How Evolutionary Thinking Affects People's Ideas About Aging Interventions

Abstract

Evolutionary theory has guided the development of antiaging interventions in some conscious and some unconscious ways. It is a standard assumption that the body's health has been optimized by natural selection, and that the most benign and promising medical strategies should support the body's efforts to maintain itself. The very concept of natural healing is a reflection of evolutionary thinking about health. Meanwhile, a developing body of experimental evidence points to the startling hypothesis that aging is a metabolic program, under genetic control we are programmed for death. Evolution has provided that the aging program can be abated in times of stress, e.g., caloric restriction. CR mimetics are already recognized as a promising avenue for antiaging research. Beyond this, there are two ancient mechanisms of programmed death in protists that have survived half a billion years of evolution, and still figure in the aging of vertebrates today. These are apoptosis and replicative senescence via telomere truncation. Most researchers have been wary of modifying these mechanisms because they are known to play a stopgap role in cancer prevention. But intriguing evidence suggests that, despite some counter-carcinogenic function, the net result of both these mechanisms may be to shorten lifespan. Thus, interventions that suppress apoptosis and that preserve telomeres may be promising avenues for life extension research. A third element of the body's self-destruction program co-opts the inflammation response. Epidemiological evidence suggests that NSAIDs including aspirin protect against atherosclerosis, arthritis, and some forms of cancer. It may be that aging engages an autoimmune response that can be modified by drugs acting more narrowly on this same pathway. The existence of an evolutionary program that controls aging from the top down supports a new optimism concerning the types of antiaging interventions that are possible, and the likelihood that simple strategies may have dramatic results without dramatic side-effects.

Full text

REJUVENATION RESEARCH
Volume 9, Number 2, 2006
© Mary Ann Liebert, Inc.
How Evolutionary Thinking Affects People’s Ideas
About Aging Interventions
JOSH MITTELDORF
ABSTRACT
Evolutionary theory has guided the development of antiaging interventions in some conscious
and some unconscious ways. It is a standard assumption that the body’s health has been op-
timized by natural selection, and that the most benign and promising medical strategies
should support the body’s efforts to maintain itself. The very concept of natural healing is a
reflection of evolutionary thinking about health. Meanwhile, a developing body of experi-
mental evidence points to the startling hypothesis that aging is a metabolic program, under
genetic control we are programmed for death. Evolution has provided that the aging program
can be abated in times of stress, e.g., caloric restriction. CR mimetics are already recognized
as a promising avenue for antiaging research. Beyond this, there are two ancient mechanisms
of programmed death in protists that have survived half a billion years of evolution, and still
figure in the aging of vertebrates today. These are apoptosis and replicative senescence via
telomere truncation. Most researchers have been wary of modifying these mechanisms be-
cause they are known to play a stopgap role in cancer prevention. But intriguing evidence
suggests that, despite some counter-carcinogenic function, the net result of both these mech-
anisms may be to shorten lifespan. Thus, interventions that suppress apoptosis and that pre-
serve telomeres may be promising avenues for life extension research. A third element of the
body’s self-destruction program co-opts the inflammation response. Epidemiological evidence
suggests that NSAIDs including aspirin protect against atherosclerosis, arthritis, and some
forms of cancer. It may be that aging engages an autoimmune response that can be modified
by drugs acting more narrowly on this same pathway. The existence of an evolutionary pro-
gram that controls aging from the top down supports a new optimism concerning the types
of antiaging interventions that are possible, and the likelihood that simple strategies may
have dramatic results without dramatic side-effects.
INTRODUCTION
E
XPLICITLY OR IMPLICITLY
, evolutionary thinking
shapes people’s ideas of how to address dis-
ease and human aging. But evolutionary theory
has collided with a body of recent experimental
results, which suggests a surprising new picture
for the evolutionary meaning of aging.
General principles of evolution have con-
vinced people that human bodies are opti-
mized for health and longevity. If people get
sick, it is because something has gone wrong.
The preferred approach is to support and
strengthen the body’s own defenses, so that a
“natural” state of health can be restored. When
that fails, people seek to repair the damage.
Department of Mathematics, Temple University, Philadelphia, Pennsylvania.
