New Theories Support Lifespan Extension – Aging as a Life-Cycle Trait

Programmed aging theories propose that aging in humans and other animals is purposely caused by a complex biological mechanism that evolved because species that age have evolutionary advantages over those that do not. This concept provides a much better fit to observations and other evidence. This development is important because it suggests that human aging can be altered and delayed, and that lifespan extension is possible. This article suggests that aging is one of several related biological functions that operate as a function of age including reproduction, growth, and menopause.

Mammal Aging as a Programmed Life Cycle Function – Resolving the Cause and Effect Conundrum Goldsmith TC Wiley-Advanced Biology, Review Adv Biol (Weinh). 2024 Jun 16:e2300658. doi: 10.1002/adbi.202300658. PMID: 38880843

Abstract: 

Because aging and internally determined lifespan vary greatly between physically and biochemically similar animal species it is now widely accepted that aging is an evolved trait that in some way resulted from the evolution process.  This resulted in two classes of evolutionary aging theories: aging is programmed by a complex biological mechanism, and aging is not programmed.  As recently as 2002 programmed aging in mammals was widely thought to be theoretically impossible based on generally accepted concepts regarding the evolution process. However, as described in this article, genetics discoveries, results of selective breeding, and other direct evidence strongly support the idea that aging creates an evolutionary advantage and that therefore complex mechanisms evolved that control aging in mammals and other multiparous organisms. Like similar life-cycle programs that control reproduction, growth, and menopause, the aging program can adjust the aging trait during an individual’s life to compensate for temporary or local changes in external conditions that alter the optimum lifespan for a particular species population. In addition, genetics discoveries strongly support the evolvability concept to the effect that sexually reproducing species can evolve design features that increase their ability to evolve, and that aging is one such feature. Genetics discoveries also prove that biological inheritance involves transmission of organism design information in digital form between parent and descendant of any organism. This has major implications for the evolution process.

Keywords: evolution, evolvability, biology, gerontology, lifespan, senescence, digital genetics 

See the PubMed description and published version

The Evolution of Evolvability and Programmed Aging

The evolution concept has two distinct parts. The facts of evolution can be summarized as follows: Humans, and other current species are descended from earlier different species, that in turn were descended from still earlier species, that were ultimately descended from a very simple (single-cell) organism that lived billions of years ago (the universal common ancestor). Our scientific certainty in this part of Darwin’s 1859 idea has steadily increased for more than 160 years and there is currently essentially no scientific disagreement.

The second part concerns the mechanics of evolution or how the evolution process works. Here we have the reverse situation. Darwin’s concept involving mutations and natural selection is very individual-oriented: The evolution process causes organisms to acquire design characteristics that increase a wild individual’s ability to produce descendants. This idea plausibly fits the vast majority of observations concerning organism evolved design characteristics (traits) and Darwin’s ideas were virtually unopposed (scientifically) until the 1950s.

There was a problem: It was immediately obvious that aging in mammals did not fit with Darwin’s concept. Aging did not help an individual produce more descendants despite otherwise strongly appearing to be an evolved trait. Aging, because of the gross reduction in fitness aspects such as strength and sensory acuity clearly reduced the probability that an individual would produce descendants. In many other organisms, internally caused death could be explained by some evolved feature that increased reproduction at the expense of additional lifetime and indeed some species only reproduce once. This idea did not apply to mammals

Despite more than a century of effort no theory has been produced that plausibly explains observed mammal aging while simultaneously maintaining full compliance with Darwin’s individual-oriented mechanics concept.

The idea that we possess an evolved biological mechanism that purposely limits lifespan (essentially a suicide mechanism) certainly directly conflicts with evolutionary mechanics as generally understood despite increasing evidence and theoretical support. In 2022 there is still no wide scientific agreement on a solution to this problem and therefore no agreement on even the general nature of aging. Biology courses still typically state that evolution works entirely on an individual level and fail to mention the substantial disagreements. However, discoveries, especially in genetics, have exposed issues with the Darwinian mechanics concept specifically regarding the individual vs population issue. Multiple concepts now propose that evolution is more population-oriented. As shown in the figure, our collective confidence that we understand the mechanics of evolution has actually declined and the number of different mechanics concepts has increased! All of the more recent concepts are at least somewhat population-oriented. That is, they suggest that evolution is at least partly driven by the success (non-extinction and growth) or failure (extinction) of populations.

Timeline of Evolutionary Mechanics Theories

The most recent and least-known modern mechanics concept is evolvability, which can be defined as a species population’s ability to evolve or more exactly as the rapidity and precision with which a population can genetically adapt to changes in its external world. A population that could adapt more rapidly or comprehensively to changes in their world would have an evolutionary advantage over a similar population with less evolvability. Where Darwin’s concept suggests that the ability to evolve is an inherent property of all living organisms, the evolvability concept suggests that the ability to evolve is itself mainly the result of evolved characteristics that increase evolvability.

Theorists have now suggested multiple ways in which internally limiting lifespan enhances the probability that a population will survive and grow by increasing evolvability. The reason that this is critically important to anti-aging medicine is that these theories support the idea that there exists a treatable common cause of the many different manifestations of aging and therefore the idea that aging can be generally delayed. Further, evolvability theories of aging suggest different biological mechanisms cause aging and therefore suggest different possibilities for treatment approaches relative to aging theories based on other population-oriented concepts.

The need for evolvability can vary greatly between populations. Some clams and trees have apparently existed for millions of years with little change or need for adaptation. Mammals typically occupy a food-chain in which different species force adaptation on other species. A predator could evolve better ways for catching prey. The prey can evolve better ways to evade predators. This observation might explain why some clams and trees have extremely long lifespans while mammals have lifespans that are tightly controlled.

