the body? Needless to say, not all the
changes are life-threatening. Starting at the surface, cells in the outer layer
of skin—the epidermis—die faster than they can be replaced with
fresh cells coming up from below (See Inside Science No. 78). This leads to
thinning and wrinkle formation (Figure 1).
Furthermore, these new cells become
increasingly disorganised. In the layer just below—the
dermis—strength is supplied by collagen fibres. But with increasing age,
the formation of cross-links between these molecules renders them less and less
flexible (see Inside Science No. 110). Over the years, there is a stiffening of
the skin’s elastin, the protein that gives the skin its flexibility. Sebaceous
and sweat glands become less active, making the skin more vulnerable to drying
out and overheating. In the fatty layer beneath the dermis—the
hypodermis—the total number of fat cells declines, but they accumulate in
particular areas resulting in bags under the eyes, enlarged ear lobes and a
double chin. Elsewhere on the face, blood vessels and bones are increasingly
visible as a result of the overall loss of fatty tissue. The skin becomes paler
because there are fewer capillaries near the surface, and pigment cells enlarge
and gather, creating age spots.
Thanks to the constant work of bone-building cells called osteoblasts, and
bone-destroying cells called osteoclasts, our entire skeletons are replaced
every 7 years or so. As we age, the balance between bone formation and
resorption is upset, leading to a loss over a lifetime of about 15 per cent of
total skeletal mass in men, and 30 per cent in women. The loss is particularly
dramatic in post-menopausal women. In both men and women, bones become more
prone to fracture as a result of mineral depletion and increased porosity. The
flexibility of joints starts to decline from about age 20, and by old age
mobility can be severely restricted by arthritis. This is caused by the
destruction of joint cartilage, and the pain and inflammation that ensues.
Use it or lose it
Loss of strength
Exercise can help elderly people to maintain bone density, and the same is
true of muscle strength. “Use it or lose it” seems to be the rule, with
neglected muscle cells being turned into connective tissue and fat. But no
matter how much you exercise, there is an inevitable, slow decline in strength.
This is due to a poorer blood supply to muscles and less effective nervous
stimulation. Mitochondria, the powerhouses of cells, may also become less
efficient in muscle cells.
The ability of the heart to pump blood around the body declines as a result
of thickening of the wall of the left ventricle. Meanwhile, the smooth muscle
layer surrounding blood vessels becomes thicker and stiffer due to a buildup of
calcium and collagen, making the vessels less able to transmit pressure waves
from the heart. In atherosclerosis, arteries may become clogged by a buildup of
fatty deposits on their inner lining.
Intelligence, at least as measured by IQ, peaks between the ages of 18 and
25, then slowly declines. Both short-term and long-term memory deteriorate. The
loss of long-term memory seems to be a problem of retrieval rather than
storage—the memories are in there somewhere, we just don’t know where we
filed them. Our brains shrink as we age, losing between 5 and 10 per cent in
weight between the age of 20 and 90 years. One tenth of all the brain cells we
have when we are in our 20s will be lost by the age of 65. But things aren’t
nearly as bad as the statistics suggest. While we may lose a lot of neurons, the
density of synapses—the connections between nerve cells—may actually
increase, offsetting much of the loss of mental agility. Unfortunately, some old
people are afflicted by Alzheimer’s disease, which causes a more alarming loss
of function (see below).
Elderly people are also vulnerable to infections that their immune systems
are encountering for the first time. This is particularly true of flu viruses,
which mutate into new strains every year. This loss of primary immunity results
from a decline in the body’s limited stock of “virgin” T cells—iܲԱ
cells responsible for spotting foreign molecules (antigens) that the body has
never come across before (see Inside Science Nos. 7 and 8). At the same time,
elderly people are more prone to autoimmune diseases, where the immune system
attacks the body—for instance in rheumatoid arthritis and Alzheimer’s.
These are some of the outward signs of ageing, but what happens at the
molecular level? Here there is a paradox. It turns out that two of the most
important substances for life do most of the damage: oxygen and sugar. Aerobic
respiration, in which oxygen is used to break down complex organic molecules
such as fat and carbohydrate to release energy, produces highly reactive
by-products called free radicals
(Figure 2). These have the potential to
wreak havoc, particularly in the vicinity of mitochondria, where respiration
occurs. As a result, the small but vital amount of DNA inside mitochondria is
especially vulnerable. Less reactive radicals, such as hydrogen peroxide,
diffuse through the cell and into the nucleus, where they may damage the DNA in
chromosomes as well. Fats also come under attack wherever they occur in the
body, for example in membranes or as part of hormones and eye pigments. The
harmful form of blood-borne cholesterol, low-density lipoprotein (LDL) is also
attacked—which might seem a good thing. But when LDL is oxidised by free
radicals, it changes into a form which cannot be recognised as “self” by the
immune system, making it a target for autoimmune attack. This process may
contribute to the development of fatty plaques in arteries
(Figure 3).
Fortunately, antioxidant vitamins such as E and C can soak up free radicals.