346
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EVOLUTIONARY THINKING ABOUT AGING 347
However, research on the genetics of aging
indicates that evolutionary theory has essen-
tially misunderstood where aging comes from,
and what is its root cause. These experiments
point to programmed death: human bodies do
not wear out, nor do they fail because they have
been optimized under pleiotropic restrictions,
trading longevity for fertility. Rather, human
bodies have simply been designed to self-de-
struct with age.
This is a jarring thesis, opposed not only by
individual-based evolutionary theory, but
also by cultural values that glorify nature and
teach that she has put her best work into hu-
mans. Scientists and laypeople alike find pro-
grammed death to be an unsettling proposi-
tion. But, for longevity medicine, the idea
offers great promise: It will be far easier to
thwart a metabolic function than to improve
upon existing defenses that have already been
optimized by millions of years of natural se-
lection.
One must deconstruct the idea of “natural,”
which has become so embedded in current
health values that people may forget from
whence it derives. The original argument is that
humans, like other living things, were shaped
by natural selection and optimized for the con-
ditions that prevailed during most of that time
when their genes were evolving. Many of the
diseases of modern life can be traced to the
stress that has resulted from living and work-
ing under “un-natural” conditions (i.e., condi-
tions that differ essentially from those under
which humans evolved). It is this kind of think-
ing that ultimately justifies the idea that herbs
should be preferred to manufactured medi-
cines. The “paleo diet” explicitly invokes an
evolutionary past in choosing appropriate nu-
trition. However, there are far more subtle
ways in which evolutionary thinking affects
research strategies and guides the search for
promising interventions to extend healthy life-
span. The origins of aging are not fully under-
stood, but people are certain that the function
of medical interventions is to fix something that
has gone wrong, or help or stimulate the body’s
natural repair mechanisms.
What is not considered is that aging may be
a program controlled by a pathway of hor-
monal signals. The idea that all one has to do
is jam some of those signaling processes to
thwart the progression of aging is not taken se-
riously. Can it be that simple?
THE EVIDENCE
The idea that aging is a genetic program
shaped over evolutionary time and selected for
its own sake, is anathema to evolutionary the-
ory. Nevertheless, the evidence for this hy-
pothesis is strong, widespread, and diverse. It
comes from recent experiments in genetics and
breeding, but it is also implicit in the phenom-
enology of aging, much of which has been
known for a long time. A more detailed recent
account
1
of this evidence is summarized in the
following.
Tradeoffs sought but not found
Genetic experiments specifically designed to
look for pleiotropy have found only soft trade-
offs and inconsistent evidence. If pleiotropy
were really the root cause of aging, these trade-
offs should jump out. Michael Rose
2
has been
breeding fruit flies for longevity since 1980,
fully expecting fertility to decline as longevity
increased. He now has flies that live more than
twice as long as their wild progenitors and they
also lay more eggs every day of their lives than
the wild type. At the back of Stearns’ textbook
3
is a table of experiments that were designed to
look for evidence of tradeoffs between fertility
and longevity in diverse animal species. About
half the studies find some relationship and half
find none. On its face, this indicates that trade-
offs between fertility and longevity are sec-
ondary modifiers of aging genes rather than
their raison d’être.
Caloric restriction and hormesis
The suppression of aging associated with
caloric restriction is prima facie evidence for the
plasticity (under genetic control) of those aging
processes. This and other hormetic phenomena
lend the impression that the metabolism
could slow the aging process, were it only pro-
grammed to do so. Theorists
4
have sought
refuge in the hypothesis that life extension in
calorically restricted animals is mediated by
6069_29_p346-350 5/3/06 11:29 AM Page 347

fertility suppression, but the correlation be-
tween increased lifespan and depressed fertil-
ity is inconsistent.
5
Hormesis refers to a strengthening response
in an organism exposed to toxins, radiation, or
other environmental stress. Paradoxically, liv-
ing things are broadly observed to live longer
when stressed. This suggests that lifespan can
be increased without cost or side-effects in re-
sponse to a more challenging and competitive
environment. Forbes
6
reviews a wide range of
hormetic phenomena and concludes that fit-
ness hormesis is surprising in the context of
evolutionary theory based on individual selec-
tion. The essence of the paradox is this: Why is
the life extension program not implemented in
less challenging times? If genes are available
for extending life and, thereby, enhancing fit-
ness, then why is this program ever shut down?
