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The nature of biological aging is one of the most enduring scientific mysteries and has remained unresolved for more then 150 years. The persistence of this issue is itself somewhat amazing. We have landed on the moon and performed other fantastic technical and medical feats. Aging affects the vast majority of people in the developed world. How could it be that such an important question remains unresolved despite such a long duration? Why is funding for aging research relatively miniscule? Why are there still scientific disagreements as to the biological mechanisms responsible for aging and even disagreement as to why aging exists in the first place?

Theories of biological aging fall into two categories. In the programmed aging theories, organisms purposely self-limit their lifespans and possess what amount to suicide mechanisms to accomplish this function. “Programmed” refers to the idea that there exists some sort of internal biological clock and a time-dependent plan or program that directs an internal limitation to lifespan. According to these theories, lifespan is genetically programmed in much the same manner as other internally driven and programmed biological events such as growth, reproductive maturity, mating seasons, birth, and circadian rhythms.

In the second category, non-programmed theories consider that aging is the result of the body’s inability to better combat deteriorative processes that affect all organized systems such as wear-and-tear, oxidation, other molecular damage, or accumulation of toxic byproducts. According to these theories, humans age in a similar manner and for essentially the same reasons as automobiles and exterior paint.

We could say that programmed aging (also known as adaptive aging or active aging) is something our bodies do to themselves while in the non-programmed (non-adaptive, or passive) theories aging is something that happens to our bodies, like an infectious disease or injury.

Although programmed theories were formally proposed as long ago as 1882 non-programmed theories are currently more popular among gerontologists and other medical researchers. However, evidence is steadily accumulating that favors programmed aging and an increasing number of theorists and experimentalists now believe in programmed aging. Which theory is correct has a potentially enormous impact on the future of medicine. The answer to the aging question could easily affect most Americans now alive!

This book explains why programmed aging is the correct theory, why this has major implications for medicine, and why science has been so slow in coming to this conclusion. Along the way, I will introduce you to many people that have had a critical impact on aging theory science and describe the history and current controversies surrounding aging and underlying evolution theories.

Ages of Man – Human Mortality

The figure below [1] describes mortality as a function of age for people who died in the United States from all causes in 1999, that is, the fraction of people that age who died in 1999.

In numerical terms, 0.015 percent of nine-year-olds died, along with 0.09 percent of 22 year-olds, 0.2 percent of 40 year-olds, and 38 percent of 100 year-olds. We can see a number of distinct mortality regimes. First, the age regime between zero and 5 years of age is the infant mortality period. This is followed by the childhood regime between ages of 6 and 14 during which mortality is extremely low. Then we have the adult period between age 15 and age 29 during which death rates are higher but not age-dependent. Adults engage in more dangerous activities than children and are subject to more stress. Starting at approximately age 30, death rates increase exponentially with age, doubling approximately every 10 years. In other words, aging becomes a significant cause of death starting at age 30 (relative to all the other causes of death). Finally, in extreme old age (100+) death rates level off. The message here is that aging is not just a problem for old people. About half of deaths among 40 year olds and 75 percent of deaths among 50 year olds can be attributed to aging.

We can define age-related diseases as those whose incidence or severity dramatically increases with age including heart disease, cancer, stroke, arthritis, and many others. Although all of these diseases have multiple causes, aging is the largest single cause of most of them. We have been extremely successful in finding ways to treat or prevent most of the non-age-related diseases that were the main causes of death in earlier times. It is the age-related diseases that are currently most resistant to prevention and treatment. We cannot hope to understand or most effectively treat and prevent age-related diseases without understanding aging!

A Brief Summary of Aging Theories

Aging is an extremely difficult subject for experimental investigation because of its diffuse and long-term nature. Aging affects many different tissues and systems so researchers cannot study a single tissue as they would in the case of the many diseases that affect only a single tissue. Because of the long-term nature of aging, experiments tend to be extremely expensive and time-consuming. A preliminary experiment to determine if a particular pharmaceutical agent is promising for decreasing pain or killing some pathogen could be performed in a matter of days. Many different agents can be tried in a relatively short time. An experiment to determine if some agent increases lifespan in primates could take decades to perform. This is one reason why progress in understanding aging has been so slow.

Aging theories have historically been very dependent on the point of view of the theorist. For those of us who are exclusively or primarily interested in human aging (most of us including most medical people) wear and tear theories of aging are attractive. These are theories to the effect that aging in humans is simply the result of the sort of generic and inevitable deteriorative processes that cause aging in automobiles, sewing machines, or other inorganic systems. Indeed, we use the same word, aging, (or if you are reading this in England, ageing) to describe gradual deterioration in humans and exterior paint although biologists use the word senescence to mean biological aging. In biological terms, wear and tear would include, in addition to mechanical damage (wear), other forms of molecular damage. For example, Leonard Hayflick in 1961 implicated telomere shortening as an aging process. Telomeres are the end-caps on chromosome molecules and progressive shortening of telomeres is known to inhibit cell division. Telomeres can be repaired by the enzyme telomerase. Vitamin stores have shelves full of antioxidants sold in the hope of slowing oxidation, also implicated as an aging process in common with inorganic systems. Stochastic theories of aging propose that accumulating random changes cause gradual degradation. Other theories propose that accumulation of toxic byproducts causes aging.

Many believers in wear-and-tear theories believe (following logic to be described) that aging is the result of fundamental limitations that cannot be altered by any possible future medical discovery. They consequently tend to logically believe that the study of aging is “academic” in the sense that it has little practical value. Money would be better spent in finding ways to improve prevention and treatment of age-related diseases (about half of the U.S. Government medical research budget) rather than “chasing after the fountain of youth.” Medical research tends to be a “zero-sum-game.” Any addition to funding of one subject implies cuts to the budget allocated to some other subject.

