The chart below shows USA 1999 deaths from all causes as a function of age at death (National Center for Health Statistics). This is a log chart. The probability of death increases exponentially from about age 30, doubling approximately every seven years. In other words, aging is a major contributor to death rate starting at age 30 and about half of deaths of 37-year-olds are attributable to aging. Curiously, death rates level off and even decline slightly for extremely old (100+) people.

Evolution Theory and Aging

Charles Darwin¹ published his book On the Origin of Species in 1859 and proposed that current organisms were descended from earlier species and further that the evolution process was directed by natural selection or “survival of the fittest.” Darwin thought that evolution was very incremental and occurred in “tiny steps.” The differences between a human and a single-cell organism were the result of accumulating these minute increments for billions of years. Note that this idea requires that the natural selection process be capable of distinguishing between minute differences in survival or reproductive capability. It was understood that the design of anything involves myriad compromises or tradeoffs. Strength might be a tradeoff with speed. A water buffalo might have the same ability to survive and reproduce as a gazelle.

It was widely known prior to Darwin that the design of a species could be altered by selective breeding (and by extension, natural selection). However, it was also known that no amount of selective breeding of dogs could ever create a cat. Selective breeding (and natural selection) can only alter traits that vary between interbreeding individuals. Species (essentially by definition) differ in regard to design characteristics that do not vary between individuals. Therefore, there was no apparent way that natural selection could create a new species. Darwin’s idea was that occasional inheritable mutations to individual organisms created new small variations within a species on a time scale that was so slow as to be unobservable.

There is currently no scientific disagreement regarding the idea that evolution of Earth life has occurred and the vast majority of biological observations match Darwin’s concept. Introductory biology courses currently teach that Darwin’s natural selection theory is scientifically generally accepted as the complete and comprehensive explanation for the evolution process.

However, in connection with aging and life span observations, major difficulties immediately appeared. Darwin’s idea was that random small mutational changes to organisms propagated in a population if they increased the ability of the organisms possessing them to survive and reproduce. Darwin did not suggest that the evolutionary value of survival or reproduction varied as a function of age. If an organism could survive longer and reproduce more, that was good; if it could survive and reproduce yet longer, that was even better. There was no reason to believe that the N^th descendent of a parent organism was any less important to the evolution process then the first descendent. Therefore, according to Darwin, the force of evolution was toward achieving immortality or the absence of internal limitations to life span or reproductive capability in addition to adapting to external conditions that imposed limitations on life span and reproduction.

It was immediately apparent that Darwin’s idea did not match aging and life span observations. Critics wrote Darwin (c. 1859) and asked, in effect: If natural selection had been accumulatively operating for billions of years selecting longer and longer lived individuals, why hadn’t immortality been achieved? If there was some fundamental age-dependent limitation to life span (or reproduction) such as a law of physics or chemistry that could not be overcome by the evolution process, why were life spans of similar species so different?

Another aspect of Darwin’s theory that is important to subsequent discussion is the idea of individual benefit. Although Darwin never used that term, subsequent interpretation of Darwin’s propagation concept seemed to logically require that individual organisms survive longer and breed more in order to propagate their individual designs. Evolved organism design characteristics including inherited behavioral traits should therefore benefit individual organisms and their direct descendents against competing members of the same species. This is the “dog eat dog” aspect of Darwinian evolutionary mechanics theory. Darwin considered that competition was fiercest between members of the same species because they, by definition, had the same requirements for food and habitat. Strict Darwinists currently believe that a design characteristic that benefits species survival or provides other more diffuse “group” benefits cannot evolve if it causes any disadvantage to the ability of individual organisms to survive and reproduce.

Since such a large proportion of observations conformed to Darwin’s idea, it was reasonable to assume that eventually we would find a conforming explanation for life span observations. This did not occur. In the intervening 150 years, theorists have proposed a number of different minor modifications to Darwin’s natural selection theory in order to accommodate aging as well as some other apparent conflicts between Darwin’s theory and observations. As described in the following sections, these modifications logically result in very different aging theories, which in turn predict dramatically different concepts for biological aging mechanisms.

Most people are under the impression that there is currently no scientific disagreement with natural selection theory (not true). Apparent discrepancies between natural selection and observations have steadily increased since Darwin. Here is a brief list of apparently conflicting observations.

Aging and life span. See above.

Altruism. Animals are observed to act in a manner not consistent with their individual best interest.

Excess age of reproductive maturity. Reproductive maturity in many animals (especially males) is delayed relative to the age plausibly required for its development, often apparently an individual disadvantage.

Mating rituals. Some mating rituals appear to represent individual disadvantage.

Biological suicide. Some instances of biological suicide present no apparent offsetting individual benefit (see octopus below).

Sexual reproduction. Sexual reproduction appears to often represent a massive individual disadvantage relative to asexual reproduction (see appendix).

Inheritance mechanisms. Many genetics discoveries raise issues with traditional natural selection theory.

Since 1962, theorists have formally proposed a number of general adjustments to natural selection theory in response to the observed discrepancies. They all suggest that more diffuse benefits in addition to individual survival or reproductive benefit can influence the evolution process.

Group Selection. A group benefit² can offset an individual disadvantage.

Kin selection. Benefit to a small related group³ can offset individual disadvantage.

Gene-oriented selection. A benefit to propagation of genes can offset individual disadvantage (e.g. R. Dawkins⁴ Selfish Gene Theory)

Evolvability. A benefit to the evolution process⁵ can offset individual disadvantage.

None of these alternative theories suggests that Darwinian natural selection is not the most important force behind the evolution process. They all suggest that other, more subtle and diffuse factors can also influence the evolution process. Proponents claim that these theories provide explanations for all of the listed discrepancies and defend violation of the individual benefit requirement with complex arguments often based on modern genetics discoveries (see Appendix).

