Content uploaded by Theodore C Goldsmith
Author content
All content in this area was uploaded by Theodore C Goldsmith on Jan 30, 2020
Content may be subject to copyright.
An Introduction to
Biological
Aging Theory
Second Edition - Revision 2
Theodore C. Goldsmith
Azinet Press
Introduction to
Biological Aging Theory
Publisher’s Notes
This e-book is available for free download (PDF) at:
http://www.azinet.com/aging/aging_theory_introduction.pdf
A paperback version of this book is available:
ISBN: 978-1677359066 https://www.amazon.com/dp/1677359064
This educational material was written to avoid unnecessary arcane terminology and is
considered suitable for AP Biology students and above.
A set of aging theory questions and answers is in production.
A short presentation (free PDF) of this material titled Theories of Biological Aging and
Implications for Public Health is available at:
http://www.azinet.com/aging/Theories_Summary.pdf
Please take a moment to rate this book. If you liked or disliked something about this
book, the publisher, author, and future readers would very much appreciate it if you would
also write a customer review.
Comments, suggestions, or inquiries for the publisher may be sent to:
books@azinet.com. Please include book title and version in your communication.
The author’s blog may be found at: http://aging-theories.org
--Azinet Press--
Introduction to Biological Aging Theory
Theodore C. Goldsmith
Copyright © 2012, 2020 Azinet Press
E-Book: ISBN-13 978-0-9788709-1-1 ISBN-10 0-9788709-1-3
Paperback: ISBN-10: 1677359064 ISBN-13: 978-1677359066
Azinet Press
Box 239 Crownsville MD 21032
1-(410) 923-4745
Keywords: aging, ageing, senescence, evolution, gerontology,
geriatrics, health and fitness, bioscience, theories of aging, evolvability, aging theories,
regenerative medicine, anti-aging medicine, medical e-books, education
Cover art: Bulent Ince
Other illustrations by author
Editorial assistance: Elaine Evans
Amazon Kindle edition ASIN: B004L62CEQ
Apple iBook edition: ISBN 9780978870911
Web PDF: http://www.azinet.com/aging/aging_theory_introduction.pdf
Revised: 8/24/2012
Second edition: 4/28/2014
Revised 1: 12/2/2014
Revised 2: 1/10/2020
Contents
Introduction.................................................................................................................... 1
Human Mortality ........................................................................................................ 1
Legacy Aging Theories .............................................................................................. 3
Aging – Key Observations.......................................................................................... 4
Modern Aging Theories.............................................................................................. 5
Evolutionary Mechanics Theory and Aging ................................................................ 5
Non-Programmed Aging Concepts 1952+ ...................................................................... 8
The Force of Evolution Declines with Age ................................................................. 8
Aging Must Convey a Compensating Evolutionary Advantage ................................... 9
Inter-Trait Genomic Linkage Concept Introduced ....................................................... 9
Modern Evolutionary Mechanics Concepts 1962+ ........................................................ 10
Population Benefit Theories ..................................................................................... 10
Evolvability Theories ............................................................................................... 11
Programmed Mammal Aging ....................................................................................... 13
Evolutionary Value of Life ........................................................................................... 13
Aging Mechanisms and Processes ................................................................................ 15
1. Simple Deterioration ............................................................................................ 16
2. Maintenance and Repair ....................................................................................... 16
3. Programmed Aging .............................................................................................. 17
4. Regulated Programmed Aging .............................................................................. 18
Programmed Lifespan Regulation Strategy ............................................................... 19
Aging as a Biological Function ................................................................................. 20
Empirical Evidence Supporting Programmed Aging ..................................................... 20
Genetics Discoveries Affecting Evolutionary Mechanics .......................................... 20
Lifespan Regulation by Sensing of External Conditions ........................................... 21
Caloric Restriction and Lifespan ............................................................................... 21
Stress and Lifespan................................................................................................... 22
Aging Genes............................................................................................................. 22
Hutchinson-Guilford Progeria and Werner Syndrome ............................................... 22
Negligible Senescence .............................................................................................. 22
Octopus Suicide ....................................................................................................... 24
Programmed Cell Death -- Apoptosis ....................................................................... 24
Superficial Nature of Lifespan .................................................................................. 24
Hormones - Blood Experiments ................................................................................ 25
Non-Science Factors Favor Non-Programmed Theories ............................................... 25
Programmed/ Non-Programmed Controversy - Status .................................................. 26
Recent Arguments Against Non-Programmed Aging ................................................ 27
Arguments Against the Disposable Soma Theory ................................................. 27
Arguments Against the Antagonistic Pleiotropy Theory ....................................... 27
Issues with Non-Programmed Aging Mechanisms ................................................ 28
Recent Arguments Against Programmed Aging ........................................................ 29
Social Issues with Aging Theories ............................................................................ 29
Anti-Aging Medicine ................................................................................................... 29
Anti-Aging Research ................................................................................................ 31
Summary ...................................................................................................................... 33
Further Reading ........................................................................................................... 34
References ................................................................................................................... 37
Index ............................................................................................................................ 39
Introduction to Biological Aging Theory
1
Introduction
This book summarizes the current situation, history, major controversies, and medical
implications of scientific biological aging theories.
Scientific theories of biological aging (senescence) attempt to answer two questions:
How do we age? What are the specific biological mechanisms that cause aging? Aging is
a very difficult subject for experimental investigation for two reasons:
First, aging is very diffuse and affects many different systems and tissues. If, for example,
aging only affected the liver, we would have probably long since definitively determined the
mechanisms behind aging.
Second, aging is a long-term process. An experiment to determine if a pharmaceutical
agent suppresses a particular pathogen or helps with pain could be performed in a matter of
days. An experiment to determine if an agent or protocol increases lifespan in humans or other
mammals could take years or decades to perform.
Understanding the aging process is critical to our ability to understand and treat highly
age-related diseases such as cancer and heart disease that currently kill the majority of people
that die in developed countries, some at relatively young ages.
Why do we age? It is apparent that aging and lifespan characteristics are very specific to
individual species and vary greatly between even very similar species. We can define lifespan
as the age a typical individual would achieve in the absence of any external limitations such as
predators, starvation, lack of suitable habitat or food supply, or harsh environmental conditions
i.e. internal limitations on life time.
Mammal lifespans vary over a range of more than 200 to 1 between Bowhead whale (>
200 years) and the shortest-lived mouse (~0.8 years), and fish lifespans vary over a range of at
least 1300 to 1 from Pygmy Gobi (8 weeks) to Koi (> 200 years). Some aspect of the design
of each particular species therefore must determine lifespan. We look to evolution theory to
explain why different species have different designs and evolution theory is consequently
critical to attempts to explain why we age. Unfortunately, as will be described, aging and
lifespan observations are among the few observations that appear to conflict with Darwin’s
ideas and no wide scientific agreement has been reached regarding evolutionary explanations
for aging despite more than 160 years of effort.
Because of the experimental difficulties, theories as to why we age are very important in
providing guidance to experimental approaches in medical research on diseases of aging. Many
experimental proposals are suggested by a specific evolution-based aging theory.
As will be described, current arguments regarding the nature of aging are essentially
arguments regarding arcane details of the evolution process.
Human Mortality
Fig. 1 shows USA 1999 death rates 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 ten years. In other words,
Introduction to Biological Aging Theory
2
aging is a major contributor to death rate starting at age 30. Curiously, death rates level off and
even decline slightly for extremely old (100+) people. Major diseases of aging are so age-
dependent they are essentially symptoms of aging.
According to U.S./CDC data (1999) an American 80-year-old is about 270 times as likely
to die of cancer as a 20-year-old and numbers for heart disease and stroke are larger. Some
diseases like Alzheimer’s disease are essentially non-existent in young people.
Fig 1. USA Mortality by Age in 1999
In effect the chart says that in the U.S. about half of all deaths of 40-year-olds, three-
fourths of all deaths of 50-year-olds, and so forth, result from aging.
Fig. 2 shows how deaths as a function of age in the U.S. have changed between 1933
and 2017. Improvements in medicine, general behavior, and safety have greatly decreased
mortality in infants, children, and younger adults increasing the importance of aging in
medicine and health care.
Introduction to Biological Aging Theory
3
Fig 2. USA Deaths from all causes vs. age at death in 1933, 1999, and 2017
Legacy Aging Theories
Many people believe that aging is simply the result of accumulating deterioration caused
by mechanical wear and tear, oxidation, other molecular damage, or other natural process that
causes gradual degradation. Stochastic theories suggest that aging is the result of accumulating
random changes that negatively affect biological systems. Aging could be the result of the
accumulation of toxic byproducts, damage due to nuclear radiation, or other gradual
deteriorative process.
Aging could be the result of fundamental limitations, such as laws of physics or chemistry
that cannot be overcome by the evolution process. This idea has some appeal because in many
ways the effects of aging on humans are similar to the sort of gradual degradation that occurs
to automobiles, exterior paint, and other inanimate objects. We use the word aging to describe
both. In addition, the idea that aging is caused by fundamental limitations fits well with
evolution theory as understood by most people. People who believe in legacy theories tend to
believe that contravening the aging process is theoretically impossible.
However, few gerontologists and other bioscientists currently believe in wear and tear and
other legacy theories because they utterly fail to explain enormous differences in lifespans
between physically and biochemically similar species. If aging is the result of fundamental
limitations or other deteriorative processes that presumably affect all organisms, why are
lifespans of even very similar organisms so different? Why does a parrot live six times longer
Introduction to Biological Aging Theory
4
than a crow? They also fail to explain many other observations and do not take into account
the fact that living organisms possess many damage repair mechanisms.