A major difficulty with the wear-and-tear theories comes from observations of many non-human species. Mice and humans are radically different from a naked-eye “macro” viewpoint but are much more similar at the cell level and even more similar at a molecular level. Pharmaceutical research and testing using mice exploits this similarity. Some mice or mouse-like mammals such as the Argentine desert mouse or marsupial mouse have lifespans that are as much as 100 times shorter than human lifespans even though they have very similar biochemistry with presumably very similar exposure to generic molecular deterioration. Some might say that these mammals simply live their lives 100 times faster than humans. No doubt, they have much higher respiration and heart rates. However, again at the cell and molecular levels, differences in metabolism are much smaller than 100 to 1. Elephants and humans have about the same lifespan. Lifespans vary enormously even between very similar species. It is obvious from an even cursory multi-species examination that lifespan differences cannot be explained by generic damage mechanisms that affect all species equally. Why would a crow (lifespan 12 years) wear out about 6 times faster than a parrot (lifespan 70 years)?

Failure of the generic damage theories to explain multi-species observations led eventually to evolutionary theories of aging that try to explain how the observed gross multi-species lifespan differences could have resulted from an evolutionary process in a manner similar to the process that produced all of the other differences in the designs of different species. There are two main schools of thought. One school says that for various reasons, organisms did not need to live longer than some species-specific lifespan (or had a reduced need) and therefore did not evolve and retain the capability for doing so. The other school says that for various reasons organisms needed to limit their lifespans to some species-specific value and therefore evolved mechanisms to purposely self-limit their lives (i.e. programmed aging). Both schools have produced theories that provide a much better match to the multi-species lifespan observations as will be discussed.

The Evolution of Aging

Charles Darwin published his book On the Origin of Species by means of Natural selection or the Preservation of Favoured Races in the Struggle for Life [2] in 1859 and it is still widely seen as the most important single work in the history of bioscience. As indicated above, lifespan appears to be one of the most species-specific of all organism characteristics. Even very similar species sometimes have very different lifespans. Different varieties of salmon have lifespans that vary enormously even though otherwise they appear to be nearly identical. We look to evolution theory to explain why organisms have their particular designs and so it was natural to develop evolutionary explanations for aging.

Unfortunately, major problems immediately appeared. Darwin’s theory, as explained by Darwin and currently taught in high-school biology classes is incompatible with lifespan observations and the resulting issues and controversies have now continued for more than 150 years. General religion-driven controversy about evolution increases the overall confusion and no scientific agreement currently exists regarding evolutionary explanations for aging and lifespan observations.

Prior to Darwin, there was no reason to consider that aging and lifespan were different from any other organism design characteristic. Whatever caused a rat to have beady eyes and a long tail presumably also caused it to have a particular lifespan.

What are the current scientific agreements and disagreements concerning evolution? First, there is no scientific disagreement with the idea that evolution of life on Earth has occurred and that current species including humans are descended from earlier species. The evidence for this is overwhelming. Darwin extensively documented (complete with his own drawings) that species have family resemblances to each other similar to those that exist between individuals and that these resemblances are geographically distributed in a manner that makes logical evolutionary sense. Fossils added to evidence of evolution. Since Darwin, genetic analysis has added extensive confirmation of the idea that species are descended from earlier species and even revealed specific relationships between current species. Mice and humans share a common ancestor that lived about 30 million years ago.

Second, there is no scientific disagreement with the idea that “survival of the fittest” or natural selection is the main driving force behind the evolution process. Suppose we give a high school biology class the following assignment: “Identify one hundred different design characteristics of a zebra. Explain how each one of these characteristics increases the zebra’s ability to survive or reproduce.” The class would have no difficulty in doing this, as there are thousands of such zebra characteristics. Virtually every bone, muscle, tendon, ligament, organ, nerve, blood vessel, and even inherited behavioral trait plausibly contributes to survival or reproduction. Other complex species have drastically different designs from the zebra but in each case the thousands of characteristics of that particular species’ design work together to promote survival or reproduction. In total, there are literally millions of observed organism design characteristics that each obviously add to the individual possessing organism’s ability to survive or reproduce.

For many of us, thinking in “survival of the fittest” terms is second nature learned at a young age:

“Daddy, why does that bird have a sharp beak?”

“Son, he needs a sharp beak to dig worms out of the ground to eat and defend himself from being eaten by the family cat.”

Darwin thought that evolution occurred very incrementally in “tiny steps.” Any sudden large random change (such as a change to the number of heads, limbs, or other major anatomical features) was almost certain to be adverse to survival and reproduction. Evolution therefore involved the very slow accumulation of small changes. The tiny steps concept leads to the requirement that the evolution process must be able to select between very small differences in an organism’s survival and reproductive capability. Is slightly longer claws better than slightly shorter claws? Note that Darwin’s theory is all about the functional or performance aspects of an organism’s design. How well does the design perform in surviving and reproducing?

Darwin discussed natural variation as a required precondition for the evolution process to operate. In order for natural selection to select individuals that were faster, smarter, or better at climbing trees there obviously had to exist individuals that varied with regard to their capability for speed, intelligence, or tree climbing ability. Further, this variation had to exist locally, that is, between individuals that were plausibly in competition with each other.

Darwin claimed to explain how a single, individual, primordial organism on the order of a bacterium could have evolved into all the life forms we see on Earth today in tiny incremental steps with natural selection operating at every step. We can imagine that some sort of cosmic family tree that recorded every organism now alive or that ever lived would show how each of those organisms is descended from that original organism. Incidentally, Darwin did not (contrary to some popular sentiment) claim to know how that original organism came to exist. The step from a collection of simple chemical compounds to an organism capable of living, reproducing, and evolving by itself in an inorganic world, is a very big step.

To summarize, Darwin teaches us that all organisms are trying to live as long as they can and breed as much as they can and are acquiring through the evolution process design characteristics that aid in this quest. Further, organisms can adapt through the evolution process to changes in their external world.