The primary scientific objection has historically concerned propagation. Some proponents of traditional Darwinism still contend that it is “impossible” for a characteristic to propagate and be retained in a population if it causes a net individual disadvantage, regardless of any diffuse benefit.

All of the alternative theories support the idea that a limited life span could produce a selectable evolutionary benefit and that therefore organism design characteristics that purposely limit life span could be evolved and retained. Aging theories proposing specific non-individual benefits for a design-limited life span have been proposed for most of them. Aging theories to the effect that evolved organism design features purposely limit life span in order to obtain a non-individual benefit are called programmed aging theories. The first such theory was proposed by August Weismann in 1882. Weismann thought that self-limited life span or “programmed death” aided the evolution process by increasing resources available for younger and therefore minutely more evolved individuals. Since then, many other non-individual benefits for self-limited life span have been proposed⁶. Some theorists use the term adaptive aging to mean programmed aging. Aging is an adaptation that evolved because it provides a useful function.

As will be described in the next section, other theorists have proposed changes to Darwin’s theory that are specific to the aging/life span issue in order to support various non-programmed theories of aging in mammals.

As a further confusing factor, there is substantial religious objection to both the idea of evolution and the idea that natural selection could be a comprehensive explanation for the existence of current species, especially humans. Resulting pseudoscience proposals (creationism and intelligent design) obscure genuine scientific issues surrounding evolutionary mechanics.

Evolutionary Value of Life

The evolutionary benefit or cost of a particular organism life span is central to evolutionary theories of biological aging.

The sketch below illustrates four different scientific concepts regarding the evolutionary value of life as related to age of reproductive maturity. The benefit or cost is a measure of evolutionary force toward adapting changes in the design of an organism. Each of these concepts logically leads to an entire family of corresponding biological aging theories that in turn logically lead to particular concepts regarding the aging process.

Everybody agrees that it is beneficial for an organism to live long enough to reach reproductive maturity and that degradation due to internal limitations (aging) prior to that point would represent an evolutionary disadvantage. Further, as illustrated, life span beyond the minimum required for reproduction would be useful for organisms such as mammals and birds that need additional time to protect, nurture, or train their young. Other characteristics of specific species could affect details of the evolutionary benefit of life and therefore the shape and length of the curves below.

The germane scientific disagreements concern the later (older) portions of the curves during which aging occurs.

Darwin, (interrupted horizontal line 1), did not suggest that the evolutionary value of survival varied with organism age. Any incremental increase in life span added to an organism’s opportunity for reproduction and therefore created evolutionary benefit that continued indefinitely. The force of evolution was therefore toward development of immortality. Darwin’s critics immediately noted that most organisms were not immortal and that life spans varied greatly between otherwise similar organisms. Further, some plant and animal species died immediately after reproducing for the first time. These observed conflicts with Darwin’s idea eventually led to development of the other three concepts.

Peter Medawar⁷ (solid line 2) proposed in 1952 that the evolutionary benefit of extended (substantially beyond age of reproductive maturity) life span in mammals becomes so negligible as to have no evolutionary effect at some species-specific age linked to reproductive maturity. Genetic drift could then introduce random changes that cause aging as long as their negative effects only occurred subsequent to that age. This led to the mutation accumulation theory of mammal aging. A yet longer life span has negligible evolutionary value but no disadvantage. His argument was that few wild mammals live long enough for aging to become a problem and the few that do have little effect on the evolution of a population. Wild organisms are subject to external limiting factors such as predators, intra-species warfare, harsh environment, lack of food supply or habitat, and infectious diseases. According to Medawar, a wild population of non-aging mammals would be very similar to a population of aging animals and would evolve in exactly the same way.

Many other proponents of non-programmed mammal aging (e.g. G. Williams⁸, T. Kirkwood⁹) subsequently proposed (dotted line 3) that the evolutionary benefit of additional life span free of the deleterious effects of aging never declines to zero, essentially splitting the difference between Medawar and Darwin. A longer life would allow progressively more opportunity for reproduction and consequently at least some advantage in the propagation of an individual organism’s design. In addition, aging causes degradation at relatively young ages and this degradation has obvious negative effects on survival potential. These theorists therefore proposed that aging must be an unavoidable adverse side effect rigidly linked to some beneficial design property or properties. Because, according to this concept, the evolutionary benefit of life declines once an organism has had some opportunity to reproduce, the ultimately catastrophic disadvantage of aging could be outweighed by a relatively smaller compensating advantage to younger animals. The assumed rigid linkage prevents the evolution process from producing a design that accomplishes the benefit without the adverse side effect. Note that both concepts 2 and 3 were developed prior to the development of any of the alternative evolutionary mechanics theories mentioned earlier.

Finally, advocates of programmed aging^10,11,12,13 (dashed line 4) contend that beyond some species-specific life span, also dependent on age of reproductive maturity, additional life span creates an evolutionary disadvantage and that therefore organisms evolved mechanisms for proactively regulating their life spans to achieve an optimum life span. In this case, there would be evolutionary force (f) to both achieve the species-specific optimum life span by means of myriad evolved survival characteristics and to avoid exceeding it by means of an evolved life span regulation mechanism. Because, unlike the other concepts, there is evolutionary force toward limiting life span, there is an evolutionary rationale for the development of a complex mechanism to accomplish the limiting function. In a manner similar to many evolved mechanisms, such a regulation mechanism could include means for detecting local or temporary external conditions and optimizing an individual’s life span to fit those conditions. This concept provides a much better fit to empirical evidence than the others but requires a larger, more general, adjustment to Darwin’s idea than concepts 2 and 3.