Note that aging theories tend to vary widely in scope. A theory only intended to explain
human aging could ignore conflicting non-human evidence. A mammal aging theory could
avoid explaining non-mammal evidence. In addition, aging theories generally apply only to
multiparous (or iteroparous) gradually aging organisms. Semelparous organisms, that die after
reproducing only once, can usually be explained as an extreme example of a reproduction vs.
survival tradeoff that is supported by Darwin’s theory. Rather than investing resources in
surviving to engage in a second or subsequent reproduction, the organism invests those
resources in increasing the chance that the first reproduction will be successful.
Aging – Key Observations
Modern aging theories consequently attempt to accommodate and explain a number of
key observations concerning senescence:
1. Immediate causes are different. It is widely agreed that the immediate causes
of the many different age-related diseases and conditions are different and that
different treatments directed at the different causes have been effectively
developed and deployed. The causes (and treatments) of cancer are different
from heart disease, etc. Different types and even stages of cancer have different
treatments.
2. Similarity of symptoms. Mammal species exhibit similar but not identical
symptoms of aging. Dogs and humans share cancer, heart disease, stroke,
cataracts, deafness, weakness, and other symptoms of aging.
3. Synchronization of symptoms. In any given species, the symptoms of aging
(age-related diseases and conditions) appear on a similar age-schedule. They are
clearly related to each other because they have a common cause (aging) that
causes the majority of cases.
4. Huge variation in lifespan. Internally determined lifespans of different species
vary enormously between biochemically and physically similar species, more
than 200:1 in mammals, 1300:1 in fish.
5. Aging appears to be a trait. Aging closely resembles an inherited organism
design characteristic that has been determined by the evolution process (a trait).
a. Like other traits, aging and lifespan vary greatly between similar species.
b. Like other traits, aging and lifespan are highly related to other traits
possessed by the same species. Example: aging is highly related to
reproduction. A species that died of old age or even was significantly
degraded prior to reaching reproductive maturity would not make
evolutionary sense.
6. Maintenance and repair. Unlike vehicles, sewing machines, and exterior paint,
living organisms have extensive capabilities for preventing or repairing damage.
The trillion-dollar question: Does biological aging, per se, have treatable common
causes?
Introduction to Biological Aging Theory
5
Modern Aging Theories
Modern evolutionary aging theories followed by most medical researchers fall into two
categories:
Modern Non-Programmed Aging Theories contend that we age because our bodies do
not provide a better defense against natural deteriorative processes such as mechanical wear,
oxidation, and other damage including more disease-specific biological damage mechanisms
that cause each of the age-related diseases. This situation exists because each species only has
an evolutionary need to live and reproduce for a species-specific life time and therefore only
evolved and retained the maintenance and repair capabilities needed to obtain that life time.
Modern Programmed Aging Theories contend that we age because we possess what
amounts to a biological suicide mechanism or aging program that purposely limits internally
determined lifespan to a species-specific value in order to obtain an evolutionary benefit.
Having the internal capability for living and reproducing longer produces an evolutionary
disadvantage that caused the evolution and retention of the lifespan limiting mechanism.
Both theories provide explanations for the key observations. Both theories require
modifications to traditional Darwinian evolutionary mechanics as taught by Darwin and
currently taught in introductory biology courses.
For many decades, programmed aging theories were thought to be literally theoretically
impossible because of the mechanics of the evolution process and researchers therefore
followed non-programmed theories despite substantial and increasing conflicts with
observations. More recently developments to be described have dramatically changed this
situation and modern programmed theories now have better theoretical support and provide a
better fit to direct evidence. As we will see, the newer modern programmed aging theories are
built on and represent a logical extension of the older evolutionary non-programmed theories.
Because the theories have very different predictions regarding the nature of aging and age-
related diseases, this development could have a large effect on public health by leading to
major improvements in our ability to treat and prevent age-related diseases like cancer, heart
disease, and stroke. Age-related diseases are now the subject of at least half of the U.S. medical
research budget, an even larger proportion of total health-care expense, and cause the majority
of all deaths in developed countries, even in relatively young people.
Evolutionary Mechanics Theory and Aging
As mentioned earlier, there is wide agreement that aging and lifespan are traits, or
inheritable organism design characteristics that have been determined by the evolution process
and consequently vary between individuals and species. Evolutionary mechanics theory or the
theory of how the evolution process operates is crucial to modern aging theories because it
became clear that lifespan is as unique to a particular species as any other evolved trait. We
look to evolution theory to explain why living species possess their particular designs and so
theorists produced evolutionary theories of aging that attempt to explain why different species
would have evolved different lifespans.
Charles Darwin [1] published his book On the Origin of Species in 1859 and proposed that
current organisms were descended from earlier different 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
Introduction to Biological Aging Theory
6
and its single-cell ancestors were the result of accumulating these minute evolutionary
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 an organism 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. A tradeoff could also exist between survival and
reproduction. A rabbit could have less ability to survive than a fox but simultaneously have
more ability to reproduce.
It was widely known prior to Darwin that the design of a species could be dramatically
and rapidly altered by selective breeding (and by extension, natural selection). However, it was
also known that selective breeding of dogs could not 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
individual members. Therefore, prior to Darwin, 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 essentially unobservable. Natural selection could then operate on these new
variations, eventually leading to very different species.
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 typically teach that Darwin’s natural selection theory is
scientifically generally accepted as the complete and comprehensive explanation for the
evolution process.
In connection with aging and lifespan 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 individual 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. Darwin
did not suggest that the nth descendant of a parent organism was any less important to the
evolution process then the first descendant. Therefore, Darwin’s concept suggested that the
force of evolution was toward achieving internal immortality or the absence of internal
limitations to life time or reproductive capability in addition to adapting ways to overcome
external conditions that imposed limitations on life time and reproduction. Darwin’s idea thus
tends to support the idea that aging is a fundamental limitation that cannot be overcome by the
evolution process (i.e. fundamental limitation theory). Surely if organisms were evolving to
live longer and breed more for billions of years, by now they would have evolved internal
immortality if such was possible.
It was immediately apparent that Darwin’s idea did not match aging and lifespan
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 internal immortality been achieved? If there was some fundamental age-dependent
limitation to lifespan or reproduction such as a law of physics or chemistry that could not be
overcome by the evolution process, why were lifespans of similar species so different? Why
would a general law of physics or chemistry affect similar species so differently?
Introduction to Biological Aging Theory
7
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. A mutational change that
initially appeared in a single individual would spread in a population if it resulted in the
possessing individuals living longer and breeding more than non-possessing individuals.
Evolved organism design characteristics including inherited behavioral traits should therefore
benefit individual organisms and their direct descendants against competing members of the
same species. This is the “dog eat dog” or “red of tooth and claw” 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” or population-oriented benefits cannot evolve
if it causes any disadvantage to the ability of individual organisms to survive and reproduce.
Millions of observations have been made regarding inherited physiological and behavioral
traits of living organisms. The vast majority of these observed characteristics plausibly increase
the ability of the possessing individuals to produce more adult descendants.
Since such a large proportion of observations conformed to Darwin’s idea, at the time it
was reasonable to assume that eventually we would find a conforming explanation for lifespan
observations. This did not occur and other apparent discrepancies appeared. In the intervening
160 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, which in turn suggest very
different approaches toward treating or delaying age-related diseases.
Most people are under the impression that there is currently no scientific disagreement
with natural selection theory as taught by Darwin and currently taught in introductory biology
venues. This is not true. Apparent discrepancies between natural selection and observations
have steadily increased since Darwin resulting in proposed modifications. Here is a brief list
of apparently conflicting observations.
Aging and lifespan. See above.
Altruism. Animals are observed to act in a manner not consistent with their individual
best interest but in a way that plausibly benefits groups of their species.
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 by
limiting the reproductive opportunity of the possessing individuals.
Biological suicide. Some instances of biological suicide present no apparent offsetting
individual benefit (see octopus below).
Sexual reproduction. Sexual reproduction appears to represent a massive individual
disadvantage relative to asexual reproduction because of the relative reproductive uselessness
of males.
Introduction to Biological Aging Theory
8
Inheritance mechanisms. Many genetics discoveries (some quite recent) raise issues
with traditional natural selection theory.
Around 1950 it was widely thought that “survival of the fittest” represented a complete
and comprehensive description of the evolution process. Since then it has become increasingly
obvious that, as happens so frequently in science, the evolution process is actually much more
complex than previously thought. Since Darwin we have become increasingly sure that
evolution of life on Earth has indeed occurred. However, our collective certainty that we
understand exactly how evolution works has actually decreased! In addition to increasing
appearance of conflicting observations, the explosion in our understanding of the biological
inheritance process (genetics) has exposed rich complexity. Because propagation of
evolutionary changes occurs by inheritance, this complexity directly affects evolutionary
mechanics.
Non-Programmed Aging Concepts 1952+
This section describes the evolutionary mechanics concepts that support modern non-
programmed aging theories.
For nine decades following the publication of Origin theorists tried unsuccessfully to
produce a plausible explanation for the gross inter-species lifespan variations that was
compatible with Darwin’s mechanics concept. Eventually starting in 1952 new evolutionary
mechanics concepts were proposed as follows:
The Force of Evolution Declines with Age
In 1952 Peter Medawar, a subsequently Nobel-Prize-winning British biologist, proposed
a modification to Darwin’s mechanics. In a presentation [7] titled An Unsolved Problem of
Biology, Medawar suggested that the force of evolution declined with the age of an organism
following the age at which it could complete its first reproduction. His logic was that even if
they were internally immortal the size of any age-cohort (members of the same species having
the same age) in the wild would decline with time because of external causes of death like
predators, harsh environment, lack of food, or infectious diseases. The combined effect that
cohort would have on the evolution process would therefore also decline with age.