Some additional comments are crucial to subsequent discussion: Darwin did not suggest that the evolutionary value of survival or reproduction varied with the age of an organism. In addition, Darwin considered that the ability to evolve was a fundamental and unvarying property of all living organisms. All organisms were subject to mutational change and natural selection and all organisms could pass their particular designs to descendents through biological inheritance.

Darwin’s ideas were immediately rejected by many on religious grounds, a situation that continues today. Especially in the United States, there are current and well-funded efforts to oppose evolution theory and promote teaching of alternatives such as creationism and intelligent design in public schools and other venues. Creationists contend that all of the existing species were created more or less simultaneously as specified in the Bible and reject the evolution concept. Intelligent design proponents contend that survival of the fittest cannot possibly explain the wondrous variety and complexity of current Earth life and believe that each individual species must therefore have been designed and implemented by some supernatural intelligence. These efforts have been rather effective and recent polls show that a majority of Americans reject the idea that humans are descended from an earlier species. On any Internet forum where biology (or even just “science”) is being discussed one can find endless “scientific” arguments to the effect that this or that observation is a valid basis for completely rejecting evolution theory despite all those millions of supporting observations. Anti-evolutionists exploit the fact that in many ways evolution is difficult science. No one can perform an experiment to see if indeed a primitive organism, given a few hundred million years, would evolve into a human or similarly complex organism. Many other aspects of evolution cannot be tested experimentally.

The pro vs. anti evolution situation has resulted in a polarization in which most people on both sides of the argument see evolution in black and white terms. Either you believe in evolution or you do not. People on the pro-evolution side are extremely reluctant to admit that there is even the slightest legitimate scientific disagreement regarding any aspect of evolution theory lest they give aid and comfort to the enemy. Because schools are the major battle zone, this reluctance is most severe with regard to textbooks and other introductory or educational material. It is extremely unlikely that you will hear in a high school biology class or other introductory venue that there is any scientific disagreement regarding “The (singular) Theory of Evolution.” As we will see this situation affects our collective ability to resolve and act on the aging issues.

Darwin’s theory was elegant, intuitive, simple, and fit the vast majority of biological observations. However, there was a major problem regarding lifespan and aging observations. We can imagine that there are two varieties of some species that are identical except that one variety has a much longer lifespan. According to Darwin’s ideas, it is a “no-brainer”, or in scientific terms, “intuitively obvious to even the most casual observer” that the shorter-lived organism would be at a huge evolutionary disadvantage relative to the longer-lived variety and would quickly become extinct. This was obviously not true. Annual plants live happily alongside similar perennial plants, fish lifespans vary from a few weeks to so long they have not yet even been measured. Contemporaries wrote Darwin and asked why, given his theory, living organisms were not immortal, that is, free of internal limitations on lifespan as opposed to the external limitations extensively discussed by Darwin such as predators, intra-species warfare, environment, food supply, and infectious diseases. If organisms had been trying for billions of years to live longer and breed more, why had they not succeeded? If living longer and breeding more was the driver for evolution, would not each succeeding generation have a longer reproductive lifespan just as they evolved to be stronger, faster, smarter, or otherwise better at surviving and reproducing? This question has now endured unresolved for more than 150 years! The obvious answer, which would occur to any perceptive high school biology student, is that aging and lifespan are imposed by some fundamental limitation such as a law of physics or chemistry that cannot be overcome by the evolution process. Many such laws indeed exist. This is of course essentially a restatement of the wear-and-tear theories. If we believe that lifespan is constrained by fundamental limitations, it logically follows that aging is an unavoidable property of life and that altering the aging process is theoretically impossible. If 3.8 billion years of evolution could not overcome the limitations that result in aging, is it likely that we will ever be able to do so? If, for example, anti-oxidants helped with aging, certainly organisms would have evolved ways to produce more of them. Darwin’s theory, as understood by most people, logically leads to wear-and-tear theories and the impossibility of altering aging. For many people interested only in human aging, this was and is the end of the story. Darwin essentially confirms the wear-and-tear theories.

However, the multi-species observations remained a problem. If aging and lifespan result from fundamental limitations, why do species appear to be designed to have a species-specific lifespan? Why do similar species have grossly different lifespans? Why do many species appear to commit biological suicide and die suddenly immediately after reproducing? Why does the 100-pound (45 Kg.) family dog develop cancer, heart disease, arthritis, cataracts, other age-related conditions, and die about seven times more rapidly than a 100-pound human? Why do some fish live at least 600 times longer than other fish? Darwin could only answer that a shorter life must convey some sort of unknown advantage that compensated for its obvious disadvantage. For biologists, zoologists, naturalists, pet owners, and others aware of multi-species lifespan characteristics, aging remained an “unsolved problem of biology.”

Medawar’s Modification to Darwin’s Theory

In 1952, more than 90 years after Darwin, famous British biologist Peter Medawar (Nobel prize for physiology or medicine in 1960, knighted in 1965) proposed a modification [3] to Darwin’s ideas in an effort to explain mammal lifespan differences. He suggested that mammals only needed (from an evolutionary viewpoint) to have a certain species-specific lifespan and that this lifespan was some species-specific multiple of the age at which the species was first able to reproduce. Once that lifespan was achieved, there was no evolutionary benefit to living longer. For example, a mammal might need to live long enough to reach sexual maturity, mate, produce young, and nurture those young to the point of self-sufficiency, but would not need to live any longer. In terms of prehistoric humans, we could imagine that all of these tasks would be completed by age 30 at the latest.

This idea is very counter-intuitive. A female deer nominally produces one fawn per year. Why would the second, third, or N^th fawn be any less important to the evolution process than the first? Medawar’s analysis assumed that even if a mammal species arose that was immortal and capable of not only living but reproducing indefinitely, that it would not have an evolutionary advantage over an aging version of the same mammal. Deaths caused by external causes such as predators, famine, harsh environment, and infectious diseases would mask the adverse effect of aging. As any cohort (group having the same age) became older, the number of surviving individuals (even if immortal) would become progressively fewer and, as a group, their impact on the evolutionary process would decline to zero.