Important Note: All of the concepts discussed here assume that reproductive decline with age is a symptom of aging not an evolutionary cause of aging. A non-aging organism would have no decline in its reproductive capability with age. If an organism had an evolved design that purposely limited its reproductive capability (e.g. otherwise unnecessary delay in reproductive maturity or purposely limited maximum reproductive age), that would present the same evolutionary issues as a design that purposely limited life span. If there was some fundamental age-dependent limitation to reproduction, why did it not apply to similar species? Some apparently non-aging organisms exist (see below) that indeed do not display either reproductive decline or decline of survival characteristics such as strength, mobility, or sensory acuity.

No one has a means for assigning any absolute value to curves 2, 3, and 4. The endless argument between proponents of these three concepts can thus be summarized: Is the evolutionary value of extended life zero, at least minutely positive, or at least minutely negative? As we will see in the next section, this hair-splitting determination defines theories of biological aging and dramatically affects the nature of aging mechanisms predicted by the theories.

Because the differences between these value-of-life concepts (especially 2, 3, and 4) involve subtle secondary effects and complex processes operating during millions or billions of years, proving that any one of them is correct has eluded science. There is no scientific agreement regarding value-of-life. All four concepts, encompassing all of the possibilities regarding evolutionary value-of-life relative to reproductive maturity, have current followers.

There is an interesting dichotomy here: Proponents of creationism or intelligent design contend that it is “impossible” that evolutionary mechanics science will ever explain how current species came to exist and that therefore God or some other source of supernatural intelligence must have directed and implemented the design of each current species. They are not pressing similar claims about geology or astronomy, which have similar direct conflicts with religious teachings.

At the polar opposite extreme, some current theorists (see quote below) contend, in effect, that it is “impossible” that their particular current evolutionary mechanics concept (e.g. value-of-life concept 3) could be less than perfectly correct and comprehensive and that therefore any conflicting empirical evidence (or theories) must be incorrect. Claims by current scientists that multiple competing scientific theories and observations are “impossible” are essentially unheard of in other scientific disciplines. Such claims in evolutionary mechanics are likely to be at least partly a reaction to the existence of intelligent design. Recognizing that there is any scientific disagreement regarding evolutionary mechanics would result in increasing already substantial pressure to include intelligent design as a “scientific” alternative to natural selection, especially in American biology textbooks.

“The way evolution works makes it impossible for us to possess genes that are specifically designed to cause physiological decline with age or to control how long we live.” L. Hayflick, et al, Scientific American, 2004.

Aging Mechanisms and Processes

This section summarizes four concepts regarding the processes and mechanisms that are associated with biological aging in humans and other organisms. There is relatively wide agreement that deteriorative processes that cause molecular damage are involved in the aging process. The concepts below illustrate that dramatically different aging mechanisms could exist that are all based on deteriorative processes but different value-of-life concepts. Each successive concept incorporates and is built upon the previous concept and is consequently more complex. Successive concepts provide progressively better fit to empirical evidence and additionally suggest more points at which we could attempt intervention in the aging process.

1. Simple Deterioration

Premise: Aging is simply the result of accumulative deteriorative processes such as oxidation, telomere shortening, other molecular damage, stochastic (random) changes, wear and tear, and disease-specific processes such as accumulation of cell mutations (cancer), or accumulation of blood vessel deposits or damage. Potentially many deteriorative processes are involved although some theorists believe one or another such as oxidation or telomere shortening dominates. This is the only one of the four concepts presented here that is compatible with Darwinian evolution theory and value-of-life concept 1 as taught in introductory biology classes. Consequently, most people are logically driven toward believing in simple deterioration theories. These theories tend to suggest that aging is an unalterable fact of life resulting from fundamental limitations. Billions of years of evolution that have resulted in human brains, eagle’s eyes, and other marvels of life have been unable to overcome aging.

Telomeres are “end caps” on chromosomes. Progressive shortening of telomeres during cell division has been implicated as an aging process, most notably by L. Hayflick¹⁴ in 1961. Telomeres can be repaired by the enzyme telomerase.

Empirical Evidence: There is wide agreement that deteriorative processes exist and cause gradual deterioration in inorganic and organic systems. However, the simple deterioration concept provides a poor fit to empirical evidence. In particular, it does not explain the very large differences in life spans observed between very similar species that presumably have very similar exposure to generic deteriorative processes.

Intervention: Agents such as anti-oxidants could be sought that directly interfere with a deteriorative process. It is common practice to seek agents that interfere with disease-specific deteriorative processes such as anti-cholesterol medications.

2. Maintenance and Repair

Premise: Deteriorative processes exist but are countered and offset by maintenance and repair mechanisms whose effectiveness varies between species. The existence of these mechanisms, corresponding to the respective deteriorating processes, slows accumulation of the deteriorating effect. The effectiveness of the maintenance and repair mechanisms varies between species because evolutionary force to develop and maintain them varies according to value-of-life concept 2 or 3. Organisms with later ages of reproductive maturity needed to live longer and therefore developed and retained more effective maintenance mechanisms. Life span is not primarily limited by fundamental limitations but rather by differences in the efficiency with which different species combat deteriorative processes, an idea that increases the plausibility of intervention.

Empirical Evidence: This concept fits gradual aging and the multi-species life span variation in mammals. Additionally, we know that various maintenance mechanisms exist: hair grows, wounds heal, dead and damaged cells are replaced, and infections are combated.

Intervention: In addition to the above, we could seek agents that act to increase the effectiveness of the maintenance mechanisms, such as by increasing production of naturally occurring anti-oxidants or telomere repair enzymes.

3. Programmed Aging

Premise: Deteriorative processes exist and are offset by maintenance mechanisms but the maintenance activities are in turn modulated (attenuated) by a species-specific genetically specified biological program to result in the observed species-specific life spans. The program involves some sort of biological clock or method for determining when to slow the maintenance functions. The program and clock could be common to multiple maintenance mechanisms suggesting that signaling is involved. This idea logically descends from value-of-life concept 4. Organisms need to limit their life spans because doing so produces an evolutionary advantage according to one of the alternative evolutionary mechanics theories.