Enzymes also play a part. Catalase, for example, converts hydrogen peroxide into
water. It has been estimated that there are as many as 10 000 instances of free
radical damage per cell per day. Most of these chemical dents are patched up by
the body’s repair mechanisms, but not all. Over the years, the damage
accumulates.
Sugars can also harm vital molecules. Glucose binds to proteins in a process
called glycosylation. For example, the cross-links that make collagen less
flexible are the result of glycosylation. The effects of this deterioration can
be seen everywhere in the body where this long-lived protein is found,
especially in arteries, tendons, ligaments and the lungs. When collagen in the
walls of arteries is glycosylated it tends to trap passing proteins, and this
may be another factor in the accumulation of LDL cholesterol. All proteins are
prey to glycosylation, which makes them less soluble and less likely to be
broken down. There is now some evidence that glycosylation is behind the
formation of Alzheimer’s plaques in the brain.
One leading theory argues that ageing is due to the buildup over a lifetime
of unrepaired damage to DNA, lipids and proteins, particularly that caused by
free radical attack and glycosylation. This is the error accumulation theory.
Although young bodies do not begin to age until puberty, older bodies really are
like ageing cars—no matter how much the rusty bodywork is patched up and
the engine retuned, they’ll never look as good or run quite as well as they did
when they were brand new. Enzymes and long-lived structural proteins become less
efficient, mainly as a result of direct damage, but sometimes because there are
unrepaired errors in the blueprint for proteins, DNA. These mutations are passed
on whenever a cell divides. The worst kinds of mutations cause uncontrolled cell
division—cancer. Mutations in tumour suppressor genes called p16 and p53,
for example, have been found in many cancers.
Luckily for us, even after DNA repair mechanisms have failed, the body still
has a few tricks left to prevent the runaway cell division that causes cancer.
One involves the shortening of structures called telomeres at the tips of
chromosomes. These lengths of DNA do not code for proteins—they are junk
DNA—but are nevertheless essential for the successful duplication of
chromosomes during cell division. The mechanics of DNA replication dictate that
a chromosome cannot be copied right to the end, so a little bit of the
expendable telomere is lost every time a cell divides. When it becomes too
short, however, genes are activated that shut down cell division. This limits
the number of divisions that each cell can undergo, and hence protects against
cancer. But in protecting itself against uncontrolled cell division, the body
also limits the capacity of tissues and organs to renew themselves.
Of course, things aren’t quite that simple, because some somatic tissues need
to go on dividing however old you are. And if the telomeres in our germ cells
shortened every time they divided, our species would be destined for extinction.
An enzyme called telomerase saves them from this fate by rebuilding the ends of
chromosomes (see below). The gene for telomerase is only switched on in cells that
need this licence to divide indefinitely. But if genes that suppress telomerase
production in an ordinary cell are damaged, it may develop delusions of
immortality and become cancerous.
Why oh why?
Evolutionary ideas
These mechanisms help to explain “how” we age, but not “why”. Only
evolutionary theories can do this. Natural selection favours characteristics
that ensure the survival of the optimum number of offspring to reproductive
maturity in a given environment. One might think that if an individual had genes
that allowed it to continue living and breeding for longer than its fellows,
these would automatically be favoured by natural selection. But this would be to
ignore environmental factors. In the wild, animals rarely die of old age,
because predators, disease or seasonal changes such as falling temperatures and
reduced availability of food get them first. To be successful in evolutionary
terms, they must reach sexual maturity quickly and produce offspring before the
food runs out or they are eaten, injured or fatally weakened by parasites. It is
easy to forget that until relatively recently in our evolutionary history, this
was also the lot of Homo sapiens.
The consequence of living in a dangerous environment is that the
effectiveness of natural selection decreases with increasing age. This means
that genes that are harmful late in life are unlikely to be weeded out of the
gene pool, because the individuals who carry them will already have passed them
to their offspring. Take the gene that causes Huntington’s disease. The jerky
movements, slurred speech and steadily worsening dementia that characterise this
illness only appear in middle age, by which time the gene responsible may
already have been passed to the next generation. This is even more likely if the
harmful gene has the effect of increasing reproductive capacity in early life.
This is known as antagonistic pleiotropy (a pleiotropic gene is one that
controls more than one attribute). For example, testosterone is essential for
male fertility, but it also suppresses the immune system, accelerates the
senescence of arterial walls, and is involved in the development of prostate
cancer.
Balancing act
Saving on repairs
Another theory sees ageing as a consequence of the balancing act between the
need to repair damage and the need to minimise the resources spent servicing DNA
and proteins—resources that could otherwise be used for growth and
reproduction. The disposable soma theory, proposed by Tom Kirkwood of the
University of Manchester, suggests that while there are genes that slow or even
prevent ageing, their price may be impaired reproductive success in early life.
Kirkwood believes that energy for growth and reproduction is made available by
reducing the accuracy with which somatic cells are copied. Immortal germ cells,
on the other hand, are copied, repaired and screened with a very high degree of
accuracy. They are like generals living in luxury far from the heat of battle,
while their expendable troops slug it out in the front line.
