Open Questions: Causes of Aging

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See also: Diet, metabolism, and health -- Evolutionary theory -- Cancer

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


Introduction

What is aging?

The evolutionary perspective

Evolutionary medicine

Caloric restriction and longevity


Recommended references: Web sites

Recommended references: Magazine/journal articles

Recommended references: Books

Introduction

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?


What is aging?


The evolutionary perspective

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.

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) improve faster.)

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 → shorter lifespan
In any 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 in principle 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.

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.


Recommended references: Web sites

Site indexes

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 IU Geriatrics
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, aging-related diseases, healthy aging, and frequent questions.
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 antioxidants, caloric restriction, and theories of aging.
TelDB
An information center for telomere research operated by Washington University. Includes a literature database (through 1999).
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

Senescence
Article from Wikipedia. See also Longevity.
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 life extension.
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."
Smart Exercise
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.
Long-Lived Worms
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.


Recommended references: Magazine/journal articles

Faulty Fountains of Youth: Adult Stem Cells May Contribute to Aging
Patrick Barry
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 longevity lynchpin.
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 improve life.
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
Damaris Christensen
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
Paul Mccarthy
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 interest.


Recommended references: Books

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 philosophy.
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 lifespan.
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 the lifespan.
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.

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Copyright © 2002 by Charles Daney, All Rights Reserved