Why should animals that have plenty to eat,
and are not poisoned, heat shocked, or com-
pelled to exercise vigorously live shorter lives?
Single genes that extend lifespan
Genetic studies of C. elegans support the hy-
pothesis that senescence is regulated by genes
independently of fertility.
7
Several point muta-
tions have been identified that extend lifespan
in a way that suggests this is happening with-
out countervailing cost. Some such genes have
homologs that extend lifespan in species rang-
ing from yeast to worms to flies to mammals.
8
Replicative senescence and apoptosis
The oldest of all senescence mechanisms are
replicative senescence and apoptosis. Both
have been observed to limit the lifespan of pro-
tists, and parallel genetic mechanisms have
been conserved over hundreds of millions of
years. Telomeres and apoptosis have been ob-
served to be active agents of senescence today,
in organisms ranging from yeast to humans.
In higher organisms, it has been hypothe-
sized that replicative senescence defends
against the runaway reproduction characteris-
tic of tumor growth. However, it may be that
telomeric aging remains an effective senes-
cence mechanism even in higher organisms. In
a recent demographic study
9
telomere length
was measured from archival samples of blood
drawn from 60-year-old individuals. In the en-
suing 15 years, people with the shortest telom-
eres in their blood cells were more than twice
as likely to die as those with the longest telom-
eres.
Apoptosis, too, has long been thought to be
a sacrifice of individual cells for the good of the
soma as a whole, but recent studies by Longo
10
demonstrate that yeast cells undergo apoptosis
when stressed by hunger, for the good of the
colony. This is a direct demonstration that
apoptosis can be an altruistic adaptation.
Semelparity
Some life histories are organized around a
single burst of reproduction. Such organisms
generally experience accelerated senescence
and die promptly when reproduction is com-
plete. This is one of nature’s most dramatic
demonstrations of programmed death. Pleio-
tropic theory insists that the burst of repro-
duction is responsible for the rapid aging and
death that follow, but the evidence is other-
wise.
Every gardener knows that flowering annu-
als wither and die shortly after their flowers go
to seed. However, if the flowers are removed
before they form pods, the plant can be induced
to flower repeatedly over an extended time. If
it were the burst of reproductive effort that
killed the plant, one would not expect the plant
to be capable of replacing its flowers so hand-
ily. It is more fitting to regard this phenome-
non as a form of programmed death, triggered
by the final stages of seeding.
After laying her eggs, the female octopus stops
eating and starves to death.
11
Lest one doubt that
this is an example of programmed death, the an-
imal’s behavior can be altered by surgical re-
moval of the optic gland, which evidently asserts
control over a genetic program. Without the op-
tic gland, the animal resumes feeding and can
survive to breed another season.
HOW COULD EVOLUTIONARY
THEORY HAVE GONE ASTRAY?
This is a question for the history and sociol-
ogy of science, to which the author can only
MITTELDORF
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EVOLUTIONARY THINKING ABOUT AGING 349
outline an answer. Darwin’s was a qualitative
theory, closely reasoned but with no mathe-
matical content. At the turn of the 20th century,
Mendelian genetics was rediscovered and in-
tegrated with evolutionary thinking. The earli-
est evolutionary theorists defined fitness in
terms of gene frequency in a population: Fit-
ness was identified with whatever qualities
permitted a gene to leave more copies of itself
(as a percentage of the population) in the suc-
ceeding generation. The Eukler-Lotka equa-
tion
12
defined a quantity called the “Malthu-
sian parameter,” denoted by r,which was
promoted by R.A. Fisher
13
as the mathematical
definition of fitness. ris, in essence, a weighted
average of the number of viable offspring cre-
ated by an individual, with weights that re-
ward fertility early in the life cycle, which leads
to a fast rate of exponential increase within the
population.
The science of population genetics developed
over the ensuing decades. A great body of evo-
lutionary theory grew from Fisher’s schema
and his identification of fitness with r. Along-
side the theory, an experimental science of
laboratory evolution grew up, which has vali-
dated the findings of population genetic the-
ory. This has created the impression among
theorists and experimentalists alike that the
theory of population genetics is well grounded
and has a broad base of experimental support.