Evolutionary theories suggest that ageing is inevitable, despite our bodies’
capacity for self-repair. They seem to say that no matter how much people
exercise or pop vitamin pills, this will not add a single day to their maximum
life span. This pessimistic conclusion seems to be borne out by animal
experiments. Exercise, for example, increases the average life span of rats in a
minor way, but it has no effect on maximum age. Physical exertion in people
improves fitness, muscle and bone strength, and decreases body fat, countering
diseases of middle age and improving quality of life, but it does not affect
late-life ailments. The story is the same for antioxidant vitamins such as A and
C, which have little or no effect on ageing and may be harmful in excess. Fruit
and vegetables seem to improve average life span, which is welcome, but there is
no evidence that eating your greens will help you beat Madame Calment’s
longevity record.
Only one sure-fire way has been found to delay ageing all over the
body—food restriction. Rats that eat between 60 and 70 per cent fewer
calories than those allowed to eat as much as they like remain energetic for
longer and have stronger immune systems and better memory. Their tissues suffer
less oxidative damage, and their tendons and ligaments stiffen more gradually.
They not only live to a greater age on average, but the longest-lived rats on
low-calorie diets may survive up to 40 per cent longer than well-fed animals. A
clear verdict has yet to emerge from primate and human studies, but for the
moment this looks like the best bet for combating ageing. It should be
remembered, of course, that the rat experiments were carried out under highly
controlled conditions, and for people the dangers of malnutrition may far
outweigh any possible benefit.
Magical “elixirs of life” have been sought for centuries, and science has
only just joined in the quest. But there is cause for optimism. As Kirkwood
points out, just because ageing is inevitable from an evolutionary standpoint
doesn’t mean life span cannot be modified. In fact, he says, his disposable soma
theory suggests the opposite. If ageing is due to the accumulation of faults in
cells as a result of an evolved tendency to economise on maintenance and repair,
then treatments that reduce cells’ exposure to this damage or enhance cell
maintenance could actually begin to reverse ageing. The idea of an elixir of
life may not be so daft after all.
THE progressive decline in mental and physical abilities caused by
Alzheimer’s disease is a prime example of harmful “ageing” genes slipping
through the net of natural selection. A protein called ApoE helps to remove
cholesterol from the blood, and the gene that codes for it comes in three
varieties, e2, e3 and e4. People who carry the e4 gene are more prone to high
cholesterol levels, heart disease and Alzheimer’s, but e2 seems to protect
against these diseases. The e3 gene is somewhere in between. Research suggests
that people who carry e4 and also suffer from hyperglycaemia (high blood sugar
levels) in middle age experience greater declines in mental function than those
who have hyperglycaemia or e4 alone. It looks as though individuals who carry
the e4 gene are less able to repair nerve cells damaged by high blood sugar
levels.
In all populations studied so far, the e3 gene is the most common, followed
by the harmful e4, with beneficial e2 bringing up the rear. How can this be?
Isn’t evolution meant to weed out damaging genes? To understand why is to
understand why ageing is inevitable: Alzheimer’s and heart disease only
strike late in life and so are likely to have only a limited effect on
reproductive fitness.
IN A few years’ time, the Human Genome Project will finish decoding the
blueprint for human life. But it will be some time before the secret of delaying
ageing is unlocked, because senescence is controlled by a plethora of genes, and
unravelling their effects will take many more years.
Animal studies have already indicated where to start in discovering the
genetic basis for ageing. In August last year a gene was found in the roundworm
Caenorhabditis elegans that, if faulty, leads to rapid ageing in the
presence of high oxygen levels. The gene, mev-1, codes for part of an
enzyme that tackles a free radical called superoxide, which accelerates ageing.
In November, a gene was discovered in fruit flies (Drosophila
melanogaster) that, in a mutant form, allows the fly to live 35 per cent
longer than average. They dubbed it methuselah. It also helps the flies
to shrug off stresses such as starvation, heat and the poison Paraquat, which
generates free radicals. Both discoveries lend support to the disposable soma
theory, which argues that ageing is a result of organisms economising on cell
repair and maintenance in order to pour more resources into development and
reproduction.
There was much excitement in January last year when scientists announced that
they had given cultured human cells the ability to rebuild their telomeres.
These chromosome structures are thought by some to be the cell’s “ageing clock”,
because they are shortened every time the cell divides until further division
becomes impossible. When the ageing cells were given an active gene for
telomerase—the enzyme that restores telomeres—they were rejuvenated
and began to divide vigorously. The cells had apparently “turned back the
clock”. But before you buy shares in Telomere Biotech, bear in mind that brain
cells age, even though they never divide and so never lose their telomeres.
Using telomerase to encourage cells to divide rapidly also raises the spectre of
uncontrolled cell division—cancer.
Genes—the good, the bad and the belated
Engineered for a longer life
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Further reading:
Why We Age: What Science is Discovering About the Body’s Journey Through Life,
by Stephen N. Austad (John Wiley & Sons, 1997) -
Aging: A Natural History,
by Robert E. Ricklefs and Caleb E. Finch (Scientific American Library, 1995) -
The Clock of Ages,
by John J. Medina (Cambridge University Press, 1996)