Empirical Evidence: In addition to fitting the multi-species life span observations, this concept fits discoveries of genes that cause aging in various species. It also fits observations of species such as salmon that die suddenly or age very rapidly at some point in their lives in that a program calling for that behavior is easily visualized whereas the necessarily gradual accumulation of un-repaired damage postulated in mechanism concept 2 has difficulty. Further, this concept fits observation of human genetic diseases that simultaneously cause acceleration of many (progeria) or most (Werner syndrome) symptoms of aging as these conditions could be affecting a common program controlling multiple maintenance functions.

Intervention: In addition to all of the foregoing, we could seek agents that interfere with the operation of the clock or interfere with associated signaling. Signaling in this context refers to chemical signals such as hormones that are used to coordinate biological processes within an organism or even between organisms (pheromones).

4. Regulated Programmed Aging

Premise: Deteriorative processes exist and are offset by maintenance mechanisms but the maintenance activities are modulated by a genetically specified species-specific biological program, which in turn can be adjusted by sensing of external conditions that act to alter the optimum life span.

Empirical Evidence: In addition to all of the above, this concept fits observations of explicit life span regulation in various organisms (C. Kenyon¹⁵, et al). It also fits observations that life spans are increased by external conditions that would nominally be expected to increase deterioration such as caloric restriction or stress because sensing of these conditions could be adjusting life spans. Known biological clocks are commonly adjusted by sensing of external conditions. For example, mating seasons and circadian rhythms are synchronized to planetary cycles.

Intervention: In addition to all of the above, agents could be sought that interfere with sense functions or associated signaling.

All of these aging mechanism concepts have associated evolutionary rationales that attempt to explain why the particular mechanism should have evolved or been retained in the designs of the possessing organisms. The evolutionary arguments involve evolutionary value-of-life concepts that attempt to explain why evolution would select more effective or less effective maintenance mechanisms (concept 2) or even select mechanisms that purposely limit (concept 3) or regulate (concept 4) organism life span. Concept 4 requires substantially the same evolutionary assumptions as concept 3 but provides a better match to empirical evidence.

Since all four aging mechanism concepts involve deteriorative processes, research into direct intervention with those processes (concept 1) is the least controversial. However, ignoring the other concepts despite their superior match to empirical evidence is likely to result in missing major opportunities for successful intervention in aging processes and consequent treatments for age-related diseases and conditions.

Major Non-Programmed Theories

Many gerontologists believe one of the following competing non-programmed theories:

The mutation accumulation theory (P. Medawar⁷, 1952) proposes based on value-of-life concept 2, which Medawar originated, that aging is effectively the result of myriad universal genetic diseases. Each of these only creates problems in the age regime during which there is no evolutionary value to further life and has therefore not been selected out by the evolution process. Medawar cited Huntington’s chorea as an example of an age-related genetic disease.

The antagonistic pleiotropy theory (G. Williams⁸, 1957) proposes based on value-of-life concept 3, which Williams originated, that mammal aging is the result of myriad adverse side effects rigidly linked to various unknown individually beneficial characteristics. If the side-effects caused problems only in later life the associated benefits to younger mammals could provide a valid tradeoff. Pleiotropy refers to the observation that a single gene often affects different and diverse phenotypic properties and that thus there exists a linkage between those properties that would be difficult for evolution to overcome, preventing the evolution process from finding a way to accomplish the benefit without the side-effect. Williams concluded that based on his theory, medical interference with the aging process was “impossible.” See Appendix for more on this theory.

The disposable soma theory (T. Kirkwood⁹, 1977) proposes that maintenance and repair of a mammal requires substantial resources and is therefore a valid tradeoff with reproduction, (which obviously requires substantial food and energy resources) based on value-of-life concept 3. Mammals consequently did not evolve the maintenance mechanisms required for longer life.

All of these mammal aging theories have been extensively criticized by proponents of programmed aging theories. They all require one of two proposed aging-specific modifications to traditional Darwinism in the form of value-of-life concepts 2 or 3 but do not require one of the more general (and more recent) alternative evolutionary mechanics theories as needed by programmed aging theories based on value-of-life concept 4.

Empirical Evidence on Aging

This section presents a summary of experimental and observational evidence that provides insight into aging mechanisms.

Life Span Regulation by Sensing of External Conditions

Some investigators^15,16 report instances in which life span of simple organisms is mediated or regulated by sensing of external signals. This is typical of evolved mechanisms. In mammals, major internal biological processes are often regulated by sensing of external conditions. Examples: Circadian rhythms and annual reproductive cycles synchronize bodily processes to planetary cues.

Caloric Restriction and Life Span

Extensive experimental evidence¹⁷ confirms that mammal life spans are typically increased, as much as doubled, when food intake is restricted and that life span continues to increase all the way to semi-starvation levels. Programmed aging theorists suggest that this behavior was selected because of evolutionary benefit. The caloric restriction effect has a group benefit in enhancing the survival potential of a group under famine conditions because a population that increased its life span while reducing its reproductive activity could survive as long with less food than another population of otherwise identical animals that did not extend their life spans and therefore had to reproduce more to maintain the same population. This idea assumes that a shorter life has an evolutionary advantage but that a tradeoff between restricting life and group survival exists. Merely surviving does not take as much energy or food as reproducing. This is a proposed example of an organism modifying an evolved genetically controlled behavior in real time to fit temporary external conditions.

Non-programmed theories have difficulty explaining the caloric restriction effect. A reduction in food would presumably reduce the resources available for maintenance and repair increasing deterioration.

Some efforts are underway to find a “caloric restriction mimetic” that would simulate the caloric restriction effect by interfering with signaling, without requiring caloric restriction.