Everybody agrees that any organism trait that caused death or even a reduction in fitness
parameters like speed, or strength would be highly selected against by the evolution process
prior to the first reproduction. There is also wide agreement that there would be zero
evolutionary force toward overcoming such a trait if it only had an adverse effect after the age
at which 100 percent of an age-cohort could be expected to be dead from external causes.
Recall that Darwin’s idea assumes competition for survival under wild conditions.
Medawar even provided a sort of math-model in the form of his “broken test tubes”
metaphor and proposed that an internally immortal animal population would be essentially
functionally identical to an aging population of the same species. Immortality would produce
no evolutionary advantage for a population.
Medawar’s idea explained why a mouse (that can reproduce at ~2 months of age) and lives
in a brutally predatory world has a lifespan of about 2 years while an elephant (that could
reproduce at ~13 years and has greater survival skills) has the internal ability to live to be about
80. Eventually many species-unique and even population-unique factors such as the degree to
which a species nurtures its young, duration of pregnancy, mating seasons, litter size, degree
Introduction to Biological Aging Theory
9
of predation, harsh environmental conditions, etc. were thought to influence the evolved
lifespans of different organisms.
This declining force concept is essential to all of the subsequent non-programmed and
programmed aging theories.
Adverse mutations were known to cause genetic diseases like Huntington’s chorea that
only caused adverse effects at advanced ages, and then only in a small portion of a population.
Medawar suggested that aging could be caused by myriad mutations that each only caused
adverse effects in older individuals. The observation that age-related diseases are not
universally seen acted to support the idea that each disease only had a small effect on evolution.
This idea is known as the mutation accumulation theory of aging. Medawar’s idea that
observed aging in mammals could be entirely explained by his declining force concept is no
longer widely accepted for reasons described below.
Aging Must Convey a Compensating Evolutionary Advantage
One of the problems with Medawar’s idea was that even according to Medawar’s model,
the force of evolution did not decline to zero rapidly enough to explain observed aging. George
Williams [8] in 1957 showed that aging caused measurable decline in survival parameters like
speed, strength, and sensory acuity at relatively young ages (e.g. 20s in humans). Under wild
conditions these declines would clearly cause an associated increase in death-rate. Indeed,
studies of wild mammal populations showed that death rates increased with age after maturity
and that therefore aging was having a negative fitness effect on the population. Williams
therefore suggested that aging must somehow convey a compensating evolutionary advantage
that offset the declining but still non-zero disadvantage of aging. This idea is central to all of
the modern theories. The huge question: What was the compensating evolutionary benefit of
aging?
Inter-Trait Genomic Linkage Concept Introduced
Darwin assumed that random mutations and consequent random changes to an organism’s
design were equally likely. This led to a simple evolutionary mechanics concept: A random
change to an organism’s design occurs; natural selection accepts or rejects the change
depending on whether it causes possessing individuals to live longer and breed more; repeat
for billions of years.
In 1957 Williams [8] suggested that a beneficial trait or traits could be permanently linked
to an adverse trait (such as aging) in such a way that it would be impossible for the evolution
process to break the linkage and produce a design having the benefit without the adverse effect.
The loss of the beneficial effect would then prevent the evolution process from selecting a
longer lifespan even though a longer lifespan and delayed deterioration due to aging
represented an increase in fitness. The linkage would need to be permanent because
presumably animal ancestors of the present species would have also benefitted from more
longevity.
Williams’ rationale for such linkage was that a single gene sometimes controls more than
one phenotypic property (pleiotropy). Therefore, a mutation changing one gene changes
multiple properties controlled by that gene introducing a linkage between them that makes it
more difficult for the evolution process to alter the one property without changing the others
in adverse ways. This particular linkage would not exist if the phenotypic properties were
controlled by different genes. Williams’ idea is known as the antagonistic pleiotropy theory of
Introduction to Biological Aging Theory
10
aging. Williams said that according to his theory, a single treatment altering the aging process
(and by extension, age-related aspects of diseases) was “impossible” because each symptom
of aging had a cause that was independent of the others. There was no potentially treatable
common cause of the many different diseases and conditions.
This is an example of an evolutionary mechanics concept that is derived from genetics
discoveries. See Controversy for arguments against the antagonistic pleiotropy theory.
There now exist many linkage theories to the effect that aging and deterioration in later
life of an organism is a side-effect of some linked biological function that creates benefit in the
earlier life of the organism. Because of the declining evolutionary value of survival, such a
benefit in early life, even if relatively minor, could compensate for the relatively major
(actually catastrophic) negative effect of aging in later life.
One such linked concept is the disposable soma theory. In 1975 T. Kirkwood proposed
[9] that maintenance of an organism required substantial resources. Possibly an organism could
discontinue maintenance (and suffer aging in late life as a result) while using the resources for
more vigorous reproduction or survival activities in early life. The early-life benefit would
offset the declined late-life disadvantage. See Controversy for arguments against this idea.
Linkage concepts are also important to programmed aging theories. It is now apparent that
there are many aspects of genomic design that introduce linkages having very different time
frames in regard to the difficulty of removing the linkage and consequently the time required
for the evolution process to accomplish the removal [6].
Modern Evolutionary Mechanics Concepts 1962+
Population Benefit Theories
Since 1962, theorists have formally proposed a number of more general adjustments to
evolutionary mechanics theory in response to observed discrepancies other than aging
(particularly animal altruism). They all propose that wider, more population-oriented benefits/
costs in addition to individual survival or reproductive benefits/ costs can influence the
evolution process and that a tradeoff can exist between individual disadvantage and population
benefit. Modern programmed aging theories are all based on one or another of these theories:
Group Selection. A benefit to survival of a group of species individuals [2] can offset an
individual disadvantage.
Kin selection. Benefit to a small related group [3] can offset individual disadvantage.
Gene-oriented selection. A benefit to propagation of genes can offset individual
disadvantage (e.g. R. Dawkins [4] Selfish Gene Theory)
Evolvability. A trait that increases the rate or precision of the evolution process [5] can
offset individual disadvantage.
None of these population-benefit (or non-individual benefit) evolutionary mechanics
theories suggests that traditional Darwinian individual-benefit-only 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.
Introduction to Biological Aging Theory
11
There is little objection to the idea that a hypothetical trait could benefit a population at
the expense of individual members and of course human civilizations are full of examples of
laws, regulations, religious commandments, and other restrictions on individual behavior in
favor of a wider benefit. All agree that the extinction (or non-extinction) of a population affects
the subsequent biosphere. The primary scientific objection to population-benefit theories has
historically concerned propagation. Some proponents of traditional Darwinism still contend
that it is “impossible” for a trait to propagate and be retained in a population if it causes a net
individual disadvantage, regardless of any population benefit. The main issue here is widely
seen as a long-term vs. short-term issue. Can a long-term wider benefit (such as increased
probability that a population or even species will avoid extinction) offset a short-term
individual disadvantage (such as decreased probability that an individual will produce adult
descendants)? Darwin’s simple mechanics concept certainly seems to definitively prohibit
such a tradeoff. However, genetics discoveries have exposed major complexity in the evolution
process and specifically revealed that the evolution process actually consists of many sub-
processes that operate over vastly different time-scales. The totality of the evolution process is
now seen as operating on a time scale that is longer than long-term benefits, even “species-
level” or “gene-level” benefits such as described above.
More specifically, inter-trait linkages such as described by Williams would work to protect
a trait having a long-term benefit from being selected out in the short-term. See much more
detailed description of the evolutionary mechanics basis for diffuse benefit theories in further
reading.
Evolvability Theories
Darwin’s theory did not consider that the ability to evolve was a species-dependent
variable but rather a constant fundamental inherent property of all living organisms. All living
organisms were subject to mutations and natural selection. Darwin did say that natural
variation in inheritable design characteristics between competing members of a species
population was essential to the evolution process. If there were no variation, there would be
nothing for natural selection to select. Note that variation is a property of a population.
Since Darwin, it has become apparent that many characteristics of particular species affect
the evolution process, particularly in complex (diploid, sexually reproducing) species.
Observed variation in complex species is mainly the result of complex and obviously evolved
biological mechanisms such as diploid genomic organization, miosis, unequal crossover, and
sexual reproduction. Identical twins result from a malfunction in the variation-producing
mechanisms!
Many other aspects of organism design affect evolvability. Brief examples: Mating rituals
that involve some sort of contest (e.g. Bighorn sheep) could enhance selection of characteristics
that are tested by the contest.
Many aspects of genomic design are important to evolvability. Many such aspects such as
repeat patterns and introns, are thought to have little or no effect on the phenotypic design of
an organism but do have plausible impact on the probability that particular mutational changes
will subsequently occur, thus affecting linkages.
Multiple evolvability advantages of an internally limited lifespan have been proposed. A
shorter lifespan (beyond maturity) produces an evolvability advantage because the natural
selection rate is proportional to adult death rate. This is because adult characteristics are only
expressed in adults and latent characteristics do not affect the evolution process. A key part of
Introduction to Biological Aging Theory
12
Darwin’s idea was that organisms do not evolve during their lives but that evolution is driven
by differences in how well individuals having a particular design survive and reproduce.
Consequently, evolution takes place at a rate determined by adult death rate. A hypothetical
species that did not ever die (even from external causes) could not evolve. Other evolvability
advantages of a limited lifespan have been proposed and some theorists [6, 10] even suggest
that gradual aging contributes more to evolvability than sudden death in semelparity. The
ability to adapt more rapidly and precisely is certainly a competitive advantage for a
population.