Future posts will describe why aging increases evolvability.

Aging, Treatability, Population Benefit, and Evolutionary Mechanics Theories

A Reply to Алиса’s comment on the book: Anti-Aging Medicine: How We Can Extend Lifespan and Live Longer and Healthier Lives.

There are two main biological aging theories: non-programmed aging and programmed aging.

There is wide agreement among gerontologists that aging has in some way been determined by the evolution process. Aging and internally determined lifespan, like other evolved traits (such as adult height), varies somewhat between individual members of a species and to a much greater extent between species. Consequently, evolutionary mechanics theory, or the theory describing the evolution process, essentially determines aging theories. Although there is wide agreement regarding the existence of Earth-life evolution there is still substantial disagreement regarding the mechanics of evolution.

Everybody also agrees that age-related diseases like cancer and heart disease have a common cause (age) that causes most cases of age-related diseases and the more universal age-related conditions. There is also wide agreement that each age-related disease has a different immediate cause. Cholesterol causes some heart disease, inappropriate cell division causes cancer, etc. The trillion-dollar question for more than 160 years has been: Is there a treatable common cause of age-related diseases and conditions? Is some single upstream biological mechanism regulating the multiple immediate-cause mechanisms resulting in the multi-species aging observations?

Darwin’s evolutionary mechanics concept, as we all learned in high school, is very individual-oriented. An inheritable mutational change occurs in a single individual. If that change causes descendant individuals to produce more adult descendants, it propagates in a population. This idea explains the vast majority of organism traits.

However, there is wide agreement that aging does not help but hurts the ability of individual mammals to produce more descendants leading to an obvious question: Why didn’t evolution produce internally immortal organisms. Unfortunately, despite more than 160 years of effort no one has produced an aging theory that even semi-plausibly explains multi-species aging observations while remaining completely compatible with Darwin’s mechanics.

This eventually led to the development of population-oriented evolutionary mechanics theories in which evolution is driven by the success (survival and growth) or failure (extinction) of populations of a particular species. Genetics discoveries support this view.

Modern Non-programmed aging theories propose that aging only weakly negatively affects populations even though it is catastrophic as seen from an individual’s viewpoint. This is obviously true. Mammals (including humans) have evolved to their current state despite aging. This concept leads to the idea that each of many different maintenance mechanisms that act to prevent each of the many age-related diseases and conditions only evolved the effectiveness needed to produce the lifespan needed by a particular species population. Therefore, there is no treatable common cause of agingmanifestations. This idea fits well with the existing medical paradigm.

More recent programmed aging theories suggest that aging, in addition to having little negative effect, actually produces a net evolutionary benefit for a population and that therefore organisms evolved biological mechanisms that purposely limit their lifespans. We possess what amounts to a biological suicide mechanism, which represents a treatable common cause of the age-related diseases! Anti-aging medicine including generally delaying aging (lifespan extension) is possible.

There is still major disagreement among gerontologists and medical researchers on this issue. As described in the book current science greatly favors programmed aging but non-science factors favor non-programmed aging. As described by Алиса, some gerontologists and many medical people still see programmed aging proponents as lacking “respectability” and interfering with “serious” research. However, serious, substantially funded research efforts based on programmed aging are now underway by organizations such as Alphabet Calico, AbbVie, and NIH. Gerontology journals increasingly accept pro-programmed aging articles and major textbooks on aging include programmed aging concepts. Programmed and non-programmed theories suggest very different biological mechanisms are ultimately behind age-related diseases so this issue is critical to research.

There have been few attempts to disprove any of the multiple population benefits of aging or to disprove the specific supporting evolutionary mechanics theories such as evolvability theory. Objections are usually based on the idea that it is “impossible” that the objector’s chosen evolutionary mechanics theory (incompatible with programmed aging) could be incorrect.

So Алиса if you (or anyone) has specific scientific arguments against the pro-programmed aging arguments summarized in the book (or in the cited literature) please post a summary and links to applicable journal articles.

New Book – Anti-Aging Medicine

Anti-Aging Medicine: How We Can Extend Lifespan and Live Longer and Healthier Lives – Theodore C. Goldsmith

Ebook version: http://amazon.com/dp/B08H5TQ62X

Paperback: : https://www.amazon.com/dp/0978870964

FREE PDF Version: http://www.azinet.com/aging/anti-aging-medicine-book.pdf

We can slow aging!  Until recently it was widely thought that human aging was an unalterable fact of life.  However, exciting new theories and supporting evidence now tell us that aging is a treatable condition! This book describes the history and current status of scientific thinking on aging and anti-aging medicine.  

Non-Aging Species – Negligible Senescence

Are there species that do not age? Some species apparently lack any internal limitation on their lifespans. What implications does this have for aging theories and dependent medical research on aging and age-related diseases?

Observed Long-Lived Species

We can use the term internal immortality to refer to the absence of any internal limitation on how long members of a species can live. Of course such a species would still be subject to death from external causes such as predators, intra-species warfare, starvation, lack of suitable habitat, and infectious diseases. A number of animal and plant species live extremely long lives and might be internally immortal.

It is infeasible to prove that any such species is or is not internally immortal. For example, we could keep a statistically large number of individuals under zoo conditions for 300 years and see if any survived. Such an experiment would probably require multiple zoos in multiple locations to prevent the entire zoo population from being wiped out by fire, earthquake, or epidemic, would take 300 years to perform, and would only show that a lifespan of 300 years was possible.

