Open Questions: Causes of Aging
See also: Diet, metabolism, and health --
Evolutionary theory --
I grow old... I grow old...|
I shall wear the bottoms of my trousers rolled.
Shall I part my hair behind? Do I dare to eat a peach?
I shall wear white flannel trousers, and walk upon the beach.
I have heard the mermaids singing, each to each.
I do not think they will sing to me.
T. S. Eliot
Aging is a puzzle, because it's hard to understand what function it has.
Clearly, all multicellular organisms age. (The situation with unicellular
organisms that reproduce by dividing is less clear.) In the spirit of
the quote from Ernst Mayr, above, aging should be understandable in
terms of evolution. So aging should be a product of evolution. But how?
Again, all multicellular animals and plants die eventually, but not only
from aging directly. Especially with smaller, more vulnerable animals
(and plants), the direct cause of death is usually predation, accidents,
infectious diseases (due to parasites, which are internal predators), or
other external factors. But even small animals age, and increasing
debility, a side effect of aging, is often a contributing factor
to death from other causes.
Large animals, such as humans, or other animals which are less
vulnerable to predation (such as birds), tend to live longer, and more
often die from age-related debility or disease. But all still undergo
the aging process. How has evolution brought this about?
Why do complex organisms (such as ourselves) experience aging and
(eventual) death? It's a simple question which is hard to avoid wondering
about on both an abstract philosophical level as well as a very
concrete personal one. On the personal, practical level, the natural
follow-on question is: Is there anything we, as individuals, or medical science
as a whole, can do to extend life, and if so, by how much? There probably
aren't any questions in science that come with much more compelling
interest than these.
Aging and death are not quite the same thing, of course. Even if our
bodies did not suffer from degeneration and aging in the way that they do,
we would still be at risk of death from external factors such as:
Let's consider this problem of death first.
- infectious diseases, parasites
- being killed by other organisms (for food, sport, or spite)
- accidents (falling, fires, storms), seasonal weather changes
- starvation -- failures of food supply
In the spirit of the quotation above from the biologist Ernst Mayr,
let's look at death from the point of view of evolution. Speaking
very generally and naively, we would expect evolution to equip an
organism with as many defenses against death as possible. With respect
to predators, for instance, we would expect organisms to evolve in certain ways,
such as to become larger and stronger (so as to be predators instead
of prey), to develop means of evasion (being able to run faster or hide
better), or to come up with more lethal weapons (sharper claws, toxins
in the body that deter predators).
Of course, evolution doesn't try all these approaches at once. In any
particular situation where a species finds itself under pressure from
external threats, some one random mutation will occur first that improves the
survivability of an individual in one specific way -- better camoflage,
for instance. If that mutation is "good enough" to reduce the
pressure, then the incentive to develop additional protective measures
is reduced. There is less need to evolve additional defenses, and so
it probably won't happen -- unless and until a new threat appears or the
predators evolve to counter the new defenses of the prey. This leads
to evolutionary "arms races" between predators and prey to keep evolving
new and better survival tactics.
One specific tactic which can evolve in a prey species is especially
worth noting. Since what really matters in evolution is ability to
reproduce rather than to stay alive, instead of evolving better
defenses, the species may simply get better at reproducing, by having
offspring more often and/or in larger numbers. But there is a cost to
reproducing -- more food/energy is required, and there is more wear and
tear on the organism. So the trade-off is that the organism may have
more offspring but a shorter lifespan. However, if the lifespan is
limited anyhow, by external predation or availability of food, that may
not matter so much. This strategy is known as "live fast - die young".
It is actually quite common, and shows how evolution can actually
favor shorter rather than longer lifespans. Why should an organism
in this situation bother to evolve ways to avoid aging, if it's only
likely to be some other animal's breakfast anyway?
This scenario applies even to large animals that are "prey" to much
smaller animals -- parasites, in other words. Even a comparatively
large animal like a human or an elephant will not have an evolutionary
incentive to acquire an indefinitely longer lifespan, since it will
still be vulnerable to infections (parasites), accidents, or
degenerative diseases (cancer, senility, etc.)