Evolution of Acquisition Traits
Intelligence belongs to a family of organism design characteristics that depend for their
utility on the acquisition of something that accumulates during the organism’s life and
consequently present a special evolvability problem. Intelligence is the ability to acquire
information about the external world, store that information, and use the information to
improve survival or reproductive capability. Intelligence is useless without the acquired
information (experience) and conversely experience is useless without intelligence. The
selectable property is therefore wisdom, essentially the product of experience and intelligence
or more simply the product of age and intelligence. Experience gradually accumulates during
the life of an organism. If animals were internally immortal, the difficulty is that an older, less
intelligent but more experienced animal could have more wisdom and therefore more fitness
than a younger, less experienced but more intelligent animal. This situation would work against
the evolution of intelligence. A design-limited lifespan acts to limit this otherwise destructive
effect of increasing age. According to this concept, more complex animals that display
intelligence would obtain a larger evolvability benefit from a purposely limited lifespan than
simple organisms like trees and clams.
Immunity presents a similar problem. The evolved characteristic here is the ability to
acquire immunity to pathogen infection through progressive accumulative exposure to
different pathogens. The selectable characteristic is the acquired immunity. Immortality would
work against the evolution and retention of the very complex design characteristics that provide
for acquisition of immunity.
Animals with a social structure can acquire social status, which also tends to increase with
age and results in a similar acquisition issue.
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 traits 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
including mammal aging, and suggest solutions for the propagation issues.
Two different evolutionary mechanics concepts apply to evolvability: If evolvability is
seen as producing a long-term benefit (increased probability that a species will evolve and
consequently survive to produce descendant species) linkage concepts suggested earlier would
apply to evolvability. Since the linkage does not have to be permanent but only long enough
Introduction to Biological Aging Theory
13
for the long-term benefit (e.g. survival of a population) to occur, antagonistic pleiotropy
linkage and other linkages work better for programmed aging than for non-programmed aging.
In addition, evolvability is a component of the natural selection process and the proposal
has been made [6] that evolvability therefore operates on the same time-scale as natural
selection.
Major discussions regarding evolvability are relatively recent (1995+) and post-date
development of the major non-programmed aging theories.
Programmed Mammal Aging
All of the programmed theories support the idea that a limited lifespan could produce a
selectable evolutionary benefit and that therefore organism design characteristics that
purposely limit lifespan could be evolved and retained. Aging theories proposing specific
population benefits for a design-limited lifespan have been proposed for most of them [10, 11,
12, 13].
The first such theory was proposed by German biologist August Weismann [5] in 1882.
Weismann thought that self-limited lifespan or “programmed death” aided the evolution
process by increasing resources available for younger and therefore minutely more evolved
individuals (according to Darwin’s “tiny steps” concept). The population possessing
programmed death would be able to adapt more rapidly to changes in their world and thus have
an evolutionary advantage. Since then, many other population benefits for self-limited lifespan
have been proposed. At the time there was no evolutionary mechanics basis for programmed
lifespan limitation and Weismann’s theory was widely discounted on evolutionary mechanics
grounds.
All of the modern programmed aging theories are backed by the sort of extensive
evolutionary mechanics logic described here and in much more detail elsewhere [6] in addition
to superior match to empirical evidence to be described.
Evolutionary Value of Life
The evolutionary benefit or cost of a particular organism lifespan is central to evolutionary
theories of biological aging.
Fig. 3 below illustrates four different scientific concepts regarding the evolutionary value
of life as related to age of reproductive maturity. The benefit or cost of living and reproducing
beyond a species-specific age is a measure of evolutionary force toward determining the design
of an organism’s lifespan traits. Each of these concepts logically leads to a family of
corresponding biological aging theories that in turn logically lead to particular concepts
regarding the aging process and age-related diseases.
It is clear that it is essential for an organism to live long enough to reach reproductive
maturity and completion of a first reproduction and that degradation due to internal limitations
(such as aging) prior to that point would represent an evolutionary disadvantage. Further, as
illustrated, lifespan 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 and populations could affect details of the
evolutionary benefit of life and therefore the shape and length of the curves below.
Introduction to Biological Aging Theory
14
Fig 3. Evolutionary Cost/Benefit of Continued Life vs. Age – Three Concepts.
The germane scientific disagreements concern the later (older) portions of the curves during
which aging occurs.
Darwin, (interrupted horizontal line A), did not suggest that the evolutionary value of
survival varied with organism age. Any incremental increase in lifespan 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 internal
immortality. Observed conflicts with Darwin’s idea eventually led to development of the other
three concepts.
Peter Medawar [7] (solid line B) proposed in 1952 that the evolutionary benefit of
extended (substantially beyond age of reproductive maturity) lifespan in mammals declined
beyond some species-specific age linked to reproductive maturity because deaths due to
internal causes (aging) would be masked by deaths from external causes.
Proponents of modern non-programmed mammal aging (e.g. G. Williams[8], T. Kirkwood
[9] dotted line C) subsequently proposed that the net evolutionary benefit of additional lifespan
free of the deleterious effects of aging declines to essentially zero at some species-specific age
because of the combined effect of declining value of survival and some compensating benefit
of aging. There is no evolutionary advantage but also no evolutionary disadvantage to having
the internal capability for living and reproducing longer than the species-specific age.
Finally, advocates of programmed aging [e.g. 10, 11, 12, 13] (broken line D) contend that
beyond some species-specific lifespan, also dependent on age of reproductive maturity,
additional lifespan creates an evolutionary disadvantage and that therefore organisms evolved
mechanisms for proactively limiting and even regulating their lifespans to achieve an optimum
lifespan. In this case, there would be evolutionary force (f) to both achieve the species-specific
optimum lifespan by means of myriad evolved survival characteristics and to avoid exceeding
it by means of an evolved lifespan control mechanism. Because, unlike the other concepts,
there is evolutionary force toward limiting lifespan, there is an evolutionary rationale for the
Introduction to Biological Aging Theory
15
development of a complex mechanism to accomplish the limiting function. In a manner similar
to many evolved mechanisms, such a mechanism could include means for detecting local or
temporary external conditions that affect optimum lifespan and optimizing an individual’s
lifespan to fit those conditions, i.e. regulation. Programmed aging provides a better fit to
empirical evidence than the others but requires the newer evolutionary mechanics ideas relative
to concept C.
Important Note: It is widely agreed that living much beyond the age at which an organism
stops reproducing has little evolutionary value. All of the concepts discussed here assume that
reproductive decline with age is a symptom of aging and not an evolutionary cause of aging.
A non-aging (negligibly senescent) 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 lifespan. 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 C, and D. The endless
argument between proponents of these two concepts can thus be summarized: Is the net
evolutionary value of extended life essentially zero, or at least somewhat 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 C and D) involve
subtle secondary effects and complex processes operating during millions or billions of years,
proving that any one of them is correct by evolutionary logic alone has eluded science. There
is no wide scientific agreement regarding value-of-life. Both concepts have current followers.
Aging Mechanisms and Processes
This section summarizes four concepts regarding the biological mechanisms and
processes that are associated with 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.
Introduction to Biological Aging Theory
16
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 his value-of-life concept A 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. Hayflick [14] 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 very poor fit to empirical evidence. In particular, it does not explain the
very large differences in lifespans 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 the effectiveness of which varies between species. The existence of these
mechanisms, corresponding to the respective deteriorating processes, slows accumulation of
the deteriorating effect. The effectiveness of each maintenance and repair mechanism varies
between species because evolutionary force to develop and maintain them varies according to
value-of-life concept C. Organisms with later ages of reproductive maturity needed to live
longer and therefore developed and retained more effective maintenance mechanisms.
Lifespan 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
Deteriorative
Processes
Deteriorative
Processes
Maintenance
Mechanisms
Introduction to Biological Aging Theory
17
the plausibility of intervention. See Issues with Non-Programmed Aging Mechanisms for
arguments against this premise.
Empirical Evidence: This concept fits gradual aging and the multi-species lifespan
variation in mammals. Additionally, we know that various maintenance mechanisms exist:
hairs grow, 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 a particular maintenance mechanism, such as by increasing production of
naturally occurring anti-oxidants or telomere repair enzymes.
According to this concept, each of a potentially large number of maintenance mechanisms
would have independently evolved just the level of effectiveness needed to support the
necessary lifespan. If cancer at too young an age was a problem for a mammal species, that
species would evolve better anti-cancer mechanisms, and so forth. Some general deterioration
mechanisms such as oxidation and telomere shortening might be common to multiple
manifestations of aging and treatment agents affecting them might thus aid treatment of
multiple symptoms. Other deterioration mechanisms associated with specific diseases might
have little or no commonality with others. Finding a treatment agent that generally retards
aging depends on commonality in the causing mechanisms. Consequently, non-programmed
aging theories suggest that there is no treatable common factor causing the many aging
symptoms and research efforts should be entirely directed at specific diseases.
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 lifespans. 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 in diverse tissues suggesting that signaling is involved. This idea logically
descends from value-of-life concept D. Organisms need to limit their lifespans because doing
so produces an evolutionary advantage according to one of the programmed aging theories
based on one of the population-oriented evolutionary mechanics theories.
Empirical Evidence: In addition to fitting the multi-species lifespan 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 1 or 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.
Deteriorative
Processes
Maintenance
Mechanisms
Aging
Program
Introduction to Biological Aging Theory
18
Intervention: In addition to all of the foregoing, we could seek agents that interfere with
the operation of the biological clock or interfere with associated signaling. Signaling in this
context refers to chemical signals such as hormones that are often used to coordinate biological
processes within an organism or even between organisms (pheromones). Because this concept
suggests that there is substantial commonality in the root cause of many or most symptoms of
aging, we can expect to find agents that more or less generally delay aging, i.e. anti-aging
medicines. Programmed aging theories suggest that substantial research efforts should be
directed at determining the precise nature of the common aging mechanism and finding agents
capable of retarding its operation to supplement disease-specific research.