It is widely agreed that deteriorative processes such as the ones enumerated by the wear-and-tear proponents exist. We also know that living organisms, unlike automobiles and exterior paint, have means to repair damage. Wounds heal, hair and nails grow, dead and damaged cells are replaced. If an organism did not need to live longer than a certain lifespan to fulfill its evolutionary goals, it would not try to resist the deteriorative processes once its designated lifespan had been achieved. Deteriorative changes including random mutations causing damage to the genetic design of an organism would not be opposed by the evolution process if they only caused problems after the designated lifespan had occurred.

Medawar’s idea provided a much better fit to the multi-species observations. A lab mouse is reproductively capable at about 2 months of age and lives to be about 2 years old. A human can reproduce at about 13 years of age and lives to be about 80. It was also obvious that an organism that died of old age at 2 (like a mouse) but was not reproductively capable until 13 (like a human) would not represent a workable design. Clearly, age of reproductive maturity is a factor in determining how long an organism has to live in order to possess at least a minimally viable design. Many organisms including some mammals die after reproducing only once.

Further, it was obvious that a mutation that caused a 100 percent incidence of fetal death or death at any other age prior to puberty would be immediately “selected out” in the first generation and could not propagate in a population. In prehistoric humans, a mutation that caused 100 percent mortality in 80 year-olds would have very little effect because almost no one was living that long anyway. All of the external limitations on lifespan masked the effect of any internal limitation on lifespan that affected only old individuals.

Medawar noted that some human genetic diseases such as Huntington’s chorea only produce adverse symptoms at relatively advanced ages even though the individual has possessed the genetic defect since birth. He thought aging could be the result of a large number of such accumulated mutations each of which only caused problems to older mammals. Even if a species had originally possessed a longer lifespan, perhaps because of being a descendent of a species having an older age of reproductive maturity, unopposed mutations would accumulate and degrade lifespan to fit the criteria. Note that Medawar is thus associated with two ideas: an evolutionary mechanics theory that describes how the evolution process works and is a modification to Darwin’s theory, and a theory of aging mechanisms describing specific biological processes (unopposed adverse mutations) that cause aging. Survival and reproduction are very central to Darwin’s theory. The idea that survival and reproduction have no effect beyond a particular age is a major modification to Darwin’s theory.

Although Medawar proposed his ideas as a solution to the problem of mammal aging there does not appear to be any reason that they would not be applicable to essentially any organism that had a defined age of reproductive maturity. The associated mechanism of aging suggested by Medawar is now known as the mutation accumulation theory of aging.

Many non-mammals had behaviors such as more obviously programmed death that did not fit well with Medawar’s idea and subsequent genetics discoveries exposed additional issues (see Appendix I). Medawar’s idea worked well with mammals such as mice that lived in a world characterized by vicious predation. We can readily imagine that few wild mice would survive long enough to reproduce twice much less even longer. It works less well for species like elephants that have few predators and actually commonly or even typically die of old age (or age-related conditions) in the wild.

Some current theorists consider Medawar to be “the father of modern gerontology” and there is no question that he initiated a completely new approach to the problem of aging.

Williams’ Modification to Darwin’s Theory

In 1957, George Williams proposed an extension of Medawar’s idea [4]. He noted that aging causes not only increased death rate due to internal causes but also causes gradual deterioration in strength, speed, sensory acuity, and many other parameters that obviously would affect survival potential in prehistoric humans or any wild mammal. Under wild conditions, these effects would indirectly increase mortality and thus create an evolutionary impact that began at rather young ages. It was also difficult to believe that subsequent reproduction following initial capability would have zero evolutionary benefit despite Medawar’s analysis. He consequently proposed another evolutionary mechanics alternative to Darwin and Medawar. His suggestion was that after achieving an age similarly determined by age of initial reproductive capability, the evolutionary value of additional life declined but not to zero, effectively splitting the difference between Darwin and Medawar. This raised an obvious question: If extended life had even a very small benefit, why did not evolution find a way to make short-lived mammals live at least as long as long-lived mammals? We all have eyebrows even though they presumably only result in a minute advantage. Why would we not live longer if it resulted in even a tiny advantage? To solve this problem, Williams proposed that there existed many hypothetical beneficial organism design properties that were rigidly linked to aging in such a way that an organism could not merely evolve the beneficial property without incurring the penalty of aging. Because the evolutionary benefit of further life had declined there could now exist a tradeoff between properties that created even minor beneficial effects for younger animals and the consequent unavoidable loss of further life due to aging. The evolution process therefore accepts aging in order to obtain the unspecified linked properties that benefit younger mammals where the evolutionary value of life and reproduction is greater.

Williams postulated the necessary rigid linkage based on a genetics-based concept called antagonistic pleiotropy and stated that according to his theory, medical intervention in the aging process was “impossible.” Rigid in this context means that no matter how long a period elapses and no matter how long the evolution process attempts to remove the linkage and evolve the beneficial property without the harming effect of aging, it cannot. This is crucial to Williams’ concept because there is no general reason to believe that a shorter life would have had any less of a disadvantage for the long series of ancestor species that preceded any current species.

Many other theorists built on the idea that aging results from rigid linkage between aging, seen as a mildly adverse property per Williams’ concept, and some beneficial property and that consequently a tradeoff could occur. A medically popular idea is that human aging is an unavoidable side effect of some process that attacks cancer. If we did not age, many more would develop cancer at an earlier age and the evolution process has been unable to find a way to oppose cancer without incurring aging. There is extensive evidence from non-human sources (see Evidence) contravening this idea.

