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

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