Stress and Life Span

Experimenters have found that several forms of stress¹⁸ in addition to caloric restriction counter-intuitively increase life spans in various organisms. For example, exercise appears to increase life span and inactivity decreases life span. Followers of programmed aging theories suggest that this is also a selectable behavior with group benefit in a manner similar to caloric restriction. If a population of animals was under heavy predation, its members would no doubt feel more stress than another population that had few predators. If such a population increased its life span, that would tend to compensate for the higher death rate caused by predation. The adapting population would therefore have a competitive advantage over a non-adapting population.

Non-programmed theories have difficulty with the stress response. Stress would presumably increase the rate at which deterioration occurred.

Aging Genes

Several experimenters¹⁹ have reported discovering genes that limit life span in various organisms. Deleting the genes through genetic engineering has resulted in life span increases of as much as a factor of six. Operating (expressed) genes and their associated products and processes are generally accepted to be evolved features of an organism. Programmed aging proponents say aging genes are parts of evolved mechanisms that purposely limit life span. Followers of non-programmed aging theories based on value-of-life concept 3 contend that the deleted genes must all have some individually beneficial function that compensates for their individually adverse nature. To date, no such function has been found.

Cynthia Kenyon is a leading experimentalist in this area and has found aging genes, internal hormone signaling (e.g. between digestive system and aging function), and instances where a life span regulation system is mediated by detection of external signals. Valter Longo has also found experimental evidence for programmed aging.

Hutchinson-Guilford Progeria and Werner Syndrome

Hutchinson-Guilford progeria²⁰ and Werner syndrome²¹ are single-gene human genetic diseases that dramatically accelerate multiple symptoms of aging. This suggests that there are mechanisms that are common to multiple manifestations such that a single-gene malfunction could affect multiple symptoms. This fits programmed aging theories (common life span management system) better than non-programmed theories in which multiple maintenance and repair mechanisms independently evolved.

Negligible Senescence

Organisms that do not possess deterioration with age²² are important to aging theories and aging research because they suggest that aging is not the result of some fundamental and unalterable limitation and additionally provide clues distinguishing various theories.

Senescence refers to gradual deterioration with age (aging) and is typically very obvious under protected (zoo) conditions. More specifically, senescence refers to deterioration in survival parameters such as strength, mobility, and sensory acuity, age-related increases in disease incidence and associated death rate, and decrease in reproductive capability. Death rates for humans and most animals dramatically increase with age beyond reproductive maturity. Senescence refers to internal causes of deterioration and restricted life span as opposed to external causes such as pathogens, predators, harsh conditions, and lack or food or habitat.

A very few species exhibit negligible senescence (NS). Theorists consider an organism negligibly senescent if it does not exhibit any measurable decline in survival characteristics such as strength or mobility with age, does not have a gradually increasing death rate with age, and in addition does not exhibit any measurable reduction in reproductive ability with age. The few NS species live among a wide variety of similar senescing species.

Some examples:

The Aldebra giant tortoise has a measured maximum life span (so far) of 255 years.

The Rougheye rockfish (Sebastes aleutianus) has been measured at 205 years.

Lobsters are also believed to be negligibly senescent and even apparently have increased reproductive capacity with age.

The lake sturgeon (Acipenser fulvescens) is long-lived (152 years) and may be NS.

The naked mole rat (Heterocephalus glaberis) is the only one of approximately 5500 mammal species believed to exhibit NS. These approximately mouse-size (35 grams) rodents have been observed to live 28 years vs. 1-3 years for similarly sized rodents and longer than any other rodent. Cancer has not been observed in this species.

Some clams such as Panopea generosa have long lives (~160 years) and may be NS.

The oldest known single living organism is the “Methuselah Tree,” a bristlecone pine located in California and currently 4842 years old.

Organisms that do not age or age immeasurably slowly still die of external causes such as predator attack, accident, starvation, exposure to adverse environmental conditions, and infectious diseases. Extremely old specimens are therefore extremely rare. In some cases, measuring the age of a caught wild specimen requires killing the animal in order to measure age marks (similar to tree rings) on internal bones. We therefore have no way of knowing the maximum age that could be achieved by one of these organisms. Note that the key point with NS is lack of gradual deterioration. A hypothetical species that lived for 20 years without measurable deterioration and then died suddenly from some internal process such as semelparity would still be considered a NS species.

Theories to the effect that gradual deterioration is an unavoidable result of fundamental physical or chemical limitations obviously have a problem with NS. Although there are differences in metabolism between species, which could be considered differences in the rate at which the organism lives its life in a deterioration scenario, these differences are insufficient to explain the enormous differences in observed life spans, especially between species with similar metabolisms.

Semelparity and Biological Suicide

Many species of plants and animals reproduce only once (semelparity) and die suddenly after reproducing. The pink salmon dies suddenly after reproducing (at two years of age) of an apparently accelerated aging process. Some varieties of salmon survive one or two spawning periods then die suddenly following the second or third spawning showing that reproduction and associated stress is not the cause of death.

The male marsupial mice are the only semelparous mammals and die suddenly following mating at about 10 months of age.

A common explanation for semelparous behavior (compatible with value-of-life concept 3) is that suicidal behavior allows the organism to be reproductively more effective and therefore is a valid individual-benefit tradeoff with self-limited life span. In the case of the salmon, some theorists contend that the dead bodies of parents provide nutriment for their spawned immediate descendents (an individual benefit). Programmed aging proponents contend that design-limited life span has a direct evolutionary benefit.

The octopus has an especially interesting semelparous behavior. The female octopus reproduces, broods her young, and then dies of starvation. It starves because it does not eat. It does not eat because it no longer feels hunger despite its starving condition. Experiments in which the eyes were surgically removed (Wodinsky²³) resulted in octopi that continued to eat and survive after reproducing. This demonstrates that the octopus has a complex suicide mechanism that involves connections to the nervous system to implement the behavior modification function, suggests that signaling is involved, and suggests a sense function is involved in determining when to execute the starvation behavior. This closely resembles the system described in concept 4 of the aging mechanism section. Further, the suicide of the octopus does not have any apparent individual benefit.