Williams also proposed a mammal theory and disregarded non-mammal evidence although again there does not appear to be any reason for his idea to apply only to mammals. Efforts to experimentally demonstrate Williams’ idea such as by finding some beneficial property having a strong negative correlation to lifespan have been unsuccessful. Since Williams suggested that many beneficial properties might be linked to aging, this would be difficult to do. See Appendix I for more problems with the antagonistic pleiotropy theory.

Thomas Kirkwood proposed a modification or sub-theory to Williams’ idea in 1975 [5]. He suggested that, given Williams’ idea that the evolutionary value of life declined following reproductive maturity, a tradeoff could exist between living longer and reproduction. It is clear that reproduction requires major energy and material resources. Kirkwood suggested that maintenance and repair of mammals also required substantial energy and material resources and that therefore a tradeoff could exist between not providing as much maintenance and accepting aging in return for enhanced reproductive capability in younger animals. This idea is now called the disposable soma theory of aging. Soma refers to the non-reproductive aspects of an organism, which were being traded against reproductive aspects. Like the others, disposable soma was proposed as a mammal theory even though apparently applicable to non-mammals. Efforts to establish a strong correlation between reproduction and lifespan have failed and extensive observational evidence against and logical flaws with the disposable soma theory have been identified by opponents. See Evidence and Appendix I.

All of these theories suggest that the evolutionary benefit of survival and reproduction declines (or disappears completely) with age at some point following reproductive maturity and thus key lifespan to reproductive maturity. These are non-programmed theories because the lack of evolutionary motivation to live longer does not provide any evolutionary reason for purposely limiting life. According to these theories, there is no evolutionary disadvantage in living too long, only the relative lack of an evolutionary advantage. Consequently, there is no evolutionary motivation for developing biological mechanisms that purposely limit lifespan and aging occurs “by default” or “by neglect” rather than “purposely.”

These theories are slightly more optimistic regarding the potential for medically altering the aging process. Rather than resulting from fundamental laws of physics or chemistry, aging is the result of a potentially large number of separate and independent design deficiencies that affect the organism’s ability to live longer than its species-specific target age. Possibly some way will eventually be found to compensate for at least some of these deficiencies (see Mechanisms).

You may have noted that these alternatives to traditional theory only claimed to explain mammal aging and thereby avoided discussion of contrary evidence from non-mammal species. The above non-programmed theories attacked each other and failed to match many observations beyond lifespan variation. Attempts to verify predictions of the theories generally failed and proponents of programmed theories have written extensively exposing apparent logical flaws (see Appendix I). None of these theories achieved general acceptance although they continue to be favored by many gerontologists and other medical researchers.

Evolution Theory’s Individual Benefit Clause

It is a basic tenet of traditional Darwinism that an evolved design characteristic must benefit the possessing organism’s personal or individual ability to produce adult descendents. I like to call this the individual benefit clause of traditional Darwinian theory. Darwin’s idea was that by living longer and/or breeding more an individual organism propagated its personal design in the population of its species. Darwin thought that design changes originated in a single individual and spread because they increased the ability of possessing individuals to survive and reproduce. He thought that individuals were in competition with other members of their own species in a dog-eat-dog contest to see which could survive longer and reproduce more. Although species compete with each other, competition was more severe between members of the same species because they had the same requirements for food and habitat. Elephants are not really in competition with ants but do compete with other elephants. This is an aspect of traditional Darwinism that makes some people uncomfortable beyond religious considerations because many aspects of human society and civilization, in addition to most religions, involve individual sacrifice in favor of group benefit. One answer to this problem is to say that civilized behavior is one characteristic that separates humans from animals but Darwin’s major and most controversial message is that humans are merely another species of animal, produced in the same way in response to the same sort of conditions.

We can summarize the individual benefit clause as saying that an evolved design characteristic must result in a net increase (after any tradeoffs) in the ability of individual organisms, their mates, or direct descendents to survive or reproduce. All of the previously described theories at least nominally satisfy the individual benefit clause.

When I talk about aging, somebody typically says, “Of course there is no evolutionary motivation to live longer than the age at which an organism stops reproducing and no 80 year-old women are producing children.” This is more or less true as far as it goes. Some have pointed out that grandmothers provide nurturing to their own grandchildren that can increase the survival potential of those direct descendents. Therefore, the existence of post-reproductive grandparents in humans, other mammals, and possibly other organisms that nurture descendents could aid in survival of their personal descendents. This is one of the species-specific factors that affects how long beyond reproductive maturity an organism needs to live in Medawar’s scenario. However, in a larger sense, the question is: What causes limits to the age at which reproduction can take place? If the limitation is purposely caused by the design of the organism (it is designed to stop reproducing at some species-specific age), that has the same problems with traditional Darwinism as an organism being designed to die at a certain age. Why would an organism acquire a design that limited its own ability to reproduce? Why did the organism fail to evolve the means to reproduce longer? If the limitation is due to some fundamental limitation, then why do species vary so greatly regarding reproduction? All of the theorists mentioned in this book consider that upper age limits on reproduction are a symptom of aging and not an evolutionary cause of aging as suggested by the questioner. A hypothetical immortal organism would be able to reproduce indefinitely. Some organisms (see Evidence) apparently do not age and do not suffer age-related decline in reproductive capability.

More Discrepancies with Traditional Darwinism – Group Selection

Around 1960 theorists were increasingly concerned with other observations (beyond the lifespan observations) that seemed to conflict with traditional Darwinism, particularly with the individual benefit clause. Some cooperative behavior between animals such as might be observed in herds, flocks, and packs can be justified within the individual benefit context because such cooperation might well increase the probability of individual survival. However, some observations of animal behaviors referred to as altruism did not seem to produce an individual benefit but rather seemed to involve an individual disadvantage in favor of a group benefit. For example, it was common to observe an animal protecting the young of an unrelated member of the same species at risk to itself but without apparent individual benefit. This led to another proposed modification to Darwin’s ideas: In 1962, V. C. Wynne-Edwards proposed that a group benefit could trade off against an individual disadvantage and result in group selection of an individually adverse design characteristic like altruism [6]. Eventually, others proposed different “levels” of group selection. Perhaps a trait producing an individual disadvantage could benefit relatively closely related individuals in kin selection. Perhaps it could benefit the herd, flock, pack, or other local group in small group selection. Ultimately, perhaps an individually adverse characteristic could actually benefit the species or even future descendent species in species-level group selection.