4. Regulated Programmed Aging
Premise: The many deteriorative processes are offset by many 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 or internal conditions.
This allows genetically specified lifespan to be increased or decreased in response to
temporary or local external conditions that affect the optimum lifespan for a population as
suggested by value-of-life concept D.
Empirical Evidence: In addition to all of the above, this concept fits observations of
explicit lifespan regulation in various organisms (e.g. C. Kenyon, et al [15]). It also fits
observations that lifespans are increased by external conditions that would nominally be
expected to increase deterioration such as caloric restriction or other stress because sensing of
these conditions could be adjusting lifespans in order to optimize population benefit. Known
biological clocks are commonly adjusted by sensing of external conditions. For example,
mating seasons and circadian rhythms are synchronized to planetary cycles. Note that an
organism that could adjust its lifespan to accommodate changes in its own age of reproductive
maturity would have an evolutionary advantage according to all of the evolutionary theories
of aging. Reproductive maturity and other aspects of mammal reproduction are themselves
known to be controlled by a complex regulated mechanism involving sensing, biological
clocks, and signaling.
Intervention: In addition to all of the above, agents and protocols 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 (2 above) or even select mechanisms that purposely limit
or regulate organism lifespan (3 or 4 above). Regulated aging requires substantially the same
Deteriorative
Processes
Maintenance
Mechanisms
Aging
Program
Sense
Mechanisms
Introduction to Biological Aging Theory
19
evolutionary assumptions as non-regulated programmed aging but provides a better match to
empirical evidence and more opportunities for intervention.
Since all four aging mechanism concepts involve deteriorative processes, research into
direct intervention with those processes is the least controversial and provides the best fit with
the current highly disease-specific medical and pharmaceutical organizations. 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.
Programmed Lifespan Regulation Strategy
Any biological regulation scheme requires three elements; means for detecting the
relevant local or temporary condition; some logical process or strategy for determining when
to apply regulation; and means for altering the relevant biological function. As a trivial
example, some mammals have the ability to alter their fur density. The obvious strategy would
be to increase fur density in the winter and reduce it in the summer. This scheme requires some
means for detecting the season and would benefit a population by allowing it to operate over a
larger geographic range without migration.
Regulation of aging is based on several concepts: First there exists a particular optimum
lifespan for a given population as described for programmed aging. Second, the optimum
lifespan for a population varies depending on external and internal circumstances such as
predation and age of reproductive maturity. Third, there is a close relationship between
reproductive functions and aging. Fourth, the evolutionary benefit of limiting lifespan is
relatively long-term and less urgent than responding to immediate short-term threats to a
population like avoiding immediate extinction due to increases in predation or unusually severe
environmental conditions.
We can now discuss possible strategies for a mammal regulation scheme that coordinates
lifespan with reproduction in response to various external conditions.
In response to famine a population could decrease its reproduction while increasing its
lifespan. This would increase the short-term survival of a population because merely surviving
takes less food resources than surviving and reproducing.
In response to predation or unusually harsh environmental conditions a population could
increase lifespan to compensate.
In response to overcrowding a population could decrease reproduction and possibly
lifespan to avoid population crashes and extinction events resulting from overpopulation.
Overpopulation could be sensed by detecting pheromones. Starvation and stress due to
harsh environments involves many internal conditions that could be sensed but how would a
population sense predation? One possibility is that predation typically involves terror and
sudden intense physical activity in targeted animals that certainly result in physiological
changes that could be sensed in survivors.
As described below there is actually considerable evidence supporting the sort of
regulation schemes described above. However, there is little scientific agreement concerning
regulation and different mammal species likely possess different regulation schemes. In
particular short-lived animals might have different responses to different stress conditions than
longer-lived species. Example: a typical famine might be long in relation to mouse lifespan but
short relative to human lifespan resulting in differences in regulated response.
Introduction to Biological Aging Theory
20
Aging as a Biological Function
Biological functions evolved because they serve a necessary purpose and share many
common characteristics. Programmed aging theories propose that aging, per se, accomplishes
a necessary function as seen from an evolutionary standpoint. Therefore, programmed aging
theories predict that the aging mechanism will share these characteristics:
Coordination of activities between different tissues and systems. Functions like
digestion, vision, and mobility require that many different tissues and systems operate in a
coordinated manner in order to accomplish the function. This would also apply to an aging
function in that many tissues are affected by aging.
Signaling is ubiquitous in biological functions in order to implement coordination.
Nervous signaling involves specialized nerve cells in animals that can respond rapidly.
Chemical signaling involves generating, distributing, and detecting chemical signals (e.g.
hormones and pheromones) and is common in living organisms including plants. In mammals
such signals are commonly circulated in the blood.
Biological clocks coordinate activities that need to take place as a function of time
obviously including an aging function.
Regulation involves the detection of internal or external conditions that affect the
optimum operation of a function and adjusting the function’s operation to compensate.
Regulation is common in organisms including plants.
Sensing of external or internal conditions is essential to regulation. Biological clocks are
often derived from or synchronized to external conditions such as planetary cycles.
Researchers following programmed aging theories will be looking for signals, receptors,
coordination of activities, regulation, sensing, clocks, and other characteristics that are
common to biological functions.
Empirical Evidence Supporting Programmed Aging
This section presents a summary of experimental and observational evidence that provides
insight into aging mechanisms, aging theories, and underlying evolutionary mechanics
theories. As we will see, current empirical evidence strongly favors programmed aging and
even supports the idea that aging can be altered by detection of conditions that alter the
optimum lifespan for a population, i.e. a regulated aging function.
Genetics Discoveries Affecting Evolutionary Mechanics
Darwin’s theory was largely based on detailed comparisons of externally obvious
phenotypic characteristics of various plants and animals. Darwin showed that species were
descended from earlier species and that the succession and propagation process was affected
by geographic barriers such as mountains and oceans. Evolution of Earth life is widely thought
to have originated in a single prokaryote species and Darwin did not attempt to explain the
origin of that species. Species displayed the same sort of family relationships that can be seen
in observations of individuals.
Our ability to perform similarly detailed comparisons of genomic characteristics between
species and individuals is in its infancy. In 2003 it required about 3 years and three billion
dollars to determine a single human full sequence genome. In 2020 a full sequence genome
Introduction to Biological Aging Theory
21
costs less than $1000. As suggested earlier, the genomic design of an organism affects the
evolution process in many ways.
Digital Genetics. In the mid-20th century it was discovered that biological inheritance
involves the transmission of information in digital form between parent and descendant of any
organism. This digital nature of biological inheritance has a long list of implications regarding
the evolution process [32] in particular in supporting evolvability theories and dependent
programmed aging theories.
Mutation vs. Selectable Property. Darwin’s concept assumes a very close relationship
between a mutational change that originally occurs in a single individual and an organism
property that can be selected by the evolution process. This idea is still probably substantially
valid in haploid species like bacteria and strongly implies that only mutations that cause
possessing individuals to produce more adult descendants can be selected. However, in diploid,
sexually reproducing species a population can possess millions of individual mutations such
as single nucleotide polymorphisms, each of which typically has a minor effect on phenotypic
design. The variation we see is mainly the result of recombining alleles to produce sets that
create more significant phenotypic differences. In addition, because of the possibility of a
recessive trait, not all descendants will express a trait even though an organism possesses one
allele. Consequently, the evolution process is not the same in diploid species as in haploid
species, and there does not exist a close relationship between mutation and selectable property.
Complex Process. Genetics discoveries generally suggest that the evolution process in
diploid organisms is much more complex than previously thought and that therefore we should
give more weight to direct evidence than to arcane theory arguments. Few having studied the
history of genetics science would consider that we are even close to completely understanding
biological inheritance. More specifically, discoveries suggest that evolution is an even longer
and more time-consuming process than previously envisioned.
Lifespan Regulation by Sensing of External Conditions
Some investigators [15,16] report instances in which lifespan of simple organisms is
mediated or regulated by sensing of external signals. This is typical of evolved mechanisms.
Caloric Restriction and Lifespan
Extensive experimental evidence [17] confirms that mammal lifespans are typically
increased, as much as doubled, when food intake is restricted and that lifespan 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 lifespan while reducing its reproductive activity could survive
as long with less food than another population of otherwise identical animals that did not
extend their lifespans 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. 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.
Introduction to Biological Aging Theory
22
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 Lifespan
Experimenters have found that several forms of stress [18] in addition to caloric
restriction counter-intuitively increase lifespans in various organisms. For example, exercise
appears to increase lifespan and inactivity decreases lifespan. 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 lifespan, 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 because the immediate short-term threat to a population is more urgent
than a longer-term need to genetically adapt to changes in external conditions.
Non-programmed theories have difficulty with the stress response. Stress would
presumably increase the rate at which deterioration occurred.
There is increasing interest in the idea that high intensity interval training (HIIT) increases
lifespan and beneficially affects multiple age-related diseases. This concept fits with the logic
described in Programmed Lifespan Regulation Strategy.
Aging Genes
Several experimenters [19] have reported discovering genes that limit lifespan in various
simple organisms. Deleting the genes through genetic engineering has resulted in lifespan
increases of as much as a factor of ten. 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 lifespan. Followers of non-programmed aging theories based on value-of-life concept B
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 [19] 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 lifespan regulation system is mediated by detection of external signals.
Hutchinson-Guilford Progeria and Werner Syndrome
Hutchinson-Guilford progeria [20] and Werner syndrome [21] 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 idea fits programmed aging theories
(common lifespan management system) better than non-programmed theories in which
multiple maintenance and repair mechanisms independently evolved.