Some species have internal indicators of age like tree rings or similar markings on fish scales or internal bones so we can determine the age of a captured wild individual by dissection. Because wild species are subject to myriad external threats a very large number of such examinations would be necessary to demonstrate an even very long lifespan much less demonstrate the presence or absence of internal immortality.

Rougheye Rockfish - Maximum measured lifespan 140 years

Rougheye Rockfish – Maximum measured lifespan 140 years

 

Giant Sequoia – maximum measured lifespan >3000 years

Giant Sequoia – maximum measured lifespan >3000 years

Negligible Senescence

Another approach to the species senescence issue that avoids the lifespan measurement problem is to measure symptoms of aging. Humans and most other organisms have very obvious multiple senescence symptoms. A negligibly senescent species is one in which no measurable evidence of senescence such as decreased strength, speed, sensory acuity, reproductive ability, or increased incidence of diseases has been observed.

Some have claimed that the mouse-sized naked mole rat (interesting because it is a mammal) is negligibly senescent even though maximum lifespans of about 30 years have so far been observed. Lab mice live about 2.5 years and some mice live less than one year. Naked mole rats have a reproductive scheme similar to colony insects. In any underground colony only one “queen” female reproduces. This behavior and other strange characteristics likely affect their need for lifespan.

Naked Mole Rat – Maximum observed lifespan ~30 years, may be negligibly senescent

Naked Mole Rat – Maximum observed lifespan ~30 years, may be negligibly senescent

Aging Theory Implications of Non-Aging Species

A reader might conclude that trees, fish, and maybe even rats have no significance regarding human aging. However, as explained earlier, modern aging theories attempt to explain why different species have different lifespans and how aging relates to the evolution process and to other characteristics of a particular species.

An individual tree that has lived for more than 3000 years proves that there is not some fundamental limitation on how long an individual living organism can live (at least up to 3000 years). Trees actually share many life processes (such as sexual reproduction) with more complex species such as mammals so this is significant.

Modern non-programmed (non-adaptive) theories assume that each species only has an evolutionary need to live for a certain minimum lifespan but that there is no evolutionary disadvantage from living longer. For example, even if internally immortal, very few wild mice would live as much as three years because of external factors such as predators, starvation and harsh environmental conditions. Therefore having the internal ability to live longer would have very little value for a population of wild mice. This is the logic used by Medawar in 1952 to suggest that each species only needed to evolve the ability to live for a certain species-specific period. Because there is no disadvantage from living longer there is no evolutionary motivation to evolve a suicide mechanism that purposely limits lifespan.

These theories assume that various natural deteriorative processes would limit lifespan beyond the species-specific age at which there was an evolutionary need to live, thus leading to the huge variety of observed lifespans. There is no scientific disagreement that natural deteriorative processes such as oxidation, random mutations, and mechanical wear and tear exist.

However, non-programmed theories make a subtle but important and undefended assumption:  They assume that each increment of lifespan requires a different organism design because living X +1 years is somehow more difficult or otherwise a different task than living X years for any value of X. They further assume that if an organism inherited a longer lifespan than it needed, the natural deteriorative processes would degrade its design to fit its current external world thus resulting in the huge variety of lifespans observed. These assumptions “assume facts not in evidence.” It is not obvious why replacing dead skin cells or hairs would be any more difficult or require a different organism design in an 80-year-old than in an 8-year-old. Similarly why would preventing or repairing the causes of cancer or other age-related condition be more difficult with age?

In addition to this assumption, modern non-programmed theories assume that each species has an evolutionary need to live for a lifespan that is determined by internal design parameters (such as age of puberty) and external conditions (such as predation). Therefore they have the (so far mainly unaddressed) problem of explaining why some apparently non-aging or negligibly senescent species needed to live so long, even possibly indefinitely! Non-programmed proponents typically suggest that apparently non-aging species must actually age. Readers will recognize this as an example of circular logic: It must be true because our theory says it must be true!

Modern programmed (adaptive) aging theories assume that each species has a particular optimum lifespan, similarly determined by internal and external conditions, that living too long creates an evolutionary disadvantage for a population, and that therefore organisms evolved aging mechanisms designed to produce senescence symptoms on a species-specific schedule. Biological programs that stage various life-cycle events are common (e.g. growth, puberty, mating seasons). Programmed aging theories suggest [1] that negligibly senescent species have lost the ability to age and are therefore more likely to become extinct. This could have been caused by mutations that disabled their aging program.

[1] Goldsmith T. The Evolution of Aging 3rd ed. 2014 ISBN 978978870959 Azinet Press

 Aging Theories Articles Index

Non-Science Factors Influence Aging Theory Consensus

Aging TheoriesWHY is it that despite more than 150 years of effort there is still no scientific agreement on even the nature of human aging?  Is aging the result of fundamental limitations that could not be overcome by the evolution process, or a consequence of the lack of an evolutionary need for our ancestors to live longer, or the result of our possessing an aging program or biological suicide mechanism because populations of our ancestors received an evolutionary benefit from limiting individual lifespan? Many non-science factors act to bias thinking about aging and aging theories, mainly toward fundamental limitation theories or more recent non-programmed aging theories even though empirical evidence favors programmed aging theories. This is one of the reasons that no wide scientific agreement on even the nature of aging (much less details) exists today or is likely in the near future.