But let's look at the situation of a large animal a little more closely.
One way that a species can evolve to be less susceptible to accidents is
to become smarter. If death by accident is in fact the most serious
threat the animal faces, this evolutionary path may well occur. In fact,
though, this isn't that common. Evolutionary increases in intelligence
are more likely to be driven to avoid predation than accidents.
What about parasites,
then? In competition between a large animal and small parasites, the
parasites actually have a big advantage. Long lifespan, rather than
helping the large animal, can be a disadvantage if it comes with
slower rates of reproduction (remember -- this is usually a trade-off).
The parasite usually has a much shorter lifespan, but reproduces much
more quickly, and therefore evolves much more quickly. And so the
parasite can usually stay ahead in any arms race. The parasite can
mutate much faster than its host can improve its immune system.
(In fact, advanced immune systems employ evolutionary strategies of
self-improvement, but that's another issue; the parasite may still)
What about starvation and the food supply? Here again, being large is
not much, if any, advantage. A large animal may be a better predator,
but it also needs more food. Food supplies, ultimately, are always
limited, if only due to intra-species competition for food. So the
evolutionary pressure may be for smaller size. Which tends to favor
shorter lifespan (due to in part higher vulnerability to predation). We
have something like this sequence in effect:
food shortage → smaller size →
faster maturation →
faster evolution →
given environment, and given enough time, evolution will lead to
some "optimal" size for a particular species -- until things chage again.
But in any case, there's no one-way pressure for longer lifespan.
So, we've considered briefly several causes of death that an organism
faces: accidents, predation, and starvation. In these
cases, there's little clear benefit to longer lifespan. Depending on
the circumstances, the advantage could be for shorter just as well
as longer life. But what about aging and degenerative disease?
Surely, in the long run, evolution shouldn't favor aging and degeneration
of an organism. How could those promote reproductive success of
individual organisms? If anything, evolution should work against
aging and degeneration, shouldn't it?
This is the interesting case, so we need to look at it more closely.
Evolution and human lifespan
Remember that we found there could be advantages to the "live fast,
die young" strategy. However, this is tricky. We shouldn't expect that
evolution will simply be neutral about an organism's
life span. There can be active pressure to keep life span short.
An animal with a short life span will
tend to be smaller, since it just doesn't have as much time to grow.
But this is good, since the animal will require less food and energy.
There are several related reasons needing less food is good.
The animal will be less likely to starve to death,
even if it doesn't starve it will be healthier if not stressed by lack of food,
it won't have to waste as much time searching for food,
and it can provide more food for its offspring, thereby improving
their survival chances.
In addition, the process of metabolizing food produces harmful byproducts
("free radicals") that can cause genetic damage.
So "small is beautiful", and there are many advantages to being small,
even if longer life isn't among them.
We have to be careful here. It's a rather contentious issue whether
we can argue that short life is actually
beneficial since it gives the species a survival advantage. This is
the subject of many debates among evolutionary theorists -- the issue
of "group selection" vs. individual selection. The more conservative
view is that what is important in evolution is advantage to
individual organisms, not groups of organisms such as an
entire species. Characteristics which benefit individuals are favored
by evolution, since the individuals that have them produce more
offspring, in the long run, which have the same set of genes.
But we don't need to get into that here, since we've already shown
how being smaller and needing less food can be advantageous to an
individual. Mice are smallish, not because it's good for mice as
a species, but because it was good, up to a point, for the first
mutant mouse in a given environment which was a little smaller than
others. (In some other environment, it might just as well
have been a disadvantage rather than an advantage.)
So on the whole, about all we can say is that evolution tends to
be neutral in its effects on lifespan. Sometimes it can favor more
longevity, sometimes less. There's always this dynamic process going
on, and about all we can conclude is that the results we observe at
any point in time represent no more than an equilibrium, a local
optimum, based on prevailing conditions and prior history.
Even though it seems paradoxical that there might not be
evolutionary pressure on individuals of a species to live longer
so that they could produce more offspring, such is the case.
