[tt] Why do we die? Summary of biological theories of aging and death

[Hughes, James J.]

Please make sure to read this excellent summary of biological theories
of aging and death for Wed.

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http://www.americanscientist.org/template/AssetDetail/assetid/55855

September-October 2007

The Undiscovered Country

The statistics of death show leaps in modern life expectancy but fail to
answer the question: Why do we die?

Robert Dorit

I do not often picture my own death. When I do, however, the details
vary. I can picture my death as being unexpected: a stroke, a heart
attack, an auto accident. Some kind of testament to life's unpredictable
character. But I prefer to picture the other sort of exit, one far in
the future, where I have worn out my body without overstaying my
welcome. Either way, I know that my story will end-I just don't know
how.

We may be the only species that is aware of its own mortality. Yet
despite death's central role in shaping human self-consciousness,
mortality remains an elusive biological phenomenon. Fate and accident
shape some ends, but these things aside, we cannot answer what seems
like a straightforward question: Why do we die? The question, of course,
is not really simple, nor does it yield a single answer. We will each
die in our own way. But an answer collected from individual stories is
not what we are after. We are, instead, seeking a more general
explanation, rooted in material cause, which accounts for the patterns
of human mortality. For now, we will leave out deaths that come from
external causes-accidents or acts of violence-for they tell us little
about the biological underpinnings of mortality.

The pattern of death has changed through history. We can infer something
about this pattern from fossils of early Homo sapiens. Judging by the
condition of their skeletons and the extent of tooth wear, their life
expectancy has been estimated at around 25 years. Tens of thousands of
years later, as written records and gravestones become available, our
ability to estimate life expectancy takes a major leap forward. The
story told by these later records is dramatic: In the past 1,000 years,
life expectancies and, presumably, their underlying causes have
fundamentally changed. In the United States, for instance, the Social
Security Administration has predicted life expectancies for the year
2050 will reach 77 years for men and 83 years for women.

So what are we to make of so drastic a change, a tripling of life
expectancy at birth in 50 generations? It's a common misconception that
a 30-year-old in the year 1000 would have been both old and rare.
However, a 30-year life expectancy doesn't mean that at all. Many
50-year-olds walked the roads in the year 1000. Life expectancy at birth
is an artificial construct, a statistical measure that averages
survivorship across all age groups and that predicts how long an infant
born today is likely to live given the death rates in effect today. That
less-than-intuitive definition is worth pausing for, because its
implications are profound. In effect, in the year 1000 your chances of
making it to a ripe old age depended above all on surviving the first
years of your life. If you turned 5, you were quite likely to turn 60.
Life expectancy a millennium ago was determined primarily by rates of
infant mortality. Over the next 800 years, and most particularly over
the past 100 years, gains in life expectancy have come primarily from
greater survival of infants and small children, often because of public
sanitation and better treatment and prevention of infectious disease. A
sad caveat: 27 of 136 countries in the world still have life
expectancies at birth of under 50 years. For the half billion people in
those countries, the gains in infant and child survival have yet to take
deep root, or else have been offset by the dramatic increases in the
mortality of young adults brought about by war and the HIV pandemic.

More recent increases in life expectancy in the developed world no
longer stem from better infant and child survival. Increased life
expectancy now comes about through two unrelated causes: a decrease in
the number of children (which reduces the impact of child mortality on
the calculation of life expectancy at birth) and an increase in the
survival of older adults. Today, our life expectancy is greater not
because we make it to adolescence, but because we are actually living
longer, and the survivorship of older adults now has a far greater
influence on the calculation of life expectancy.

Death by the Numbers

Given the many factors that enter into the calculation of life
expectancy, however, this measure may not be the best way to understand
death. Instead, we may want to look more closely at what demographers
call age-specific measures, which quantify the probability of surviving
a particular interval of life (usually a five-year span-ages zero to
five, for example, or 40 to 45). We have known for a long time that
surviving the first five years is a struggle, whereas the intervals
between 5 and 30 are far less hazardous. We can also focus on the rate
of mortality at a specific age, also known as the force of mortality.

Much of our understanding of the force of mortality is rooted in the
work of a brilliant 19th-century English mathematician, Benjamin
Gompertz. Unable to enter the English university system because he was
Jewish, Gompertz taught himself mathematics and was eventually elected
into the Royal Society in 1819. In 1825, he published in the
Philosophical Transactions of the Royal Society of London "On the Nature
of the Function Expressive of the Law of Human Mortality, and on a New
Mode of Determining the Value of Life Contingencies." This 70-page paper
with its sexy title was Gompertz's effort to help underwriters calculate
life-insurance rates. In preparing the paper, Gompertz had examined
death records from several English towns and noticed a clear pattern for
age-specific death rates. This pattern, now known as the Gompertz curve,
shows a well-behaved, exponential increase in the force of mortality
with age. He argued that death, seemingly shaped by so many chance
events, nonetheless follows a simple and predictable path. And so simple
a path could only arise from an equally simple, age-dependent,
underlying force that operates throughout our lifetimes.