Evolution of Antagonistic Characteristics

Many people have a conceptual difficulty with programmed aging: How could an organism evolve myriad characteristics that obviously enable it to live longer and breed more, while simultaneously evolving characteristics that purposely limit life span (or reproduction). The key here is the idea that an organism can have different requirements at different ages, which is easily observed in nature. 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 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!

Programmed Cell Death -- Apoptosis

It is common for organisms to purposely kill their own cells (apoptosis) via a complex evolved mechanism in furtherance of growth or development tasks. Programmed organism death or phenoptosis is seen as a logical extension by proponents of programmed aging. Study of apoptosis might provide insight into aging mechanisms.

Superficial Nature of Life Span

Some characteristics of organisms vary significantly between very similar species and even between members of the same species. We think of these differences as being superficial in that they only weakly affect survival or reproductive fitness and therefore there is little natural selection force toward selecting one variation over the other. In humans, eye color apparently does not affect fitness significantly and therefore varies while eyebrows, as universal human features, are presumed to provide at least some minute survival or reproductive benefit.

Using this same logic, it is apparent that in some animals life span is superficial. Different varieties of salmon, otherwise very similar, have grossly different life spans. Other similar fish species have even more variation in life spans. Where it might appear that the shorter-lived varieties would be at a huge disadvantage that would rapidly result in their extinction, this is not the case. Apparently, if such an organism lives long enough to reach the age at which it can initially reproduce, nature does not care very much how much longer it lives.

These observations obviously conflict with the idea that life span is determined by fundamental limitations and also conflict with the idea that extended life span necessarily incurs some sort of individual penalty such as reduced reproductive effectiveness or loss of some other individually beneficial function.

Some theorists favoring evolvability theories suggest that the disadvantage of extended life is more severe in the case of more complex organisms that display intelligence or immunity.

Similarity of Aging Symptoms

Although there are some differences, different mammals generally share the same manifestations of aging. Cats and dogs, although having dramatically shorter life spans share human manifestations such as cancer, heart disease, stroke, arthritis, cataracts, general weakness and loss of mobility, loss of sensory acuity, mental deficits, etc.

In connection with the maintenance and repair scenarios described earlier, one might imagine that different deteriorative processes would operate over many different time regimes. Red blood cells might die in a matter of weeks while cancer could take multiple decades to develop. Shorter-lived animals would not need to have maintenance mechanisms directed at counteracting long-term deteriorative processes.

However, if this were so we would expect to see different manifestations in different species. For example, we would not expect to see cancer in cats and dogs or shorter-lived species if it takes decades to develop. Consequently, this observation suggests that the deteriorative processes generally operate over a rather short term and that therefore all of the mammals need all of the maintenance and repair processes.

Biological Inheritance Mechanisms

All living organisms transmit digital information concerning their designs to their descendents via inheritance mechanisms such as sexual or asexual reproduction. These mechanisms are critical to the evolution process because mutational changes propagate via inheritance. Since Darwin, we have exposed enormous complexity in inheritance mechanisms much of which has plausible impact on the evolution process. Most of the previously mentioned alternative theories are either directly based on genetics discoveries (e.g. gene-centered theories) or otherwise supported by such discoveries, some rather recent. The inheritance process is still imperfectly understood. Some very recent discoveries in epigenetics have the potential to radically change the way we think about biological inheritance.

Consequently, the evolution process that seemed so simple, elegant, intuitive, and certain in 1859 or even 1950 now appears to be much more complicated, messy, and uncertain.

One genetics-based concept, antagonistic pleiotropy, has been cited by proponents of both programmed and non-programmed aging theories as a justification for their positions! See appendix for more regarding effect of genetics discoveries on evolutionary mechanics theories.

Evolvability Issues

Darwin did not consider that the ability to evolve was a species-dependent variable. All living organisms were subject to mutations and natural selection. Darwin did say that natural variation in inheritable design characteristics between members of a species population was essential to the evolution process. If there was no variation there would be nothing for natural selection to select.

Since Darwin, it has become apparent that many characteristics of particular species could affect the evolution process. Brief examples: Sexual reproduction produces more variation than asexual reproduction. Mating rituals that involve some sort of contest (e.g. Bighorn sheep) could enhance selection of characteristics that are tested by the contest. A shorter life span (beyond maturity) produces an evolvability advantage because the natural selection rate is proportional to adult death rate. A hypothetical species that did not ever die (even from external causes) could not evolve. Other evolvability advantages of a limited life span have been proposed and some theorists even suggest that gradual aging contributes more to evolvability than sudden death in semelparity. The ability to adapt more rapidly certainly seems to represent a competitive advantage.

The major current scientific disagreement in this area concerns whether a characteristic that produces an evolvability advantage can be selected, propagated, and retained by the evolution process if it also produces a traditional individual fitness disadvantage. This is key because evolvability characteristics generally produce fitness disadvantage or are, at best, neutral regarding individual benefit. Proponents of evolvability theories suggest evolvability explanations for all of the previously mentioned apparent discrepancies with traditional theory, and suggest solutions for the propagation issues.

Major discussions regarding evolvability are relatively recent (1995+) and post-date development of the major non-programmed aging theories. See appendix for more discussion of evolvability.

Evidence Applicability

An obvious question: Does an octopus (or worm, or fly, or fish, or even mouse) observation have any significant relevance to human aging? Many articles about human aging essentially ignore contrary evidence from non-human sources. Articles about mammal aging often ignore non-mammals while simultaneously insisting that other mammals are relevant to humans. Could a valid case be made that many of the above observations are irrelevant to human aging? The difficulty with this is that the principles underlying aging theories are extremely broad in scope. Evolution theory is specifically proposed as applying to all living organisms. The value-of-life concepts are similarly widely applicable. Mice are used as lab animals precisely because they are so biochemically similar to humans. Any suggestion that a particular observation is irrelevant should be accompanied by a plausible explanation as to why that should be the case. This is infrequently done; caviat lector.