Negligible Senescence
Organisms that do not exhibit deterioration with age [22] 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.
Introduction to Biological Aging Theory
23
A 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 lifespan (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. Naturally occurring cancer has not been observed in this species. The naked
mole rat has a eusocial reproductive scheme seen in only one other similar mammal but similar
to colony insects. Only one pair of animals is reproductive in the colony at any one time. The
reproductive behavior is likely the cause of the large lifespan difference from other rodents of
similar size.
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 more than 4850 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.
Although some NS species have greatly delayed sexual maturity relative to similar
senescent species, others do not.
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
Introduction to Biological Aging Theory
24
to explain the enormous differences in observed lifespans, especially between species with
similar metabolisms.
Non-programmed aging theories have to assume that the NS species has some unknown
reason for requiring a very long lifespan even though similar species do not and that they
consequently evolved extremely effective maintenance and repair mechanisms.
Programmed theories suggest that NS species have suffered a mutational malfunction in
their suicide mechanism and have therefore lost their ability to age. They consequently have a
reduced probability of producing descendant species and increased probability of becoming
extinct because of loss of long-term evolutionary benefits of aging.
Octopus Suicide
The octopus has an interesting 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 sense organs were
surgically removed (Wodinsky [23]) 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.
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. For example, a frog loses
its tail by apoptosis. 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 Lifespan
Some characteristics of organisms vary significantly between very similar 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 more 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, lifespan is superficial. Different
varieties of salmon, otherwise very similar, have grossly different lifespans. Other similar fish
species have even more variation in lifespans. Where it might appear that the shorter-lived
varieties would be at a huge evolutionary 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 lifespan is determined by
fundamental limitations and also conflict with the idea that extended lifespan necessarily incurs
Introduction to Biological Aging Theory
25
some sort of individual penalty such as reduced reproductive effectiveness or loss of some
other individually beneficial function.
As described above evolvability theories of programmed aging suggest that the
disadvantage of extended life is more severe in the case of more complex organisms that
display social structure, intelligence, or immunity, leading to the more aggressive aging
mechanisms seen in mammals.
Hormones - Blood Experiments
As indicated earlier, programmed aging theories predict that signaling would be involved
in aging mechanisms. Following this idea, we could predict that components in blood would
signal various tissues to exhibit or not exhibit aging behavior.
We could further predict that these components are more likely to be in the plasma as
opposed to blood cells. The signals might be either pro-aging or anti-aging or both. That is, an
anti-aging signal would inhibit aging in cells receiving the signal where a pro-aging signal
would cause receiving cells to exhibit aging.
Some human hormones increase with age, some decrease, and some are apparently not
affected by age, a finding that acts to suggest an aging program.
This thinking led to various kinds of blood experiments. We could expose old tissue to
young blood or vice versa. We could transfuse old blood into young animals or vice versa. We
could even surgically interconnect young and old animals so they share the same blood supply.
The beauty of these experiments is that we do not have to have, in advance, the answers to the
questions in the previous paragraphs. Such experiments have been done and yielded positive
results![30]
Harold Katcher [31] has proposed that human experiments in which old plasma is replaced
by young plasma could be performed in the near future because plasma exchange is already an
accepted procedure.
Of course, the next step is to identify the specific blood components responsible for
regulating aging.
Non-Science Factors Favor Non-Programmed Theories
Many factors without scientific merit favor non-programmed aging theories.
- Education. Most science-oriented people are very familiar with Darwin’s theory but not
trained in modern evolutionary mechanics concepts. They consequently tend to believe in the
earlier fundamental limitation theories and often consider programmed aging to be ridiculous.
This affects their attitudes regarding aging, aging research, and age-related disease research.
Because the evolutionary mechanics issues affect only a tiny fraction of observations, they can
be easily ignored in introductory bioscience education.
- Inertia. Proponents of the earlier non-programmed theories tend to be older, more senior,
and therefore more influential.
- Anti-Science Effect. Existence of intelligent design and creationism “theories” tends
toward an atmosphere in which any disagreement with “Darwin’s theory” is seen as bogus.
Scientists and textbook editors are reluctant to admit any weakness by revealing scientific
disagreements regarding evolution theory, especially in introductory biology venues in the
U.S.
Introduction to Biological Aging Theory
26
Programmed/ Non-Programmed Controversy - Status
Programmed aging was first proposed in 1882 but as recently as 2009 gerontologists
widely considered programmed aging to be theoretically impossible on evolutionary
mechanics theory grounds and therefore essentially scientifically ridiculous:
“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.” No Truth to
the Fountain of Youth - Olshansky, Hayflick, and Carnes, Scientific American, 2002.
This article was endorsed by 51 gerontologists and was republished by Scientific
American in 2004 and 2009. The main purpose of this article was to warn the public against
scientifically weak anti-aging treatments:
“Fifty-one scientists who study aging have issued a warning to the public: no anti-aging
remedy on the market today has been proved effective. Here's why they are speaking up.”
However, the article describes the reality in 2002 that programmed aging was widely seen
as an obsolete idea that was somewhat popular with the general public but had no scientific
basis. Under those conditions a researcher publicly declaring a belief in programmed aging
could be risking career suicide and, at best, major difficulty in obtaining funding and other
support. Except for some islands of activity there was little support for research into
programmed aging making non-programmed aging a sort of self-fulfilling prophecy. Non-
programmed theories competed mainly with each other and despite decades of activity none
of the non-programmed theories achieved general acceptance.
By 2020, few proponents (even authors) of non-programmed aging still claim
programmed aging is “impossible” but rather suggest it is less likely than non-programmed
aging and as we have seen there is now substantial theoretical and empirical support for
programmed aging. However, programmed aging researchers often still avoid using
terminology like “programmed aging” in public articles and documents that are describing
signaling pathways, genetic control of senescence, and research directions that are clearly
associated with programmed aging.
In 2002 a competitive medical research organization (such as a pharmaceutical company)
dealing with age-related diseases could quite reasonably expend all of their resources on
research based on the idea that aging was non-programmed. Today such an organization could
not afford to summarily dismiss programmed aging concepts and major efforts following these
concepts are underway as described below. Note that for-profit companies are not motivated
to publicly share their detailed research directions.
In addition, the medical/ pharmaceutical establishment is very highly organized toward
specific diseases and conditions. We would not expect to see new prescription drugs clinically
demonstrated and approved “to extend lifespan.” Instead we can expect to see products tested,
certified, and approved for much more limited and more easily demonstrated scope in treating
specific age-related diseases, e.g. “for treatment of age-related macular degeneration in certain
elderly patients” that were developed using programmed aging concepts.
Vitamin and health food stores are full of thousands of products that are thought to be of
value in treating some disease or condition but actual effectiveness varies. As programmed
aging concepts become more popular, we can expect to see such products that are thought to
be of use in lifespan extension. The same caveats would exist.
Introduction to Biological Aging Theory
27
Recent Arguments Against Non-Programmed Aging
Arguments Against the Disposable Soma Theory
The non-programmed disposable soma theory (DST) (T. Kirkwood, R. Holliday, 1975)
[9] suggests that aging is the result of deteriorative processes that can be and are overcome by
maintenance and repair processes in living organisms. DST is based on the earlier concepts by
Medawar and Williams to the effect that the evolutionary value of survival and reproduction
declines with age in a species-specific way and that aging must produce a compensating benefit
to offset the loss of later-life survival and reproduction. DST proposes that maintenance
consumes substantial material and energy resources. If the organism decreased maintenance at
some species-specific age thus incurring aging in late-life the energy and material resources
saved might be applied to increasing survival and reproductive effort in early-life thus
producing the required compensating benefit in a way that is compatible with traditional
individual-benefit-only evolutionary mechanics.
There is no disagreement that merely maintaining life in mammals takes a lot of energy
and resources. We need to keep breathing even when asleep and much material in the form of
hairs, skin cells, etc. is discarded during life. However, a major problem is that DST assumes
that a tradeoff can be made between saving resources in early life and incurring aging and
consequent reduction in survival and reproductive capability in later life. A major problem
with this idea is that the vast majority of maintenance effort is obviously of a very short-term
nature. Blood cells, epithelial cells, and sperm cells only last a few weeks. Wounds heal and
hair grows on a short-term basis. Even if some cell type only needed to be replaced every 20
years, it is obvious that the energy and material needed to perform that function would be
negligible compared to the short-term need to replace cells with much shorter lifetimes.
Therefore, reducing maintenance effort would result in an immediate loss of fitness and the
tradeoff envisioned by DST would not work.
In addition, it is difficult to reconcile the gross lifespan differences with DST. If nature
can discontinue maintenance in a mouse’s youth to result in death 18 months later, how do we
reconcile that with the life of a human or whale? Wouldn’t the time delay between decreasing
maintenance and adverse symptoms be similar?
DST was competitive with other non-programmed aging theories during an era when
programmed aging was seen as theoretically impossible but is less competitive with modern
programmed aging theories.
Finally, DST appears to be a programmed aging theory. The evolutionary need to decrease
many different maintenance and repair mechanisms in diverse tissues on a common species-
unique schedule would appear to require a common program mechanism similar to the ones
described in this book.
Arguments Against the Antagonistic Pleiotropy Theory
The antagonistic pleiotropy theory (APT) (Williams 1957) [8] suggests that genomic
linkage between some (unspecified) beneficial property(s) and aging prevented the evolution
process from evolving a longer internally controlled lifespan despite Williams’ own contention
that aging caused fitness-adverse consequences for a population. The linkage would prevent
the evolution process from evolving a senescence-free (or delayed senescence) design because
doing so would also remove the linked beneficial trait. Williams’ concept assumes the linkage
Introduction to Biological Aging Theory
28
would be permanent because presumably aging also presented a problem for an ancestor
species and its ancestors, and so forth.