It took almost 150 years for Gompertz's curve to be seriously
questioned. In part because of increased life expectancy in certain
parts of the world, more individuals were living longer, providing
sufficient data to examine the force of mortality in later years-data
that Gompertz didn't have. The result of adding the long-lived to the
analysis was startling: The force of mortality, which grows
exponentially throughout most of one's lifetime, actually moderates
after age 75. Equally unexpected was the discovery that the dramatic
differences in age-specific mortality around the world virtually
disappear after age 75. In effect, if you are born in Bolivia, your
chance of seeing 75 is significantly lower than if you had been born in
Canada. But if you make it to 75 in either place, your chance of seeing
90 is virtually the same. Past a certain age, the imprints of birth and
circumstance seem to give way to universal forces and constraints.

Keep in mind that we have been speaking of age-specific rates of death,
and not the cumulative probability of death, which, like it or not,
always sums to 100 percent. In the end, we all die. But in the meantime,
we seem to be succeeding in delaying the inevitable. For optimists and
narcissists, the trend of increasing lifespan extends over the horizon.
Conversely, demographers, biologists and politicians have asserted over
the past century that human beings cannot possibly live beyond 70, or
80, or 85, or the nice round number of 100. Yet as they speak, the
maximum age at death continues to climb in many parts of the world. For
what it's worth, Jeanne Calment lived to be 122 years old, died in 1997,
and remembered meeting the abrasive and ill-smelling Vincent Van Gogh
when he came to live in her hometown of Arles, France. Although this
trend of ever-lengthening lifespans cannot continue indefinitely (even
for optimists and narcissists), the actual limit-and even the
demonstrable existence of a limit-is a subject of continuing controversy
among demographers and gerontologists.

This controversy arises in part because convincing statistics about
centenarians remain hard to come by, increasing the temptation to
extrapolate from isolated cases. Until recently, the number of people
aged 95-110 was so small that reliable age-specific mortality rates for
that age bracket were hard to estimate. People living past 100,
moreover, might represent a small, but unique, subsample of the human
population. Their age-specific mortality rates, buried for the first 80
or so years in the mass of data from the shorter-lived, may well have
been different throughout their entire lives, only coming to dominate
the statistics as the rest of the population drops off.

Needs a Ring Job, New Clutch

But for now let's leave aside the question of how long humans can live
and concentrate instead on why most of us will not live to see the
century mark. In 1990, the illustrious Russian biologist Zhores Medvedev
sought to classify the more than 300 theories that had been put forth to
account for this ineluctable reality. Many of these theories, compelling
in their own right, likely capture some of the underpinnings of our
mortality. Their sheer number, however, suggests as much about the
complexity of the question as it does about the difficulty of thinking
dispassionately about death. Scientists, after all, are people who are
going to die too.

Theories of death are also deeply embedded in their culture of origin.
Let's consider, for instance, the class of mechanical explanations of
death. These hypotheses invite us to accept the metaphor of the human
body as a machine with many parts that must work in concert. In this
metaphor, we die either because a key component gives way (the
catastrophic failure model) or because several interacting parts begin
to wear out and no longer work properly (the systems failure model).
These metaphors of failing machinery compel, but data supporting them
are harder to obtain. Catastrophic failures, like heart attack and
stroke, are major killers in the developed world, particularly in the
United States. Many of these deaths, however, are preventable and linked
to a sedentary lifestyle, and not to an inherent age-dependent failure
of a particular organ system.

The systems-based explanation argues that complex machinery fails
because many things go wrong. According to this model, as with your
Toyota, so too with your body: The force-of-mortality curves for
automobiles (called failure-rate curves) complied by demographers James
W. Vaupel and Cynthia R. Owens at Duke University bear an uncanny
resemblance to their human counterparts. Both human and automobile
curves show an exponential increase in the force of mortality that
tapers off in later years-the same violation of the Gompertz Law we
spoke of earlier. Surprisingly, mortality in the early years is eerily
similar in people and automobiles: Defects in manufacture (machines) or
development (organisms) reveal themselves early on. But if you (or your
car) make it past the first year, you're likely to motor along for a
good period thereafter. The patterns are tantalizing in their similarity
and may reveal some fundamental features of failure in complex systems.
Such systems, whether we speak of Toyotas or biologists, are
characterized by redundancy brought about by engineering (in the first
case) or evolution (in the second). 

But, as University of Chicago gerontologists Leonid Gavrilov and Natalia
Gavrilova have argued in their influential book The Biology of Life
Span: A Quantitative Approach, the very redundancy that permits complex
systems to endure a constant rain of light damage also allows such
damage to accumulate, resulting in aging and eventual failure.
Surprisingly, the higher the level of redundancy, the faster the force
of mortality accelerates with age. The irony is that the redundant
mechanisms that ensure survival during our early years are the same ones
that speed our twilight exit.