There is, however, still a preplexing puzzle with humans, and a
relatively few other species. Namely, humans have a lifespan that
can exceed by several decades their ability to reproduce. This is
much more pronounced in females than in males, of course. But it's
worth asking why it happens at all.
The standard answer has to do with the fact that humans have such
a long period of childhood before they are able to live on their
own without their parents -- somewhere around 15 years or so.
A mother and father will be more likely to have their genes passed on to future
generations if they live long enough to raise most of their offspring
to adulthood. (The advantages are somewhat different for men than for
women, which would explain why men can father children for a longer
portion of their potential lifespan, but we don't need to go into
that issue.) Mothers, in particular, can better raise their existing
children if they aren't pregnant with others, but again there's a
trade-off between having many children, to raise the probability that
some survive vs. fewer children to make it easier for the mother to
take care of them.
Indeed, it is even proposed that there may be a "grandmother effect", in
which a survival benefit (in terms of one's genes) exists for individuals
who live long enough to help their offspring raise the latter's own
family. But at some point diminishing returns will set in. An
individual who lived much beyond his or her ability to beget
children would become a hinderance rather than a help to the offspring.
He or she would continue to consume food and other resources without
producing additional surving copies of his/her genes.
Even if a mutation was present which enabled an individual to live well
beyond the childbearing years, it would not persist unless at the
same time the mutation extended the childbearing years also. (Or,
even less likely, a different accompanying mutation had that effect.)
Once the individual's positive contribution to the survival of his/her genes
through longer lifespan (through more offspring plus grandparenting)
falls below the negative contribution, longer lifespan is simply a
disadvantage. (It may simplify matters if you ignore the possible
grandparent effect and note that lifespan beyond the ability to
have children is then no advantage at all.)
But there is still a puzzle, because it is still possible that,
even in the absense of a grandparent effect, one mutation could
simultaneously extend both childbearing years and overall lifespan.
A mutation, for example, which slowed down the rate of aging of
individuals cells and organs in the body. The puzzle is that this
doesn't seem to have happened in human evolution. Our longer lifespans
today are attributable to things like better nutrition, better
supplies of other resources (heat, shelter), better medical
technology, etc. There's no reason to suppose that the overall
rate in humans of aging and physical degeneration of cells and organs
has diminished very much.
To address this question, we have to look in more detail at factors
that contribute to aging and degeneration.
Aging and degenerative diseases
The first point to note is that a living organism in general, and
a human in particular, is constructed in a hierarchical fashion.
Bodies are made up of various organs and tissue types. These in turn
have substructures (parts of the brain or the digestive system, for
example). The next level down is cells. And the level below that
is substructures such as mitochondria, chromosomes, and so forth.
Below that, it's chemistry. At each level, decay and degeneration
can occur in a variety of ways. We'll consider the ways in more
detail later, but here are some exmples:
In general, we can say that cellular damage and death is a result of
entropy. That is, thermodynamics tends to drive highly ordered systems,
such as cells, to a state of lesser order, i. e., more disorder.
Evolution has actually come up with many tricks to repair or limit the
damage, but these tricks are not and can not be 100% effective. Some of
the tricks such as that of the telomeres simply make the deterioration
process a little more orderly, in that they limit cell division, which
is one of the main causes of DNA damage in the first place. But all of
these tricks add up to complexity. Cells are complex machines, and all
complex things tend to fail eventually. (The process of entropy again.)
Cancer happens to be one of the main failure modes that eventually shows
up, as a statistical inevitablilty, in large multicellular organisms
made up of trillions of complex, highly-evolved cells.
- Cells can suffer damage to the DNA in their chromosomes for a
variety of reasons, including simply the hazards of cell division.
Cells with damaged DNA that isn't repaired usually die by a process
- Chromosomes have substructures called "telomeres" which are
repeating units of DNA. One unit of each telomere is lost every time
a cell divides. When there are no more telomeres left on the chromosomes,
a cell ceases to divide.