An obvious problem with this idea is: Why didn’t AP also prevent the evolution of any
other trait that had a similarly minor effect on fitness like slightly longer claws or slightly
shorter feet? Is it not an astounding coincidence that AP only affected aging? Doesn’t the APT
idea conflict with Darwin’s “tiny steps” concept?
It is understood that there can exist many phenotypic linkages between traits. For example,
longer legs might benefit an antelope. But a longer femur would be adverse unless
accompanied by larger leg muscles, stronger joints, better blood supply, and other design
changes. This supports Darwin’s “tiny steps” concept.
In addition to AP there are many other ways that genomic linkages can exist [6] in ways
that would increase the time required for the evolution process to resolve the linkage.
An AP linkage that exists because a single gene controls more than one phenotypic
property can be removed by complementary changes to multiple genes. This has to be true on
a time-scale similar to the time a mammal species has existed in order to enable the adaptation
of the differences we observe between mammal species [6].
The AP theory depends on the idea that unspecified beneficial trait(s) linked to aging
would result in essentially zero net evolutionary force toward living longer following a
relatively young age. However, following Medawar’s concept this evolutionary force is
actually a function of age as described in Fig. 3 (C). It would appear to be extremely
implausible that the value-of-life function of the linked trait, when subtracted from Medawar’s
function (Fig. 3 (B)) results in net of zero (Fig. 3 (C)). If not essentially zero, then the
evolutionary force concept leads to Medawar’s concept or programmed aging.
Issues with Non-Programmed Aging Mechanisms
The aging mechanism concept (2) that logically follows from the evolutionary non-
programmed theories has some logical issues. This idea requires a subtle but important
assumption: Each of the many maintenance and repair mechanisms must have an
incrementally different design to satisfy each increment of lifespan. An animal that needs to
live for 10 years nominally has slightly better anti-cancer mechanisms, slightly better anti-
heart disease mechanisms, etc., than an animal that only needs to live for 9 years and so
forth. This idea is somewhat counter-intuitive and implausible. Why would replacing dead
cells (or some other maintenance function) be more difficult or require more biological
infrastructure in an 80-year-old than in an 8-year-old?
Most maintenance and repair issues appear to be very short-term because they exist in
even very short-lived organisms and some maintenance activities (such as sleep) are
obviously operating on an extremely short-term basis. This is progressively more of a
problem for longer-lived animals. Are we supposed to believe that a repair mechanism is
99.99 percent effective in mice and 99.9999 percent effective in some long-lived organism?
What would be the differences in the designs of these mechanisms?
The existence of apparently non-senescent organisms is a problem for this concept. Why
and how would they have acquired negligible senescence?
None of these problems affect the programmed aging mechanism concepts.
Introduction to Biological Aging Theory
29
Recent Arguments Against Programmed Aging
A common argument against programmed aging is that just as the evolutionary force
toward living longer decreases with age because progressively fewer individuals would
benefit, the evolutionary force toward developing an aging program designed to limit lifespan
would also decline for the same reason. Why would an aging program be necessary if external
causes of death already limit a population?
Programmed aging proponents suggest that the negative impact of a relatively few long-
lived individuals could exceed a merely numerical analysis and that internally limiting the
lifespan of each individual is not the same as external circumstances that limit average
lifespan. Example, in animals with a social structure or “pecking order” a few very long-lived
individuals could significantly degrade genetic diversity in a population, reducing variation
and therefore evolvability.
Another argument suggests that it is impossible for an organism to evolve myriad traits
that help it to live longer and breed more and simultaneously evolve traits that purposely limit
lifespan and opportunity for reproduction. Isn’t this an obvious conflict?
Programmed aging proponents point out that it is common for organisms to evolve
conflicting traits at different times in their lives. A frog needs a tail at one point in its life and
so evolves a tail. It needs no tail at another stage of its life and so evolves no tail in that stage.
Metamorphosis in insects shows similar conflicting design characteristics at different life
stages. The same would apply to lifespan.
See detailed published arguments against programmed aging in these articles [24, 34, 35].
Social Issues with Aging Theories
A specific internally-limited lifespan is one of the most fundamental aspects of human
existence and affects many aspects of civilization and society. The large increase in average
lifespan in the last century has already impacted issues such as social security, retirement age,
annuities, need for term limits for elected officials, wealth imbalance between younger and
older people, etc. Until recently aging theories suggested that we would approach an ultimate
limit in lifespan as also suggested by the historic mortality chart. Programmed aging theories
suggest that a potentially much longer human lifespan and larger impact to social issues is
possible. See more below.
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, i.e. lifespan extension. As indicated earlier, most people are essentially trained to
believe that anti-aging medicine is impossible. Some physicians share this view and such a
view has been historically protective because of the many quacks and scams 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 were historically widely seen as a foolish “chase
after the fountain of youth.” Few researchers wanted to embark on a career in which progress
is widely seen as “impossible.”
Introduction to Biological Aging Theory
30
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 averse 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 lifespan. 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 much medical research is 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 diet can delay aging. There is clinical data suggesting
that some agents such as aspirin and statins have a simultaneous beneficial effect on both
cancer [27] and heart disease. Many items of empirical evidence previously mentioned strongly
suggest aging is alterable. Potential anti-aging agents include metformin, resveratrol, and
rapamycin. (Note that metformin has significant adverse side effects.)
A very minor improvement in human lifespan 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 lifespan
would be insignificant. A ten percent relaxation of aging characteristics would add more than
seven years to typical life expectancy!
Anti-Aging Medical Practices advise patients on increasing healthy life (eat less,
exercise more, avoid dangerous behaviors, follow medical advice, etc.) and can also prescribe
agents found to be promising in animal or human testing (see below). This can involve “off-
book” prescription of pharmaceutical agents and treatments.
American Academy of Anti-Aging Medicine (A4M)
From their website: “The American Academy of Anti-Aging Medicine (A4M) is a US
federally registered 501(c) 3 non-profit organization comprised of over 26,000 members
including: physicians, health practitioners, scientists, governmental officials, and members of
the general public, representing over 110 nations.
The A4M is dedicated to the advancement of technology to detect, prevent, and treat aging
related disease and to promote research into methods to retard and optimize the human aging
process. The A4M is also dedicated to educating physicians, scientists, and members of the
public on biomedical sciences, breaking technologies, and anti-aging issues.”
A4M says that 85% of their members are physicians and 12% are scientists, researchers,
and health practitioners. Many A4M members have added an anti-aging component to an
existing practice in another specialty. In addition to lifespan extension, A4M includes cosmetic
medicine and increasing the healthy/active stage of life in their definition of anti-aging
medicine.
Regarding lifespan extension or generally delaying aging, A4M participants are promoting
two initiatives:
Introduction to Biological Aging Theory
31
Telomerase Activators: As indicated earlier, telomere shortening has long been seen as
part of an aging process. Telomerase repairs telomeres and therefore agents that enhance
production of telomerase might delay aging. Non-prescription telomerase activators are now
available. A clinical trial suggested that such agents do increase telomerase but lifespan effect
has not been demonstrated.
Bio-Identical Hormone Replacement Therapy (BHRT): Age-related changes in
multiple human hormones are known to occur. Programmed aging theories suggest such
changes might be signaling associated with an aging program and that therefore interfering
with hormone levels could be an effective anti-aging treatment. However earlier attempts at
hormone therapy such as used to treat menopause symptoms were controversial because of
adverse side effects. In addition, specific hormones associated with controlling aging (if any)
have not been identified. Proponents of BHRT suggest that recent capabilities for producing
hormones chemically identical to human hormones (as opposed to only similar in the earlier
treatments) will reduce or eliminate any adverse side effects.
Anti-Aging Research
Here are brief descriptions of a few current anti-aging research efforts:
NIH/NIA Interventions Testing Program
The U.S. National Institutes of Health/ National Institute on Aging (NIH/NIA) has an
Interventions Testing Program (ITP):
“NIA's ITP is a multi-institutional study investigating treatments with the potential to
extend lifespan and delay disease and dysfunction in mice. Such treatments include:
Pharmaceuticals, Nutraceuticals, Foods, Diets, Dietary supplements, Plant extracts,
Hormones, Peptides, Amino acids, Chelators, Redox agents, Other agents or mixtures of
agents.”
Although they carefully avoid using that term, NIH/NIA is obviously supporting a search
for mammal anti-aging agents and protocols. This suggests increasing acceptance of the idea
that aging, per se, is a treatable condition and that major symptoms of aging have a treatable
common cause as predicted by programmed aging theories.
ITP involves triple-redundant and geographically separate testing facilities to increase
confidence in results. The ITP only tests oral agents (not injectables, pellets, lavage treatments,
or exercise regimens), which is a significant limitation.
Google Calico Aging Research Company
In 2013 Google (now Alphabet Inc.) started a new aging research company called Calico
Labs. This was part of Google’s “moonshot” initiative, which also includes other cutting-edge
and outside-the-box efforts like the driverless car. Google has a corporate strategy to include
such bold efforts outside their core industry as parts of their overall R & D activity.
“Calico is a research and development company whose mission is to harness advanced
technologies to increase our understanding of the biology that controls lifespan. We will use
that knowledge to devise interventions that enable people to lead longer and healthier lives.
Introduction to Biological Aging Theory
32
Executing on this mission will require an unprecedented level of interdisciplinary effort and a
long-term focus for which funding is already in place.”