Anti-Aging Medicine

We can define anti-aging medicine as protocols or agents that simultaneously beneficially affect two or more otherwise unrelated major manifestations of aging such as cancer and heart disease. As indicated earlier, most people are essentially trained to believe that anti-aging medicine is impossible because aging is the result of fundamental limitations. Many physicians share this view and such a view has been historically protective because of the many quacks and scammers that promote worthless aging remedies.

However, this view mediates against anti-aging research and is therefore a self-fulfilling prophecy. Attempts to find anti-aging agents are widely seen as a foolish “chase after the fountain of youth.” Few budding researchers want to embark on a career in which progress is widely seen as “impossible.”

In addition, aging is surrounded by moral, ethical, sociological, and even religious issues that do not apply to other areas of medicine. Very few people are adverse to developing treatments for or ways to prevent cancer yet informal polls indicate that as many as half of Americans have at least some issue with attempts to “treat” aging so as to extend “normal” human life span. Treating cancer is seen as extending productive life. Treating aging is seen as potentially extending the “nursing home stage” of life and “playing God.” In reality, an anti-aging agent or protocol acts to ameliorate or delay onset of age-related manifestations such as cancer. The best anti-cancer agent may well eventually turn out to be an anti-aging agent.

Public education regarding aging theory and underlying evolution theory is important because medical research is largely funded by taxes and charitable contributions.

Regardless of one’s view concerning theories of aging it is becoming increasingly clear that aging is more plastic (alterable) than widely thought. It is increasingly accepted that behavioral protocols such as exercise and caloric restriction can delay aging. There is clinical data suggesting that some agents such as aspirin and statins have a simultaneous beneficial effect on both cancer²⁴ and heart disease. Many items of empirical evidence previously mentioned strongly suggest aging is alterable.

A very minor improvement in human life span would have major public health impact. A ten percent increase in the life expectancy of, say, rabies patients would have little impact because so few people contract rabies and a ten percent increase in post-diagnosis life span would be insignificant. A ten percent relaxation of aging characteristics would add about six years to typical life expectancy!

Anti-Aging Research

Here are brief descriptions of a few current anti-aging research efforts:

Homo Sapiens Liberatus is an organization directed by Vladimir Skulachev, Dean of Bioengineering at Moscow State University. Recent projects include the SkQ Project to explore the use of mitochondria-targeted cationic plastoquinone derivatives (SkQs) as antioxidants specifically quenching reactive oxygen species produced by mitochondria, an event interrupting the aging program, and consequently providing treatment agents for various age-related diseases. Preliminary results in treatment of age-related eye diseases are encouraging. Skulachev is a proponent of programmed aging.

Biotime Inc. in Alameda CA (CEO Michael D. West) is investigating altering the telomere clock, telomerase therapy, and other approaches to regenerative medicine.

SENS Foundation is an organization operated by Aubrey de Grey in Cambridge, UK. Although a controversial figure, de Grey edits a journal Rejuvenation Research that attracts serious articles and has a respectable impact factor. He is a proponent of non-programmed aging.

Exeter Life Sciences is a company operated by John Sperling and Jonathan Thatcher in Phoenix AZ for research into stem cells and regenerative medicine. Their emphasis is on near-term practical applications.

Summary Conclusions

Because of the ongoing scientific disagreements regarding the relationship between aging and evolution, and the simultaneous more general disagreements regarding applicable details of evolutionary mechanics, evolution-based aging theories have been notably unsuccessful in definitively explaining why we age or in aiding experimental efforts. Worse yet, despite considerable contrary evidence, many evolution-based theories either strongly imply or explicitly state that altering the aging process is “impossible” discouraging research and inhibiting funding.

-Aging remains an “unsolved problem of biology.” There is no scientific agreement regarding how or why we age.

-We cannot really understand or most effectively treat cancer or other massively age-related disease without understanding aging.

-Different theories predict very different aging mechanisms and processes. They also produce very different predictions regarding the feasibility of interfering with the aging process.

-The choice of theories is largely between better fit to empirical evidence or better fit to traditional Darwinian evolutionary mechanics theory.

-Traditional Darwinism conflicts with observations other than aging resulting in multiple proposed alternatives since 1962. Our collective certainty that we completely understand the evolution process has declined. Evolutionary mechanics, an arcane area of academic science, has potentially large practical implications for public health.

-Solving the mystery of aging is within our current biotechnology capability. What is needed is the will to do so.

References

1. Charles Darwin, On the Origin of Species, 1859, ISBN 0-375-75146-7

2. Wayne-Edwards V. Animal Dispersion in Relation to Social Behaviour, Edinburgh: Oliver & Boyd, 1962

3. Hamilton, W, The Evolution of Altruistic Behavior, American Naturalist 97:354-356, 1963

4. Dawkins R. The Selfish Gene, 1976 revised edition 1986, Oxford University Press ISBN: 0-19-286092-5

5. Weismann, August, Uber die Dauer des Lebens, Fischer, Jena

6. Goldsmith T. The Evolution of Aging. ISBN 0-978-87090-5. 2006.

7. Medawar P. An Unsolved Problem of Biology. 1952. H.K. Lewis & Co., London.

8. Williams, G Pleiotropy, natural selection and the evolution of senescence. 1957. Evolution 11, 398-411

9. Kirkwood T.B.L. & F.R.S. Holliday, The evolution of ageing and longevity, 1979. Proceedings of the Royal Society of London B 205: 531-546

10. Skulachev V. Aging is a Specific Biological Function Rather than the Result of a Disorder in Complex Living Systems: Biochemical Evidence in Support of Weismann's Hypothesis. Biochemistry (Mosc). 1997 Nov;62(11):1191-5.