The weakness of this structure is that it is
based entirely on laboratory studies, rather
than field observations. If you ask an evolu-
tionary biologist, he will tell you that field work
is too difficult, and that real ecosystems are too
messy. The real world seldom presents situa-
tions clean enough to test the predictions of
population genetics unambiguously. Never-
theless, the great majority of laboratory studies
in evolution are based on artificial selection, in
which the most successful reproducers of the
past generation are rewarded with increased
representation in the next. In other words, the
experiments have been designed to incorporate
the selection criteria that population genetics
theory says are the right ones. This is not in-
dependent validation, but circular reasoning.
In fact, the best evidence is that the Malthu-
sian parameter is not what is maximized in na-
ture’s laboratory. Experiments have dramati-
cally contradicted the predictions of the the-
ory.
14
It is easy to evolve lines of insects or
worms in the laboratory that appear to surpass
their wild-type cousins in fertility, longevity,
growth rate, and every other factor that goes
into r.
It is the author’s belief that evolutionary
theory has failed to take sustainability of
ecosystems into account. Maximizing rgen-
erally leads to depletion of renewable re-
sources. The organism that trashes its ecosys-
tem faces prompt extinction. The author has
developed this thesis elsewhere,
15
but the
ideas herein are not dependent on this par-
ticular theoretic framework. The evidence
that aging is an independent, regulated de-
velopmental program is solid, and new the-
ory will be required account for this; but
progress in medical science of aging need not
wait on this theory.
IMPLICATIONS FOR MEDICINE
It is a robust prediction of population genetic
theory that aging cannot be selected as an adap-
tation. Aging has only negative effects on in-
dividual fitness, and if it has arisen in diverse
populations, it must have been as a side-effect,
or epiphenomenon of evolution, and not
through the explicit action of natural selection.
However, if the theory is wrong, then it may
be that humans age simply because of aging
genes. There are time bombs built into peoples’
developmental clocks that destroy them on cue.
It could be that lengthening the human lifespan
could be as straightforward as defusing some
of these bombs.
Implications for medical intervention are po-
tentially very broad, and new ideas will come
from people with an expertise that the author
cannot claim. The following examples are listed
in the hope of seeding this process.
There is evidence that three mechanisms that
protect the body in other contexts turn against
the body and (deliberately) destroy it in ad-
vanced age. These are:
•Telomeric aging
•Inflammation
•Apoptosis
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MITTELDORF
350
Although all three systems have protective
roles, there is cause to believe that simply
downregulating them in old age may have life
extension benefits.
Telomeres
There is evidence from historic blood sam-
ples that middle-aged people with long telom-
eres in their blood have greater life expectan-
cies than people with shorter telomeres.
9
Genetically engineered worms with long
telomeres live longer than controls.
16
Inflammation
Aspirin and other nonsteroidal antiinflamma-
tories are blunt instruments that merely damp
the body’s inflammation response, yet they ap-
pear to strengthen the aging human body against
arterial disease and, possibly, cancer.
Apoptosis
It has been assumed that apoptosis is a pro-
grammed response in diseased cells, which
sacrifices the cell to save the body; but there
is evidence that apoptosis is on a hair trigger;
that is, it is destroying healthy cells on a mas-
sive scale in aging mammals. In experiments
with mice,
17
knocking out some apoptosis
genes has the expected effect of slightly in-
creasing the cancer rate, but the unexpected
net effect is substantial extension of the life-
span.
CONCLUSION
An unfounded faith in Nature’s benevo-
lence has been steering antiaging research
away from some straightforward approaches
to antiaging medicine. In particular, several
lines of experiment in the last decade suggest
that broad systems of aging are controlled by
a handful of genes. Expressions of these genes
point to upstream controls that provide
promising targets for medical intervention.
Hormonal systems that trigger senescence
may be indicating the royal road to longevity
interventions.
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Address reprint requests to:
Josh Mitteldorf, Ph.D.
Department of Mathematics
Temple University
7209 Charlton St.
Philadelphia, PA 19119
E-mail: josh@mathforum.org
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