It might appear that if a population or species became extinct it would hardly matter if it did so because of an individual disadvantage or a group disadvantage. Dead is dead. However, there is a timing issue. Darwin tells us that design traits spread because the possessing individuals live longer and breed more. The obvious question with group selection is: How does the propagation of an individually adverse design characteristic take place for long enough that the group benefit such as non-extinction of a herd, larger population, or species could be achieved? An individual disadvantage seems to operate much more rapidly than a group benefit. The larger the group the longer it would appear to take for a group benefit to be felt as the design change propagated and the more difficult it would apparently be for an individual disadvantage to be overridden by a group benefit.

Traditional Darwinists and believers in Medawar’s and Williams’ modifications rejected group selection and accused group selectionists of ascribing human characteristics to animals in connection with altruism. George Williams, defending his own alternative to Darwin, wrote a book in 1970 dedicated to attacking group selection [7] and some of his followers still consider it a “definitive demolition” of group selection. Nevertheless, today one can find theorists that ascribe to each of the above described levels of group selection in addition to traditional Darwinists and adherents of Medawar’s or Williams’ modifications.

Gene-Oriented Selection

In 1975, Richard Dawkins proposed yet another adjustment to Darwin’s ideas in his book The Selfish Gene [8]. Dawkins attacked group selection and suggested his own replacement. He proposed for complex genetic reasons that an individually adverse organism design characteristic like altruism could be propagated and retained by the evolution process if it produced a benefit to the propagation of genes that were common to a population. A tradeoff could exist between gene benefit and individual disadvantage. Functionally, this was a replacement for group selection that, like group selection, allowed violation of the individual benefit clause.

A common theme should be emerging. All of these post-1962 modifications allow a tradeoff between individual disadvantage and a more diffuse larger benefit and thus attack the individual benefit clause. They speak to the following question: How does extinction or non-extinction of a group of members of a species relate to the survival or non-survival of individuals?

It should be clear by now that there is currently substantial, long-term, and continuing scientific disagreement regarding the finer details of evolutionary mechanics. These disagreements result from apparent discrepancies between scientific observations and the predictions of traditional theory and are absolutely crucial to evolutionary theories of aging.

More Discrepancies – Evolvability Theory

My involvement in all this started in the early 1990s. I had earlier graduated from MIT with a degree in electrical engineering and gone to work in the aerospace industry. One of my main responsibilities was designing and implementing digital data systems to be used in spacecraft and ground systems that handle digital data being produced by NASA’s scientific instruments in space.

Biological inheritance mechanisms are essentially digital data systems that provide for the transmission of digital data (in the form of a genetic code) between the parent(s) and descendents of any living organism. The transmitted genetic data specifies the inherited design of the descendent organism. As Watson, Crick, and Franklin famously demonstrated in 1953 [9], the digital data is conveyed via the sequence of bases in DNA molecules. One base (or base-pair, or nucleotide) corresponds to two bits of digital data. The inherited design of a human is specified by about 6.6 billion bases or about 1.6 gigabytes of digital data. An E coli bacterium is defined by about 1.1 megabytes of inherited digital data.

I began to study biological inheritance, originally in the hope of finding some aspect of the natural digital systems that could be applied to man-made digital systems. Eventually it became clear that the digital nature of biological inheritance systems provided clues that might aid in resolving the endless arguments regarding the details of the evolution process and consequent nature of aging because many fundamental properties of digital systems constrain both nature and NASA. These digital genetics clues join many others that favor evolvability theory and evolvability-based theories of programmed aging to be described. Along the way, I worked briefly for the U.S. National Institutes of Health developing electronics for medical research and learned quite a bit about the medical research establishment. I have since been writing about evolution, aging theories, and other technical subjects.

A number of other apparent discrepancies between traditional Darwinism and biological observations have appeared in addition to the lifespan and altruism observations, particularly regarding the individual benefit clause. Here is a brief list:

-Some mating rituals, obviously arising from evolved behavioral characteristics, appeared to be individually adverse. Bighorn sheep have a mating ritual that involves head-butting contests to select those to be allowed to mate. Naturalists estimate that a typical sheep becomes reproductively capable at 2 years of age but does not actually mate until age 5 or later. The sheep therefore appear to have an evolved design characteristic (the inherited mating behavior) that limits reproduction and is therefore individually adverse. Sheep that did not have this trait would be able to mate earlier and therefore have an individual advantage over sheep that had the trait. Why did this trait continue to exist?

-Many reptiles and fish have very late ages of reproductive maturity relative to other similar species. Would this not be an individual disadvantage, especially in males? It does not appear to be plausible that there is some fundamental limitation that delays maturity in the case of an organism that is similar to another organism that does not have the limitation.

-Especially for species such as reptiles that do not nurture or protect their young, sexual reproduction appears to be grossly individually adverse relative to asexual reproduction. In sexual reproduction, which evolved after asexual reproduction, only half of the animals (the females) can produce descendents, a factor-of-two reduction in reproductive capacity relative to asexual reproduction where all of the organisms can produce descendents. What individual benefit compensated for this massive individual disadvantage and allowed evolution and retention of sexual reproduction? Other aspects of sexual reproduction also appear to be individually adverse. For example, sexual reproduction in diploid organisms like mammals results in a situation in which, because of the possibility of a recessive trait, mildly individually adverse traits would tend to propagate better and mildly individually beneficial traits would propagate less well than in the case of asexual reproduction. This is counter to Darwin’s propagation concept. Why would an organism adapt and retain a reproduction method that interfered with its ability to propagate individually beneficial characteristics and enhanced the propagation of individually adverse characteristics?