- Organs and organ systems start to fail when a substantial number of
their constituent cells die due to apoptosis or physical damage.
- The condition known as cancer can develop over a period of decades as
harmful genetic mutations occur in the DNA of particular cells
and eventually accumulate to the point where cells with sufficiently
mutated DNA become in effect harmful parasites on the body and its organs.
So, from a top-down perspective, evolution has no particular
reason to result in longer lifespan. And from a bottom-up perspective,
all of the wonderful mechanisms that evolution has devised to avoid or
repair localized damage eventually fail of their own complexity and
are co-opted by the endogenous parasites known as cancer cells.
It is possible in principle that evolution could come up with
cleverer ways to detect and correct DNA damage. But without selective
pressure to do so, why should it? And even if it did, the increased
complexity that resulted might well be countered by an escalation
of the arms race with cancer cells, in which cellular defenses
are circumvented or co-opted and turned against the defenders.
But hope springs eternal. Is there any reason why evolution can't
proceed and develop even more clever ways to handle these problems?
In some sense, unfortunately, there probably is. And it is due to
the very hierarchical organization of cells into organs that makes
multicellular animals possible in the first place. At least, this
seems true of the kind of evolution which has occurred on this planet.
Why could not evolution, for example, have come up with ways that a
complex animals, humans in particular, could regenerate whole organs or
organ systems which are failing or damaged for some reason, the way a
salamander can grow a new tail? We don't know for sure why evolution
hasn't accomplished this. Maybe it simply hasn't had enough million
years to do the trick. In any case, we know that it hasn't.
But even so, is there any reason that human
technology couldn't accomplish the same thing much more quickly?
It would appear that there are good reasons that evolution hasn't
done the trick, and that it may be very difficult even for human
technology. Just think of the analogy of keeping an old automobile
in good running condition.
Other Aging Related Links
- External links provided by the
Indiana University Center for Aging Research
Sites with general resources
Indiana University Center for Aging Research
- Research institute home page. Includes external links and
a newsletter called
National Institute on Aging Intramural Research Program
- Information and resources related to
on gerontology research programs.
American Federation for Aging Research
- "Infoaging.org is dedicated to providing the knowledge we
all need to live healthier, longer lives. The site delivers
the latest research-based information on a wide range of
age-related diseases, conditions, issues, features, and news."
Site features include information on the
biology of aging,
healthy aging, and
HealthandAge.com Information from The American Federation
for Aging Research
- Presents information on a variety of topics in cellular aging
and the general biology of aging. Each topic includes frequently
asked questions, information on recent research, external links,
and lists of books and other references. Example topics include
caloric restriction, and
theories of aging.
- An information center for telomere research operated by
Washington University. Includes a literature database
Genes and Longevity
- Good collection of resources on the topic -- external links,
magazine articles, and books.
Unraveling the Secrets of Human Longevity
- Web site of researchers Leonid Gavrilov and Natalia Gavrilova.
Contains articles and papers on their work and some external links.
Surveys, overviews, tutorials
- Article from
Mechanisms of Aging
- A ScienceWeek
"symposium" consisting of excerpts and summaries of
articles from various sources.
Mechanisms of Aging
- A fairly detailed review of different theories about the
mechanisms of aging, by
Ben Best. Topics include
evolutionary theory, free radicals, mitochondria, glycation,
DNA damage and repair, longevity genes, telomeres, hormones,
the immune system, cancer, and caloric restriction.
The author is interested in the general subject of
I want to live forever
- Informative interview with aging researcher Cynthia Kenyon.
Calories May Not Count in Life Extension
- June 2005 Science News article about how extension of
longevity may not be so much related to total calories consumed as
it is to reductions in certain nutrients such as carbohydrates.
Low-Cal Diet May Reduce Cancer in Monkeys
- November 2000 Science News article about studies with
monkeys that showed a connection between a low calorie diet and
reduced risk of diseases like cancer and endometriosis.
Running on One-Third Empty
- March 1997 Science News article about experiments
in primates with calorie-restricted diets.