Education and Training

Most people are trained to believe Darwin’s individual-oriented evolutionary mechanics concept, which does not support more recent population-oriented evolutionary mechanics concepts and dependent modern programmed and non-programmed aging theories. Therefore they are, in effect, trained to believe in fundamental limitation theories. This logically leads to the idea that altering human aging is impossible. Very few of these people go on to obtain training in modern evolutionary mechanics concepts and dependent aging theories. Although modern non-programmed aging theories also conflict with traditional evolution theory, they do not present the gross and diametrically opposed conflict associated with programmed theories. The public is also accustomed to extravagant claims regarding discoveries and developments in medicine.

People who think that altering aging is impossible would logically be against funding research into anti-aging medicine or possibly even in studying aging on the basis that funds and other resources would be wasted. This situation also decreases motivation into studying age-related diseases and conditions. If aging is the result of fundamental limitations isn’t our ability to treat highly age-related diseases likely to be severely limited? Try comparing government funding of research on aging and age-related diseases to the defense budget. Now compare the death rates from age-related diseases to those resulting from enemy attack! We could ask the following question: Would funding for research into aging and age-related diseases increase if it was widely thought that aging, per se, was a treatable condition?

Anti-Science Influences

There are substantial anti-science influences at work in biology and medicine. Possibly the largest single anti-science effort currently extant is religious attacks against evolution theory. This effort strives to show that evolution theory cannot explain various observations without the intervention of supernatural intelligence and publishes pseudoscience articles to that effect. They then cite the pseudoscience in efforts to push teaching of anti-evolution religious concepts like creationism and intelligent design especially in introductory venues. This effort has been so successful that as of 2005 a Harris poll showed that the majority of Americans did not believe in evolution theory. Evolution is extremely central to the nature-of-aging issue and the anti-evolution situation leads to non-science biases toward fundamental limitation theories and non-programmed aging theories:

  • Proponents of fundamental limitation and non-programmed theories have, until recently, been able to dismiss programmed aging theories as non-scientific (and similar to anti-science proposals about evolution such as creationism and intelligent design) because of the conflict with traditional evolutionary mechanics.
  • Efforts to teach evolution, especially in more introductory venues like K-12 biology classes, would like to avoid any indication that there is any scientific disagreement regarding evolution theory and thus avoid giving support to the anti-science effort. This contributes to avoiding any mention of scientific disagreements about evolutionary mechanics or specific modern evolutionary mechanics theories.

The Zero-Sum Game

Funding for medical research tends to be rather flat (after inflation) on a year-to-year basis. Consequently, funding for new areas of research (like programmed aging or anti-aging medicine) must come from reducing funding to existing research avenues. Those researchers can be expected to fight fiercely against the new activities.

Scientific Inertia

Some senior bioscientists have a major public and long-term, even career, commitment to the older non-programmed theories. Such a person might well suspect that they are now betting on the wrong horse. However, for such a person to switch now would in many cases be like an Episcopal Bishop deciding to start over as an entry-level Methodist minister – possible but extremely unlikely.

Ethics and Health Policy Issues with Aging Theories

The fact that humans only live for a certain period is one of the most central and seemingly unalterable aspects of human existence and has profound ethical and policy implications. What happens to annuities, health insurance, pensions, social security, and Medicare if people start living significantly longer? What about the need for term limits for elected and life-time-appointed government officials? How do we increase retirement age? Would wealth imbalance increase?

Many have ethical concerns with altering aspects of human design that are “normal.” Most people would consider it unethical to genetically engineer humans to be taller, stronger, or more intelligent. It is certainly acceptable to the vast majority to attempt to treat or even cure cancer, heart disease, or other massively age-related disease because these conditions are not “normal” in that they do not occur in everybody. A very small part of the population does consider trying to treat cancer or other serious disease as interfering with God’s will and therefore sinful.

However, the more or less universal aspects of aging are certainly “normal” including “dying of old age.” Would it therefore be ethical to try to treat aging, per se? Worse yet, programmed aging theories suggest that humans possess an evolved suicide mechanism that limits their lifespans and that they are consequently designed to age. Aging is a feature of an organism’s design (like height) and not a defect (like a disease or injury).

On the other hand, just as it is obvious that different species age at very different rates, it is widely agreed that the aggressiveness of senescence, per se, varies substantially between individual humans. Therefore if a person inherited relatively aggressive senescence, should that person be able to seek medical aid to delay his senescence in such a way as to be able to enjoy a “normal” lifespan? Extending this idea, should we all be able to ethically enjoy the internally-determined lifespan seen by the longest-lived humans?

Many are concerned with medical advances that might extend the “nursing home stage” of life and favor advances that increase the “healthy” stage and decrease the nursing home stage.

Because they are concerned with the policy, ethics, and religious issues, some are against development of medical technology that would “extend normal lifespan” and are consequently against research in directions that might support lifespan extension – including programmed aging research, and even possibly including research as to the nature of aging such as initiatives specifically designed to determine if aging is programmed or not programmed. Some consider that because aging is a natural and normal aspect of human existence it is not a proper subject for medical research and medicine should be confined to treating dysfunction.

My conversations with thoughtful members of the general public indicate that there is substantial concern over these issues. Informal polling suggests that more than half of the U.S. population has at least some ethics, moral, or policy issues with research into lifespan extension or altering aging.

There is no doubt that senescence is surrounded by serious health policy, ethical, and religious issues. However, in my opinion it does not make logical sense to spend billions on research into treating massively age-related diseases without understanding aging and that doing so amounts to a “fool’s errand.” How can we hope to understand and best treat such a disease without understanding aging? If the majority of deaths due to highly age-related diseases (even in 40-year-olds) are caused by aging, how can we ignore aging in devising treatments for these diseases? Senescence is what it is. Ignoring scientific evidence pointing toward a certain conclusion regarding aging mechanisms is like ignoring global warming or ignoring all the evidence that the Earth orbits the sun.