-Inheritance is crucial to evolution theory because design changes are propagated by means of inheritance. Genetics discoveries including the previously mentioned digital data aspects have exposed steadily increasing detail regarding the design of organism inheritance mechanisms. As you have already read, Medawar and Williams based their ideas, in part, on various aspects of inheritance. Some aspects of inheritance mechanisms also appeared to conflict with the individual benefit clause (see Appendix II).

Evolvability

In the early 1990s G. Wagner, L. Altenberg, and others began publishing articles about evolvability, that is, the design aspects that are required in order for a system to have the capacity for evolution [10]. This has resulted in yet another proposed adjustment to traditional Darwinism. Recall that Darwin thought the capacity for evolution (we can call this evolvability) was a fundamental and constant property of all organisms. The evolvability concept defined here is that at least for complex sexually reproducing organisms, evolvability is largely the result of evolved design characteristics and that therefore evolvability can and does vary between populations and species. An increase in evolvability represents an evolutionary advantage because possessing organisms could evolve (adapt to changes in external conditions) more rapidly than competing organisms that possessed less evolvability. Proponents of evolvability theory (including me) believe that an organism characteristic that increases evolvability but is somewhat individually adverse can nevertheless evolve and be retained in an organism’s design. This is key to the evolvability argument because most organism characteristics that appear to improve evolvability are individually adverse or at best, neutral. Evolvability advantage can thus trade off against individual disadvantage. This is of course a violation of the individual benefit clause and traditionalists, Medawarists, and Williams followers consider evolvability a form of group selection (by default – it is obviously not individual selection). Worse yet, because evolvability appears to benefit the species or even future species, it could be considered a form of species-level group selection, widely seen as the least feasible of the group selection levels.

An organism’s need for evolvability would tend to be driven by conditions in its external world comprised of predators, prey, environmental conditions, pathogens, etc. Some species, the cockroach is always mentioned in this regard, seem to be able to live for very long periods without significantly evolving. Mammals and other complex species essentially drive their own evolution and create need for evolvability. As predators evolved, prey had to evolve. As prey evolved, predators had to evolve. Even if environmental conditions and other factors remained constant, mammals and other complex organisms would be under more or less continuous evolutionary pressure and differences in evolvability would be more significant to their evolutionary success. Proponents (including me) claim that all of the above apparent discrepancies with traditional Darwinism including programmed aging can be explained by compensating evolvability benefits.

The previously mentioned digital genetics analysis showed that variation is not natural in digital systems such as the biological inheritance system. Digital systems naturally produce exact copies. The variation we see in complex organisms is actually mainly the result of a large number of obviously evolved complex mechanisms that comprise sexual reproduction. Hence, sexual reproduction while individually adverse produces a major evolvability advantage by greatly increasing local variation. For more on this subject see Appendix II.

There does not appear to be much scientific opposition to the idea that species could vary with regard to their ability to evolve and there are many characteristics that vary between species that plausibly alter evolvability. There is also little opposition to the idea that a population that could evolve more rapidly would have an evolutionary advantage. The major objection by traditionalists and followers of Medawar and Williams is to the idea that an evolvability or group benefit could override an individual disadvantage and therefore cause a characteristic having an evolvability benefit and individual disadvantage to be selected and retained by the evolution process. See two specific counter arguments in Anti-Aging Research.

To summarize, an evolvability characteristic enhances the rate at which a possessing species can evolve in response to changes in its world. Such characteristics work by either increasing local variation or by increasing the effective difference between competing individuals and thereby enhancing the selection process. You will recall that Darwin specified that variation was a required precondition for the evolution process to function.

It is important to note that the diffuse benefit theories originated from a need to explain discrepancies between traditional theory and observations other than aging and lifespan.

Diffuse Benefits of Programmed Aging

A number of diffuse (non-individual) benefits of a design-limited lifespan have been proposed. Joshua Mitteldorf proposed in 2004 that a limited lifespan could provide a group benefit by limiting feast-famine swings that would otherwise occur in a group [11]. Programmed aging would therefore increase the probability that a population would avoid extinction. Giacinto Libertini discussed kin benefits of programmed aging in 1988 [12].

A limited lifespan has multiple evolvability benefits [13]. For example, the rate at which evolution takes place is nominally inversely proportional to lifespan. We can consider the life of an organism to be a trial, in a probability sense, of its particular design. If that design results in surviving longer and reproducing more, then that life is a vote “for” that design. If not, it is a vote “against.” The lifetime of one organism is mainly determined by chance or luck. The lives of many organisms having a particular design allow the evolution process to make very fine determinations regarding the effectiveness of the design. The evolution process is therefore essentially counting votes. Following this logic, the rate at which trials are conducted, and therefore the rate at which evolution proceeds would be inversely proportional to the average lifespan of the organisms. Therefore, a shorter lifespan favors the evolution process. Of course, it is also true that evolution of adult characteristics requires adults. The death of an immature organism does not contribute a trial regarding performance of adult characteristics and therefore does not contribute to evolution of adult characteristics. A baby gorilla is functionally very similar to a baby human in terms of its survival capability; the major differences only appear in the adults. We can therefore introduce the term adult death rate. The more organisms that live to become adults (and die as adults), the more trials of adult characteristics take place. Organism characteristics that increase adult death rate therefore increase evolvability. In other words organisms have to live long enough to become reproductively mature and express adult performance characteristics but not too much longer in order to maximize evolvability. This is very similar to Medawar’s and Williams’ ideas regarding the relationship of lifespan to reproductive maturity except, in this case there is an evolutionary disadvantage to an excessively long life. A disadvantage provides an evolutionary rationale for programmed aging and other biological mechanisms that purposely limit lifespan. Note that the idea that a limited lifespan can produce diffuse benefit introduces the concept of optimum lifespan. The optimum lifespan would occur at the age when the declining individual and evolvability disadvantage of too short a life just balanced the increasing evolvability and/or group disadvantage of too long a life.