Centenarians Studied to Find the Secret of Longevity
- Brief October 2008 Scientific American article,
subtitled "Healthy aging may be possible with some genetic help."
- Brief April 2005 Scientific American Mind article about
research that shows moderate physical activity in old age appears
to invigorate the mind as well as the body.
The Truth about Human Aging
- May 2002 Scientific American In Focus article about a
position paper warning against pseudoscientfic antiaging products.
Contains 16 short sidebar articles on specific topics.
Each sidebar contains numerous citations from medical literature.
Insulin Sets the Pace of Aging
- April 2001 Scientific American news article about
the involvement of insulin-like hormones with aging in fruit
flies, and an analogue of an insulin receptor protein.
- March 2001 Scientific American news article about
research of Heidi Tissenbaum and Leonard Guarente that shows
the sir2-1 gene affects the lifespan of C. elegans.
Long Live the Fruit Flies!
- December 2000 Scientific American news article about
the discovery that fruit flies with a mutation in one copy of a
gene that plays a role in energy metabolism may live almost
twice as long as their wild type cousins.
Pushing Life's Limits
- September 2000 Scientific American news article about
a finding that contends the maximum human lifespan is increasing.
If a diet of caloric restriction can extend the life span
of laboratory rats, then does the lifestyle of an athlete, who
burns calories at a rapid rate, hasten the aging process?
- October 1999 Scientific American Ask the Experts article,
which addresses the question asked in the title.
Turning Back the Strands of Time
- February 1998 Scientfic American In Focus article
on telomeres and telomerase, subtitled
"Scientists have found a major factor that controls whether a cell
dies or thrives."
The times of our lives
- October 2, 2000 feature article from Nature concerning
general theories of aging, and the role of "reactive oxygen
species" in particular.
Scientists Bet Half-A-Billion On 150-Year Lifespan
- January 12, 2001 news article concerning a wager between
experts Jay Olshansky and Steven Austad on the maximum expected
human lifespan in 2150.
Faulty Fountains of Youth: Adult Stem Cells May Contribute to Aging
Science News, February 9, 2008
Unlocking the Secrets of Longevity Genes
David A. Sinclair; Lenny Guarente
Scientific American, March 2006,
- A handful of genes that control the body's defenses during
hard times can also dramatically improve health and prolong
life in diverse organisms. Understanding how they work may
reveal the keys to extending human life span while banishing
diseases of old age.
In Pursuit of the Longevity Dividend
S. Jay Olshansky; Daniel Perry; Richard A. Miller; Robert N. Butler
The Scientist, March 2006
- What should we be doing to prepare for the unprecented
aging of humanity?
Sir2: Scrambling for Answers
Maria W. Anderson
The Scientist, June 12, 2004
- Researchers have yet to solidify links for the proposed
Forestalling the Great Beyond with the Help of SIR2
Leonard P. Guarente
The Scientist, April 26, 2004
- A simple genetic program might be altered to prolong and
The Serious Search for an Anti-Aging Pill
Mark A. Lane, Donald K. Ingram, George S. Roth
Scientific American, August 2002,
Making Sense of Centenarians
Science News, March 10, 2001, pp. 156-157
- Studies of centenarians by sociologists, gerontologists, and
geneticists are advancing our understanding of aging.
- Can Human Aging Be Postponed?
Michael R. Rose
Scientific American, December 1999, pp. 106-111
- Aging is a highly complex process. In order to succeed in
extending the life span, anti-aging therapies will need to
address each part of the process.
- Confronting the Boundaries of Human Longevity
S. Jay Olshansky, Bruce A. Carnes, Douglas Grahn
American Scientist, January-February 1998, pp. 52-61
- Humans in developed countries now live far beyond the point
where reproductive success should play a part in natural
selection. The question then is what places biological limits
on life span.
- Mitochondrial DNA in Aging and Disease
Douglas C. Wallace
Scientific American, August 1997, pp. 40-47
- Defects in DNA occuring in mitochondria (and therefore outside
the chromosomes) have been implicated in a variety of diseases,
including degenerative diseases of aging.