Average human lifespans have substantially increased in the last century and few would really like to return to a much earlier age. Is it likely that there is going to be such a sudden and large increase in human lifespan that there would be huge social upheaval as a result?

Conclusion: A substantial portion of the U.S. population has issues with research into interfering with human biological aging mechanisms because they think such interference is impossible or because of ethical, religious, or policy issues. These attitudes obviously impact funding and support for research into aging and age-related diseases.

Aging Theories Articles Index

 

Aging Theories in the Commercial Medicine World

The situation regarding the programmed vs non-programmed aging controversy in the commercial world (doctors, patients, pharmaceutical companies) is very different from the situation in the academic world. Patients and doctors tend to be relatively unconcerned about obscure nuances in the theoretical basis of a treatment approach and much more concerned with effectiveness and lack of adverse side-effects. Certification of drugs and treatments generally does not involve extensive theoretical discussion but rather demonstration of effectivity and reasonable side effects.

Commercial operations are much more private and internal thinking about the theoretical basis of some treatment development effort can be closely held.

The global pharmaceutical industry (including biopharmaceuticals) is one of the largest in the world (with a current market capitalization of more than a trillion dollars) and can be expected to grow as populations of developed countries continue to age. According to a study published in JAMA (1/2010), in the U.S. “the pharmaceutical industry is the largest contributor towards funding research, funding over 60 percent. The government contributes to about a third of the costs, with foundations, advocacy organizations and individual donors responsible for the remaining investments.”

During the long period during which programmed aging was virtually universally thought to be theoretically impossible, it was entirely reasonable for a pharmaceutical company dealing with age-related diseases to invest all of its resources into research based on non-programmed aging concepts.

However today, an even cursory review of the literature would reveal that programmed aging can no longer be considered to be “impossible.” Consequently, any such company would need to perform a “due diligence” study of the current situation and produce an internal estimate of the probability that programmed theories are correct along with an estimate of the likely nature of the human aging program and the research directions suggested by that estimate. Any such study would need to consider the following:

  • Programmed aging theories suggest new paths toward treating age-related diseases that consequently present the possibility for rapid initial progress or “low hanging fruit.”
  • A programmed aging approach involves interfering with the operation of a biological program, likely to be similar to other programs and involving signaling, hormones, receptors, proteins, etc. This is a relatively familiar problem.
  • Programmed aging theories suggest that aging, per se, is a treatable condition and therefore suggest that treatments can be devised for delaying and potentially reversing at least some aging symptoms and diseases, especially in relatively older patients.
  • Competitors (e.g. Google Calico and AbbVie) are known to be already pursuing programmed aging research.

There is of course no such thing as certainty in any drug development effort. Any such research project is essentially an informed wager based on the available information. Given the foregoing it seems unlikely that any larger pharmaceutical company dealing in age-related diseases and conditions would conclude that they can completely ignore programmed aging concepts in developing their research planning. Programmed aging researchers may go from being semi-pariahs to being in high demand!

Are we likely to see the introduction of drugs that have been clinically tested and FDA approved “to delay human senescence?” This is very unlikely to happen because the claim is too broad, the claim is controversial, and the claim is extremely difficult to prove. We are much more likely to see a drug claim along the lines of: “reduces the adverse effects of macular degeneration in certain elderly patients.” Notice the narrow claim, much easier clinical demonstration, and lack of controversial claims. In addition, for programmatic reasons companies would be likely to want to develop 50 drugs to treat 50 different diseases and conditions of aging as opposed to one or a few drugs to treat senescence.

Conclusion: We can expect to see increasing efforts by pharmaceutical companies to explore drug development based on programmed aging concepts.

Aging Theories Articles Index

Aging Theories in the Academic Gerontology World

Aging TheoriesThinking about theories of aging in humans and other mammals in the academic gerontology and more general bioscience community now centers around two concepts: Aging (and an organism-design-limited lifespan) is genetically programmed and an adaptation because limiting lifespan created an evolutionary advantage, or, it is not. Opinions in the gerontology community tend to be highly polarized on this issue.

Members of the programmed aging faction tend to think that current published science overwhelmingly supports programmed aging.

Many members of the non-programmed faction consider programmed aging to be scientifically ridiculous because it conflicts with evolution theory as generally understood. Some non-programmed proponents have compared programmed aging to popular but scientifically ridiculous concepts about evolution such as creationism and intelligent design. Non-programmed aging is still more popular in the academic community and general science-aware public but programmed aging provides a better match to empirical evidence.

Life in the academic world is very public; we could say “publish or perish.” The scientific journal system including peer review is widely seen as necessary to maintain scientific integrity, especially for articles describing experimental or observational results and procedures. However, the system is less amenable to theoretical work. The “peer” review process tends to work against publication of new or unpopular ideas and some gerontology journals effectively will not accept articles that favorably describe programmed aging. Gerontology journal editorial boards are usually staffed by senior people who tend to follow older theories, in this case non-programmed theories, and often contain dedicated proponents of and even authors of non-programmed theories. This creates a rather hostile academic work environment for one considering performing research in programmed aging. Publicly declaring a belief in programmed aging could well amount to career suicide if one’s boss or institution thinks that programmed aging is “nuts.” Few researchers can afford to follow such a path.

In addition, the vast majority of the science-aware general public has essentially been trained to believe in non-programmed aging. No institution wants to be seen as performing research that is widely seen as scientifically ridiculous. Funding sources do not want to be seen as funding junk science.