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Appendix – Evolutionary Mechanics Issues

This appendix provides some more detail on unresolved arguments that have concerned the tiny community of evolutionary mechanics theorists for at least 50 years and summarizes a few of the many genetics discoveries that affect modern thinking about evolutionary mechanics. As noted earlier, there are two main schools of thought: The traditional or “Darwinian” school believes that “individual” selection essentially as taught by Darwin comprehensively explains the evolution process while the other school believes that at least some general adjustment (such as one of the alternative theories like group selection or evolvability) is necessary to explain observations. There is little opposition to the idea that an organism trait could produce a group or evolvability benefit. The major question is: Can an organism trait that produces a net decrease in the ability of an individual organism to propagate its personal design still propagate and be retained? If so, how? See two proposed affirmative answers below.

Evolution discussions tend to be rather philosophical and involve “apples and oranges” comparisons that are very difficult to quantify. Would an increase in litter size and consequent improvement in reproductive capability compensate for the associated increase in maternal and offspring death rates?

Delayed Benefit Issue

All of the alternative theories (group selection, kin selection, evolvability, and gene-oriented selection) propose that a more diffuse benefit can offset an individual disadvantage. These benefits appear to require a much longer time period than individual advantage for their beneficial effect to be obtained. For example, a shorter life span would appear to be an immediate disadvantage to every organism possessing that design. Whether or not a species does or does not become extinct operates on a very much longer period. Evolvability also appears (see below) to be a long-term issue. If a species could not adapt it might still continue to exist for a long time. Is this not a very long-term issue relative to whether individuals die early?

This suggests a crucial question: Can a long-term benefit (no matter how large) offset a short-term disadvantage (no matter how small)? Some theorists believe in “species-level group selection”, that a benefit to species survival could offset at least minor individual disadvantage; some believe only properties creating benefits to smaller groups that would become effective in a shorter time would propagate and be retained. Traditionalists reject group selection completely. Note that this takes the apples and oranges problem to a completely new level: Can future apples offset present oranges? How should future benefit be discounted relative to present cost?

This question is in turn very dependent on the speed with which the evolution process is seen to operate. If the process is very slow to react then the difference between “short-term” and “long-term” would be less significant.

In this connection, most people think of selective breeding. If we took the tallest male and female dogs in the world and breed them we could produce yet taller dogs in a few generations, an eye-blink of evolutionary time. This conveys the impression that natural selection works very rapidly. The enormous anatomical differences between dogs show what can be accomplished with selective breeding in a relatively very short time.

However, there is a major difference between selective breeding and evolutionary natural selection: The breeder is attempting to enhance some specific design parameters and does not care too much about the inadvertent changes to other parameters that typically occur. Evolution “cares” about the combined net effect of all of an organism’s design parameters on survival and reproduction. This is one reason domesticated species seldom survive long in the wild.

Genetics discoveries have exposed the fact that different evolutionary processes operate over a very wide range of time periods. Let us imagine that an organism needs an evolutionary change. An anteater needs a longer snout because ants are building deeper nests. The evolution process needs to accomplish this change without randomly disturbing any other unrelated design parameters because any such changes are nominally adverse. The following describes the major differences in time regime that might be required.

-If the change can be accomplished by merely recombining genetic differences that already exist in the local population of a species, the change could be produced very rapidly. This is the kind of change that can be produced by selective breeding. For reasons described above, this is unlikely to satisfy the evolutionary need to produce the change without adverse changes to other parameters. In the human population, only about 0.1 percent of genetic data varies between individuals and it is unlikely that wild populations of other mammals have even that degree of variation. The other 99.9 percent cannot be altered by selective breeding or natural selection.

-If the change can be accomplished by means of a new mutation to a single gene (in addition to recombination), it would take much longer. We would need to wait until that particular mutation occurs and propagates. This is also unlikely because changing just one gene is likely to introduce adverse changes to multiple unrelated design parameters, the antagonistic pleiotropy problem.

-If the change can be accomplished by making many complementary mutational changes to many genes, it would take still longer. This is the level likely required to produce the anteater’s snout and represents the genetic differences seen between mammal species.

-If the change requires creation of a functionally new gene, we can readily imagine it might take very much longer and yet, as organisms became more complex, new genes were clearly periodically required. The creation of a functionally different new gene involves massive “chicken and egg” problems associated with signals, receptors, etc. and operates on a time scale that is long relative to the time individual species exist. Genes are consequently substantially conserved between mammal species regarding their gross functionality although they vary as to details. This is the basis of the “selfish gene theory.” Gene lifetime is generally longer than species lifetime.

Linkage and Rigidity

The above discussion described a few of the different ways in which a particular organism design parameter could be linked to other design parameters. There are other ways in which linkages could occur and it is increasingly apparent that the specific design of an organism’s genome affects the path evolution follows and thus affects the evolution process.

We can use the term rigidity to describe the difficulty and therefore the time regime necessary for the evolution process to remove a linkage and allow the existence of the particular parameter without the previously linked parameter(s). How many of the above-described steps would be required for such a change? How long would it take for the evolution process to accomplish a particular change without associated linked adverse changes?

It does not appear that linkage is generally a problem within the time period a species exists. If one compares say, foot designs of various mammals, they all seem to have different designs tailored to each species’ needs. Each foot parameter seems to be independently adjustable between species. None appears to be linked to some other parameter in ways not consistent with physical requirements.

G. Williams, in 1957, described how linkage due to antagonistic pleiotropy between aging, a mildly individually adverse characteristic, and some unspecified individually beneficial characteristics could result in evolutionary retention of aging despite its individually adverse nature.

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