For two centuries, biology has profited from Rene Descartes's conception
of the human body as a machine, subject to, and more importantly,
explainable by, material laws. Compelling as the Cartesian metaphor of
the body-as-machine might be, it may, however, conceal some important
differences between my automobile and me. Repair, for instance, is a
process central to survival. I depend on my excellent mechanic, an agent
external to my automobile, to keep my car on the road. In contrast,
bodies, for the most part, repair themselves: More than 100 genes in our
genome are devoted to detecting and repairing DNA damage.

This notion of the body as a self-policing, self-correcting system has
spawned a second class of death explanations, those related to
maintenance. Although the human body can detect and remedy a startling
array of defects, this capacity to self-renew declines with age. Even
the raw materials for repair-those stem cells recruited to replace
exhausted counterparts-become depleted. The damage to our bodies,
meanwhile, continues unabated throughout our lives. Much like the
inventive mechanics in Cuba who keep Edsels and Cadillacs from the '50s
running without spare parts, the body struggles to patch up broken
functions as replacement cells decline. But it is, ultimately, a losing
battle. In a final ironic twist, the repair process, like the existence
of redundancies, becomes a source of trouble as we get older. The
inflammation that accompanies injury and repair is itself a source of
further damage. Aging and death may come about when we can no longer
keep up with the maintenance required to stay alive.

Short-term Investments

A third class of evolutionary explanations for aging and death suggests
that natural selection focuses largely on the young and the fertile and
is indifferent to those past their reproductive years. In the years
prior to reproduction, for instance, natural selection appears to
suppress many genes that underlie disease. After reproduction, however,
when such genes have comparatively minor effects on an organism's
reproductive success (though not on its health), they are free to exert
any malign influence. This scenario may explain why so many diseases,
notably cancer and cardiovascular disease, increase precipitously in the
fifth decade of our lives. Mutations that benefit the young-even if they
cause problems later in life-will always gain traction.

Further support for an evolutionary approach to understanding death
comes from the demonstration that fruit flies prevented from reproducing
until late in life evolve significantly longer lifespans. By delaying
reproduction, the experiment keeps natural selection in play for a
longer amount of time, favoring genetic changes whose deleterious dark
side is also delayed. In just a few generations, average lifespan
increases. Nevertheless, harmful mutations eventually, inevitably
accumulate into insurmountable, irreparable damage. These models lead to
one conclusion: Aging and death occur when natural selection takes its
eye off the ball in the later years.

A newer set of theories, prompted in part by our predilection for
molecular explanation, have recently come on the scene. Such
arguments-we'll call them fatalistic theories-suggest that a series of
clocks tick away at the cellular level, marking our remaining time. They
argue that evolution has programmed organisms to know when it is time to
die. Critical to this argument is the observation that in a lab dish,
most mammalian cells divide about 50 times and then die. We now know
that chromosomes, those densely packed spools of DNA inside each cell,
get shorter every time they're copied. Past a certain point, this
chromosomal shortening kills the cell.

But we still can't connect the mechanisms of cell death with the
mechanisms of our death (or, for that matter, the death of any other
multicellular organism). Once again, the body is not just a collection
of cells that behave independently. Our ability to repair and
regenerate, to conscript circulating stem cells-whose chromosomes don't
shorten when copied-into regenerating tissues and organs significantly
complicates these hypotheses of aging and death.

More recently, some weight has been given to the idea that longevity is
simply the result of certain trade-offs. Experiments showing that very
low caloric intake (starvation) significantly increases lifespan suggest
that there is a tradeoff between lifespan and active metabolism (which
produces damaging chemical waste). Many studies in other species show a
negative correlation between reproduction and longevity, suggesting that
energy spent in reproduction would otherwise be spent in living a longer
life. Some find in these trade-offs a guide for living. To me, their
emphasis on the longevity benefits of an ascetic lifestyle sound
slightly puritanical.

Ultimately, what does it suggest to have so many competing theories of
death? I would argue it is the hallmark of a vibrant field, one in its
early phases. The many explanations jostle and compete, driven by our
shared belief that death may be inevitable, but it is not
incomprehensible. The identification of genes involved in determining
lifespan, the demonstration that lifestyle and environment can delay
death, the technologies that extend life-all fuel our fascination with
the topic. But the aging population in the developed world (including
its scientists) also propels the field. In the end, however, if our real
motivation is to loosen death's grip on humanity, we need to go beyond a
material understanding of the biology of aging, lifespan and death. Most
of humanity still does not die of old age, "sans teeth, sans eyes, sans
taste, sans everything," as Jaques laments in As You Like It. Instead,
most of humanity dies young, of preventable causes brought about by
poverty and unequal access to health care. Any account of the causes of
death that focuses solely on biology without considering the social and
economic settings in which our biology plays out is at best incomplete,
and at worse, misguided. Over my lifetime, cheating death may not be
about tricking the limits of our biology, but instead about changing how
we live our lives.
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