Only a few research institutions publicly support the idea that human aging is genetically programmed because such a design created an evolutionary advantage. One such is Moscow State University.

This creates a situation where some researchers are performing research that does not make any sense under non-programmed theories but scrupulously avoid controversial terminology such as “programmed aging” or worse yet “suicide mechanism.” One sees creative ways of “finessing” this issue such as journal articles with titles along the lines of “Semi-programmed non-programmed aging.”

Nobel-prize-winning physicist Max Planck famously said: “A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it.”  Younger researchers are more likely to follow programmed aging concepts.

One workaround for the journal problems that has proved successful is for a journal to host a special issue to specifically compare opposing schools of thought, in this case programmed vs. non-programmed aging. Authors for both sides can then be assured that their review is going to be performed by someone who is in their faction and that therefore rejection is not preordained. In addition this creates a useful “shoot out” context where readers can compare multiple pro and con arguments. See example [1]. Note that this requires the journal to concede that programmed aging has attained a level of scientific plausibility that at least justifies serious discussion. Some journals (like Elsevier Medical Hypotheses) are specifically designed to allow reviewed publication of unpopular theories using a modified review process.

Until about 2005 many senior gerontologists dismissed programmed aging as ridiculous and “impossible” without providing any attempt at serious rebuttal or refutation of arguments and claims by programmed aging proponents. However, some senior non-programmed proponents now concede that programmed aging is possible “under certain circumstances’ and are arguing details, a significant change in attitude [2].

NIH PubMed now (Jan 2018) shows 1323 articles in a search for “programmed aging.”

Conclusion: No one would be surprised if the endless academic arguments regarding the programmed vs. non-programmed nature of aging continued for another 150 years! However, venues for publication of programmed aging articles are increasing and the programmed aging faction is growing in size, popularity, and impact. The research environment in the commercial world (e.g. pharmaceutical companies) is much more favorable to programmed aging as will be discussed in a companion article.

[1] Current Aging Science Vol 8 Nr1 Programmed vs. non-programmed aging, 2015, Libertini G. ed. open access

[2] Curr Biol. 2011 Sep 27;21(18):R701-7. Kirkwood TB, Melov S. On the programmed/non-programmed nature of ageing within the life history.

Aging Theories Articles Index

Medical Implications of Aging Theories

Aging TheoriesAs can be seen from the figure (U.S. mortality data), human death rates from all causes in developed countries increase exponentially starting at about age 30 and doubling approximately every ten years. We can define age-related disease or condition as one where the incidence and severity drastically increase with age to the point where aging is by far the main cause. Massively age-related diseases include heart disease, stroke, cancer, arthritis, cataracts and other vision deterioration, hearing loss, and loss of strength and balance. Alzheimer’s disease is essentially unknown in young people. Death rates for 40-year-olds are approximately twice the rates for 30-year-olds so we can consider that nominally half of deaths in 40-year-olds are caused by aging along with three-quarters of deaths of 50-year-olds and so forth. Aging and age-related diseases cause about three-quarters of all deaths in developed countries and represent more than half of medical research and health-care costs.

There is wide agreement that there are different immediate or direct causes associated with each age-related disease and condition. The immediate causes of heart disease are not the same as the causes of cancer or the causes of arthritis, etc. Western medicine is largely based on the idea that we need to find different treatments and pharmaceutical agents to treat different diseases and conditions. This approach has obviously been substantially successful in treating age-related diseases.

The current trillion-dollar question is whether or not aging, per se, although obviously the main cause of the age-related diseases is itself a treatable condition. If so, treatment of aging could be used in parallel with the existing medical paradigm in our efforts to treat age-related diseases and conditions. As described below, different aging theories suggest drastically different answers to this question.

Fundamental limitation theories, wear and tear, stochastic, etc. strongly suggest that aging is an untreatable condition. We can find treatments for individual symptoms such as cancer and heart disease but we cannot find ways to treat aging, per se, as it is the result of fundamental limitations that could not be overcome by the evolution process and are very unlikely to be overcome by medical advances.

Modern non-programmed aging theories suggest that aging is not the result of fundamental limitations but rather the result of a large number of different independent factors as explained by George Williams in 1957. Unlike inanimate objects, living organisms obviously have many biological mechanisms for repairing or preventing damage. Wounds heal; dead cells are replaced; immunity is acquired, and so forth. Therefore humans and other organisms reasonably would have developed biological mechanisms to delay the appearance of cancer, other methods for dealing with the different damage mechanisms associated with heart disease, and myriad other mechanisms for delaying the occurrence of other age-related diseases and conditions.

This concept explains why different mammals have such different internally determined lifespans while having very similar biochemistry and similar symptoms of aging. This idea assumes that all of the different maintenance and repair mechanisms each presumably independently evolved and retained just the effectiveness needed to deliver the minimum necessary species-specific internally-determined lifespan called for by modern non-programmed theories based on Medawar’s evolutionary mechanics ideas.

These concepts support the accepted idea that we can find different ways to treat each specific age-related disease. However, these concepts suggest that there is some ultimate age beyond which further progress in extending human lifespan would cease because eventually every aging symptom would appear at catastrophic levels. They further suggest that there is no treatable common factor behind age-related diseases and conditions. These theories therefore support the current medical paradigm of ever-increasing specialization by disease, disease sub-type, and even personal disease variety.