Scientists Finding Evidence Of Caloric Restriction's Benefits
The Scientist, May 26, 1997
- Caloric restriction research has come a long way
since Cornell University nutritionist Clyde McCay published
a ground-breaking 1935 paper that showed that rats on
calorically restricted, nutritionally sound diets lived
longer than rats that were allowed to eat as much as they wanted.
- The Oldest Old
Thomas T. Perls
Scientific American, January 1995, pp. 70-75
- Studies of the most elderly individuals -- more than 95 years
of age -- show they are often stronger and healthier than the
average of those 10 or 20 years younger. Determination of the
factors that account for such robustness is a matter of obvious
- Mark Benecke – The Dream of Eternal Life: Biomedicine,
Aging, and Immortality
Columbia University Press, 2002
- Five chapters in this short book cover a large amount of
scientific and philosophical ground. – why death is part
of the normal cellular life cycle, what has been learned about
factors that extend or limit human life span, how biomedicine
may extend typical human life span beyond 100 years, why
immortality might not be such a good thing, and how death
might be seen as giving "meaning" (whatever that is) to life.
There's a lot of factual information here, and just as much
- S. Jay Olshansky; Bruce A. Carnes -- The Quest for Immortality:
Science at the Frontiers of Aging
W. W. Norton & Company, 2001
- The authors are both leading researchers in the science of
aging. Their book is a relatively brief and nontechnical survey
of topics such as the history of the subject, life expectancy,
anti-oxidants, genetic medicine, and prospects for the future.
There is a good deal of debunking of exaggerated claims by
"life extension" enthusiasts of various sorts.
- Tom Kirkwood -- Time of Our Lives: The Science of Human Aging
Oxford University Press, 1999
- Kirkwood is one of the originators of the "disposable soma"
theory of aging and death. His book gives a well-written
presentation of that theory and other topics like why aging
occurs, processes involved with cellular senescence, why women
live longer than men on average, the relationship of cancer with
aging, and possible ways (like caloric restriction) to extend
- William R. Clark -- A Means to an End: The Biological Basis
of Aging and Death
Oxford University Press, 1999
- In this book Clark takes a much more detailed look at
aging and death than he offered in the earlier Sex and the
Origins of Death. Many topics are covered, such as
the relations among aging, senescence, and lifespan, evolutionary
and developmental biology of senescence, human diseases that mimic
the aging process, the apparent effect of caloric restriction on
lifespan, the role in aging played by oxidants and free radicals,
and the effects of aging on the human brain.
- Steven N. Austad -- Why We Age: What Science is Discovering
about the Body's Journey through Life
John Wiley & Sons, 1997
- Austad gives a good presentation of many topics related to
aging. There is a good discussion of the relations between aging,
the rate of living, and lifespan. Questions are asked about
whether aging is genetic and what evolution can explain about
aging. There is much discussion of the process and effects of
aging, and what can possibly be done to slow aging and extend
- John J. Medina -- The Clock of Ages: Why We Age - How We Age -
Winding Back the Clock
Cambridge University Press, 1996
- The first two-thirds of the book gives a detailed description
of what happens to the body in the process of aging. The remainder
considers two theories of aging (accumulation of errors and
genetic program), as well as possible ways to forestall aging.
- William R. Clark -- Sex and the Origins of Death
Oxford University Press, 1996
- Clark is a superb expository writer on biological and
medical topics. This short book takes a high-level view of the
process of death in single cells and multicellular organisms.
The author suggests that the "reason" for death has its origins
in the division of labor between DNA which occurs in germ cells
and in somatic cells.
- Leonard Hayflick -- How and Why We Age
Ballantine Books, 1996
- Hayflick discovered the fact that there is an upper limit
to the number of times a normal cell can divide, the "Hayflick
limit". The book discusses this work, along with a great deal
of other information about the process of aging, possible causes
of it, and how to control it and extend the lifespan.
Copyright © 2002 by Charles Daney, All Rights Reserved