Another evolution issue surrounds organism design characteristics that depend for their utility on the acquisition of something that accumulates during the life of the organism. The problem here is that in the absence of a limited lifespan the acquired characteristic would be competing with the inherited design characteristic and acting to inhibit the evolution process. For example, I have suggested [14] that the evolution of intelligence would be difficult unless the lifespan of the possessing organism was limited, thus adding to the evolvability advantage of a limited lifespan in the case of complex organisms possessing nervous systems. This is because intelligence is useless without acquired knowledge and acquired knowledge is useless without intelligence. Similar arguments can be made about immunity and other organism characteristics that involve long-term accumulative acquisition of properties that affect fitness.

Another benefit of programmed death concerns genetic diversity or variation in a population. In an immortal population, some individuals would live very long lives and produce very many descendents. This would tend to adversely affect genetic diversity and variation and thus adversely affect evolvability. This problem is worse in more complex organisms because of social characteristics such as pecking order.

Again, there is little scientific opposition to any of these proposed evolvability or group benefits of a purposely limited lifespan. The objection is to the idea that an individually adverse characteristic, regardless of any group or evolvability benefit, would propagate and be incorporated and retained in an organism’s design.

Vladimir Skulachev [15] and I [14] have proposed that gradual aging produces an evolvability advantage over sudden biological suicide by increasing the apparent difference between more and less fit individuals and therefore enhancing the evolution process. Gradual aging provides a challenge that can be overcome by a more fit organism increasing selection differential.

One of the counterintuitive aspects of programmed aging is illustrated by this question: How could an organism, or organisms generally, evolve myriad design characteristics that help them live longer and breed more while simultaneously evolving a complex suicide mechanism that purposely limits lifespan and reproduction? Is this not obviously contradictory? The key to understanding this is that it is common for organisms to have contradictory goals at different ages. Programmed aging proponents say that prior to their optimum lifespan organisms indeed have an evolutionary motivation to live longer and breed more but that after that age they have an evolutionary motivation to limit lifespan and consequently reproduction. An organism can have different and conflicting requirements at different ages. For example, the North American Magicicada or 17-year locust lives in the ground as a digging animal for 17 years then changes into a flying animal for a few days, reproduces, and dies. As a nymph, the cicada has zero flying ability. As an emerged adult, it has zero digging ability.

The cicada is also interesting in that its entire life is obviously not only “programmed” but also extremely precisely programmed. The life spans of the cicadas in a particular brood match within about 0.1 percent! I think that this is not achieved using internal chemical clocks, which tend to be rather inaccurate, but rather involves detecting external cues including seasonal or even daily cycles and possibly the loud sounds made by previously emerged cicadas.

Weissmann’s Programmed Death Theory

An Austrian biologist named August Weismann proposed a programmed death theory of aging in 1882 [16]. He suggested that programmed death of older animals freed resources for younger animals. According to Darwin’s “tiny steps” idea, evolution proceeded in small increments and therefore the younger animals could be assumed to be minutely more evolved than the older animals. Therefore, favoring younger animals favored the evolution process by plausibly increasing the rate at which evolution takes place. Weismann’s was therefore the first evolvability theory of aging and adds to the list of proposed evolvability benefits of a limited lifespan.

Weismann was literally ahead of his time. There did not exist at the time any contemporary theories of evolutionary mechanics that supported the necessary violation of the individual benefit clause. In addition, although some efforts were made, nineteenth century bioscience was incapable of finding the extensive evidence for programmed aging that currently exists. Weismann eventually recanted his theory, probably because of peer pressure and the above problems.

Evidence Exclusion Principles

As every scientist knows all too well, it is possible to “prove” essentially any theory by the trivial expedient of considering only evidence that confirms the theory and excluding all observations and other evidence items that conflict with the theory. Using this approach, it is easy to “prove” that the Earth is the center of the Universe, or that evolution theory is “wrong,” or that NASA never went to the moon.

In a legal proceeding, both sides of an issue are represented and strict rules, enforced by a judge, control exclusion of evidence. In science, it becomes an “exercise for the reader” to note what evidence is being excluded and whether or not a seemingly valid reason is given for such exclusion. It turns out that this is especially crucial when evaluating biological aging theories.

For example, it might seem perfectly reasonable for an article about a human aging theory, written by someone interested in human aging, for an audience interested only in human aging, for publication in a journal on human aging, and peer reviewed by people interested in and knowledgeable about human aging, to exclude all mention of contrary evidence from non-human sources. However, as we have seen the most compelling evidence against wear-and-tear theories comes from non-human sources, particularly the gross lifespan differences between various similar species.

A seemingly more hypocritical instance of spurious evidence exclusion comes from proponents of evolutionary mammal aging theories who claim that other mammals are relevant to human aging specifically citing the lifespan variations, but that contrary non-mammal observations like negligible senescence, octopus suicide, or worm experiments (see Evidence) are “irrelevant” to mammal aging theories.

The major difficulty with these efforts at evidence exclusion is that evolutionary aging theories such as the mammal theories are based on evolution theory and evolution theory is specifically represented as applying to all living organisms. In order to properly exclude non-mammal data, the proponent must supply some plausible rationale as to why his theory only applies to mammals. This is very infrequently done. Caveat lector!

Evolutionary Mechanics Theories -- Current Summary

Where does all this leave us regarding the relationship between evolution theory and aging? Let us define extended life as that part of an organism’s lifespan that exceeds some species-specific multiple of the age at which it is first reproductively capable. There are four current factions in the small academic community of evolutionary mechanics theorists. These factions differ depending on how they handle extended life and how they handle the individual benefit issue:

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