Modern programmed aging theories suggest that a second path toward combating age-related diseases and conditions exists. These theories propose that the age-related diseases and conditions are coordinated by a biological aging program that stages the appearance of aging symptoms to result in a particular optimum lifespan for each species population. In addition to finding better ways to combat each particular disease we can look for ways to interfere with the aging program and therefore generally delay or reduce the severity of age-related diseases especially in older individuals. If valid, this is an exciting development because two different approaches can be used against age-related diseases. Because the anti-aging approach is new, we could reasonably expect “low hanging fruit” and rapid progress.

The effectiveness of an attempt to interfere with the aging program depends on one’s concept of the nature of that program and specifically the degree to which the program is common to the many age-related diseases and conditions and the extent to which the common program can control each symptom. For example, if senescence is controlled by a program similar to the one that controls mammal reproduction, and aging is a genetically programmed phase of life, then we could expect rather dramatic results. If we wanted to delay or advance puberty that would certainly be possible. There is considerable theoretical thinking and empirical evidence suggesting that, like reproduction, aging is controlled by a complex common program involving signaling (hormones).

There is fairly wide sentiment to the effect that aging can be generally delayed by exercise and perhaps by caloric restriction. This idea conflicts with non-programmed “damage” theories because exercise and caloric restriction would be expected to increase, not decrease, damage. Many other observations support programmed aging.

For more discussion of the nature of the aging program and supporting evidence see:

Externally Regulated Programmed Aging and the Effects of Population Stress on Mammal Lifespan

Aging Theories Articles Index

 

 

Why do we age?

Aging TheoriesThis is one of the longest-running and still-unresolved questions in science. There are hundreds of competing biological aging theories and no scientific agreement that any one of them is correct. There is not even any agreement on the fundamental nature of aging. Is aging something that happens to your body as a result of forces of nature or is aging something your body does to itself like growth or puberty? It turns out that the choice of aging theory is almost entirely driven by one’s choice of evolutionary mechanics theories or the theories describing how the evolution process operates.

Observations Concerning Lifespan and Senescence

There are a number of observations that are essential to modern aging theories. Because aging theories are essentially subsets of evolution theory, and because evolution theory applies to all living organisms, scientifically credible aging theories need to consider multi-species observations about aging and internally determined lifespan such as:

  • Lifespans and senescence vary greatly between species. Mammal lifespans vary over more than a 200 to 1 range between some whales (> 200 years) and some mice (< 1 year). Fish lifespans vary over a range of more than 1300 to 1.
  • Symptoms of aging tend to be similar but not identical between related species. Dogs and humans, even though their lifespans differ by about a factor of seven, suffer from very similar symptoms of aging like cancer, heart disease, stroke, arthritis, mobility and sensory deficits, etc.
  • Internally determined lifespan resembles an evolved trait: It varies somewhat between individuals and to a much larger degree between species.

There is extremely good scientific agreement on most aspects of Darwin’s evolution theory as described in Darwin’s book of 1859 and currently taught. However, despite the more than 150 intervening years there is still disagreement regarding arcane evolutionary mechanics details. Specifically, does the evolution process operate to benefit individual members of a species population or does it operate to benefit a population of individual members of a species? This obscure detail might well appear to be trivial and in maybe 99 percent of observations of organism traits makes no difference. This is because evolved inherited organism design characteristics or traits that benefit the ability of an individual to survive and reproduce also benefit the ability of a population of those individuals to avoid extinction and grow. Aging is one of the exceptions as described below.

This obscure detail is crucial to the aging theory issue. A high-school biology student could tell you that Darwin’s theory says that the evolution process causes organisms to acquire traits that cause possessing individuals to live longer and breed more than non-possessing individuals, and further that aging obviously does not cause an aging individual to live longer and breed more than an otherwise identical non-aging individual. On the other side, some theorists have now suggested at least a dozen ways that aging helps a population despite being adverse from an individual’s viewpoint and, so far, there has been no scientific disagreement with any of these ideas. Therefore the population vs individual issue is the controlling issue for aging theories as well as some other observations. The evolutionary mechanics issues have resulted in four classes of aging theories:

Simple Deterioration or Damage Theories

Simple deterioration theories suggest that aging is simply the result of the same sort of processes that cause gradual deterioration in non-living objects and systems. Physical processes include mechanical wear and tear, and micro-injuries. Perhaps aging results from nuclear background radiation. More chemistry-oriented causes might include oxidation, damage from free radicals, telomere shortening, random damage to DNA, etc. These theories are still popular in the general public: “We wear out” (like automobiles or sewing machines or exterior paint). There is little scientific disagreement with the idea that deteriorative processes could be parts of the mechanisms that cause aging.

However, major problems quickly became apparent in the bioscience community:

  • Living organisms obviously possessed many maintenance and repair functions that acted to prevent or reverse damage. Wounds heal, shed hairs are replaced, worn nails and claws regrow, blood and skin cells are continuously replaced.
  • Living organisms were capable of evolving changes in their designs that act to reverse or prevent deterioration.

Obvious question: If aging is the result of simple deterioration processes, why didn’t organisms evolve ways to overcome those processes as they had already demonstrated? This problem led to the fundamental limitation theories.

Fundamental Limitation Theories of Aging

As described above, Darwin’s evolutionary mechanics concept suggests that the force of evolution is toward developing non-senescent species. Individual members of a species that do not possess any internal limitation on their reproductive lifespans would be able to live longer and breed more than competing senescent individuals. Obvious question: Why, given billions of years of evolution, are there still senescent species? Obvious answer: a longer lifespan is physically or chemically impossible because of some law of physics or chemistry. Of course there are books full of laws of physics and chemistry and human aging is a gradual general deteriorative process superficially similar to aging in machinery and exterior paint. The second law of thermodynamics (entropy) is often cited in connection with aging. Today, because of their good fit with Darwin’s mechanics and human aging, fundamental limitation theories are still popular with the general public and some physicians.

However, fundamental limitation theories utterly fail to explain multi-species observations about aging. Why would a 50 Kg dog be seven times as affected by some law of physics or chemistry as a 50 Kg human?  Why would a parrot live six times longer than a crow? Articles about fundamental limitation theories typically ignore non-humans and target people who are mainly interested in human aging.

Aging Theories that Propose a Limit to Lifespan Benefit

In 1952 Nobel-prize-winning biologist Peter Medawar proposed a modification to Darwin’s mechanics to the effect that the evolutionary benefit of living longer and breeding more declined with age in a species-specific and population-specific manner, and further that internally determined lifespans needed by members of a wild species population depended on external circumstances such as predation, food supply, and habitat surrounding the population as well as internal traits such as age-at-puberty and other reproductive behaviors. Evolution is all about competition and “survival of the fittest” under wild conditions. We can easily imagine that there would be a species-specific age at which virtually no individual members of a population would remain alive because of external causes of mortality such as predators, infectious diseases, harsh environment, lack of food, or any of the myriad other causes of death in wild organisms. Consequently there would be little evolutionary motivation to develop the internal ability to live longer than a species-specific age. A population of aging individuals might be essentially as successful as a population of otherwise identical senescing individuals. This led to a family of modern non-programmed aging theories to the effect that each species only needed the internal capability for achieving a particular internally-determined lifespan and therefore only evolved and retained the ability to live that long. These theories provide a much better match to multi-species observations and are currently popular in the gerontology community.

However, subsequent (1957) widely accepted analysis by George C. Williams suggested that the deteriorative effects of aging occurred too early in life to have no negative effect on a population. Deterioration in strength, speed, and sensory acuity would affect an organism’s ability to survive and compete well in advance of the age at which most individuals would be dead from external causes and thus negatively affect survival of the population. Wild animal studies confirmed Williams’ analysis. This led to the conclusion that senescence must create a benefit for a population that offset its negative effects.

There are multiple competing theories that propose different solutions to this problem including the mutation accumulation theory, the antagonistic pleiotropy theory, and the disposable soma theory, and no agreement as to which is correct. Proponents of programmed aging (below) have described many logical and observational issues with each of these theories. Articles about mammal aging theories based on Medawar’s and Williams’ concept typically ignore non-mammals.

Programmed Aging Theories

Programmed aging theories are based on modifications to Darwin’s mechanics (and extensions to Medawar’s ideas) to the effect that aging, although adverse to individuals, benefits populations and that therefore species evolved biological mechanisms that internally limit their lifespans. Aging is an adaptation that serves an evolutionary purpose just as eyes, ears, and toes serve a competitive purpose in a wild population. Although programmed aging was first formally proposed in 1882, it was largely dismissed as obviously scientifically ridiculous because of the gross and direct conflict with Darwin’s mechanics until about 2002. Various analyses of Darwin’s mechanics confirmed that of the student: Darwin’s mechanics concept does not support population benefit or dependent programmed aging theories. The idea that we possess what amounts to an evolved suicide mechanism or “biological self-destruction clock” that limits an individual’s ability to survive and reproduce grossly conflicts with the nature of evolution as most people understand it.

However, a number of developments (and non-developments) have exposed additional issues with Darwin’s mechanics concept that specifically support population benefit and programmed aging:

  • Despite more than 150 years of effort theorists have been unable to produce an aging theory that is fully compatible with Darwin’s mechanics and simultaneously even semi-plausibly explains multi-species aging observations. Modern non-programmed (non-adaptive) aging theories are based on post-1952 modifications to Darwin’s mechanics that are more population-oriented.
  • In addition to senescence, other observations conflict with Darwin’s mechanics. These include sexual reproduction, individually adverse mating rituals and other behavioral observations such as animal altruism, and existence of apparently non-aging species. This led to the post-1962 development of multiple population-oriented mechanics theories including group selection theories and evolvability theories.
  • Genetics discoveries have exposed multiple issues with Darwin’s mechanics and support population-oriented mechanics and programmed aging theories. More generally, genetics discoveries suggest that the evolution process is much more complex than previously thought.
  • Some very explicit and obviously programmed suicide mechanisms have been discovered in non-mammals such as octopus and roundworm. Genetically engineered roundworms have been produced that live ten times as long as the wildtype!

Current Status of Aging Theories

The present situation is that current published science no longer supports the idea that programmed aging is impossible. The academic gerontology community still largely supports non-programmed theories based on Medawar’s/ Williams’ modifications to Darwin’s mechanics because such theories provide a better fit to multi-species observations than the fundamental limitation theories while not being so obviously incompatible with Darwin’s mechanics. Commercial entities (e.g. pharmaceutical companies) have begun to make major investments in research based on programmed aging theories.

Many non-science factors bias public and academic thinking toward non-programmed aging theories. For example, most people are trained in Darwin’s mechanics theory as the only science-based theory. Only a tiny fraction of these people are trained in modern population-oriented theories and dependent programmed aging theories or their supporting evidence and logic.

Because they predict that very different biological mechanisms are responsible for aging, programmed and non-programmed theories suggest very different medical research paths could be employed toward treating massively age-related diseases and conditions.

For more on evolutionary mechanics and the case for population-oriented theories and programmed aging theories see:

Evolvability, population benefit, and the evolution of programmed aging in mammals.

Aging Theories Articles Index