In September 2014 Calico and major pharmaceutical company AbbVie announced a joint
effort that each company will initially fund with $250 million. Each partner is prepared to
invest an additional $500 million. The size of Google’s current investment in Calico is unclear.
This development is very exciting, especially to programmed aging proponents, for
several reasons:
- Google/ Calico is explicitly looking for ways (“interventions”) to delay the aging
process, i.e. anti-aging medicine.
- Calico is substantially funded.
- Calico is a potentially extremely profitable investment for Google/Alphabet and its
stockholders. Imagine what the patents could be worth if fundamentally new anti-aging
treatments are developed! Anti-aging research is in the “low hanging fruit” stage as opposed
to the “incremental” and “diminishing return” stage that characterizes much medical research.
- Calico is unlikely to be as adversely affected by academic politics, traditional thinking,
and non-science factors that have crippled progress in this area for generations.
- Calico’s VP for Aging Research is Cynthia Kenyon, a leading experimentalist whose
former lab at UCSF has produced important insight into the nature of programmed aging
mechanisms.
- Calico and Kenyon’s appointment represent a tacit acceptance of the idea that aging is
programmed and that therefore agents and protocols can be found that generally interfere with
the aging program. The earlier and still more popular non-programmed aging theories suggest
that developing agents that generally delay aging is “impossible” or at least unlikely.
- Calico will likely lead to other similar initiatives and could result in major and relatively
short-term advances in efforts to delay aging and age-related diseases.
- Calico is likely to benefit from non-traditional data collection and genetic research
methods pioneered by 23andme, another Google-related company.
Vladimir Skulachev directs the Homo Sapiens Liberatus organization at Moscow State
University, which performs research on programmed aging mechanisms. 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. Prof. Skulachev is also the chief editor of
Biochemistry (Moscow), which publishes an annual special issue called Phenotopsis that
specifically supports programmed aging.
In 2012 a commercial medication, Visomitin, based on SkQ1 became available in Russia
for treatment of “dry eye” and some other age-related eye diseases.
Biotime Inc. in Alameda CA, now Lineage Cell Therapeutics is investigating altering the
telomere clock, telomerase therapy, and other approaches to regenerative medicine.
Introduction to Biological Aging Theory
33
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 strong proponent of non-
programmed aging but also believes that aging, per se, is a highly treatable condition.
Some Research Implications of Theories
Legacy and non-programmed aging mechanisms suggest that damage from aging
accumulates during an animal’s life, at least beyond maturity. This suggests that an anti-aging
agent (e.g. anti-oxidant) would need to be administered during the animal’s entire adult lifetime
to be most effective. This has major implications for research because it implies that tests of
prospective anti-agents, even in mice, will take years to perform and human trials could take
decades. This issue is more serious because of evidence that short-lived mammals do not
appear to correlate well with longer-lived mammals regarding effectiveness of agents such as
resveratrol. As indicated earlier, if aging is programmed different mammal species can be
expected to have differences in their aging programs.
However, programmed aging mechanisms suggest that the damage mechanisms actually
operate on a short-term basis (as suggested by similarity of symptoms in Key Observations)
and observed species-specific senescence is determined by an aging program that can vary
substantially between species. According to this concept the degree of damage and associated
disfunction is determined in the relatively short-term by the program. Therefore, an anti-aging
agent that affects the program could have a relatively large effect on elderly individuals.
Following this concept testing could be done in elderly animals and humans and results
determined in much shorter tests.
A similar issue concerns the relationship between damage prevention (maintenance) and
damage repair (rejuvenation). If an anti-aging agent acts by delaying as opposed to repairing
aging, late-life treatment would be less effective.
Summary
- Aging theories are critical to medical research because understanding massively age-
related diseases (more than half of the U.S. NIH medical research budget) requires
understanding aging. The current programmed and non-programmed theories predict very
different biological aging mechanisms and consequently very different age-related disease
mechanisms.
- There is currently wide scientific agreement that aging and lifespan are organism
design features that have been determined by the evolution process (traits). Recent
discoveries, especially in genetics, have exposed issues concerning the mechanics of
evolution that affect aging theory.
- Consequently, evolutionary biological aging theories are essentially entirely
determined by the underlying evolutionary mechanics theories. The figure below shows the
historic timeline at which various evolutionary mechanics concepts appeared and the
corresponding dependent aging theories.
- Our collective confidence that we understand the fine details of evolutionary
mechanics has declined since the mid-1900s because of major complicating factors exposed
by genetics research and the continued existence of unresolved conflicts with observations.
Introduction to Biological Aging Theory
34
This implies that we should place proportionally more emphasis on empirical evidence on
aging and aging mechanisms.
- Programmed aging theories provide a better fit to empirical evidence and do not suffer
from numerous logical issues that apply to non-programmed theories.
- Non-science (social, educational, academic, even religious) factors favor non-
programmed aging.
- Continued non-resolution of the programmed/ non-programmed controversy damages
the credibility of the medical research establishment and thereby reduces support and
funding.
- Large recent investments in programmed-aging-based research suggest an increasing
trend toward programmed aging.
- A growing physician community believes in anti-aging medicine.
Fig 5. Timeline of Major Evolutionary Mechanics Concepts and Dependent
Aging Theories
Further Reading
The book The Evolution of Aging 3rd Edition, ISBN 978-0-978-87090-5-9 (2014
paperback 8.5 x 11 190 pages) provides a much more extensive coverage of this subject. This
book is also widely available in e-book form from Amazon Kindle, Nook, iBooks, and PDF
format.
Introduction to Biological Aging Theory
35
The web site: http://www.programmed-aging.org/ provides extensive discussion of aging
theories with emphasis on programmed aging and includes links to many full-text journal
articles.
Information on negligible senescence: http://www.agelessanimals.org/
Human mortality data: http://www.mortality.org/
PubMed, operated by the U.S. National Institutes of Health, provides public online
searchable catalogs including abstracts of major journal articles concerning bioscience and has
articles on all the subjects mentioned here: http://www.ncbi.nlm.nih.gov/pubmed
The journal Biochemistry (Moscow) Phenoptosis is dedicated to discussions of
programmed aging and consequent medical and biological research. Free full-text access to
articles (PDF) is available at: http://protein.bio.msu.ru/biokhimiya/
Other Books and Articles by Theodore C. Goldsmith
Encyclopedia of Gerontology and Population Aging (Eds. D. Gu, M. DuPre.) Springer,
Cham. ISBN 978-3-319-69892-2 DOI: 10.1007/978-3-319-69892-2
In Biogerontology-General-1 (ed. G. Libertini):
Evolvability Theory of Aging, T. Goldsmith
Timeline of Aging Research, T. Goldsmith
Exercise and Physical Activity for Older Adults (Ed. D. Bouchard). Human Kinetics
Champaign. In production:
Chap. 2. Aging Theories, T Goldsmith
The author’s papers and e-books on aging are available at:
http://www.azinet.com/aging/
Author’s Blog: http:// http://aging-theories.org/
E-book: Aging by Design: How New Thinking on Aging Will Change Your Life. Azinet
Press. ISBN: 978-0-9788709-3-5 Revised edition 5/2014
E-book: New Truth to the Fountain of Youth: The Emerging Reality of Anti-Aging
Medicine 2nd Ed. Azinet Press ISBN: 978-0-9788709-4.2
Introduction to Biological Aging Theory
37
References
1. Darwin C. 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 1882
6. Goldsmith T. The Evolution of Aging 3rd Edition. ISBN 978-0-9788709-5-9. 2014.
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, 1975.
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.
11. Goldsmith T. 2008. Aging, evolvability, and the individual benefit requirement;
medical implications of aging theory controversies. J. Theor. Biol. 252 (4): 764–8
12. Mitteldorf J. Aging selected for its own sake, Evolutionary Ecology Research, 2004,
6: 1-17
13. Libertini, G. 2008. Empirical evidence for various evolutionary hypotheses on
species demonstrating increasing mortality with increasing chronological age in the wild.
Scientific World Journal 19 (8): 182–93
14. Hayflick L, Moorhead PS. 1961. The serial cultivation of human diploid cell strains.
Exp Cell Res 25: 585–621.
15. Apfeld J, Kenyon C. Regulation of lifespan by sensory perception in Caenorhabditis
elegans. Nature 1999.
16. Bartke, Antebi. The endocrine regulation of aging by insulin-like signals, Science
2003 Feb 28;299(5611):1346-51
17. Weindruch R, Walford RL, Fligiel S, Guthrie D. The retardation of aging in mice by
dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutrition 1986;
116: 641-54
18. Liu PY, Brummel-Smith K, Ilich JZ. Aerobic exercise and whole-body vibration in
offsetting bone loss in older adults. J Aging Res. 2011 Jan 3;2011:379674.
19. Jennie B. Dorman, Bella Albinder, Terry Shroyer and Cynthia Kenyon The age-1
and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis
elegans. Genetics 141(4), 1399-1406 (1995)
20. P Eriksson M, Brown W, Gordon L, Glynn M, Singer J, Scott L, Erdos M. Recurrent
de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature,
May 2003
21. Gray, Md; Shen, Jc; Kamath-Loeb, As; Blank, A; Sopher, Bl; Martin, Gm; Oshima,
J; Loeb, La (Sep 1997). The Werner syndrome protein is a DNA helicase. Nature genetics 17
(1): 100–3. doi:10.1038/ng0997-100. PMID 9288107
Introduction to Biological Aging Theory
38
22. Buffenstein R. The naked mole-rat: a new long-living model for human aging
research. J Gerontol 2005.
23. Wodinsky J. 1977. Hormonal inhibition of feeding and death in octopus: control by
optic gland secretion. Science, 198: 948–951.
24. Kirkwood T, Melov S. On the programmed/ non-programmed nature of ageing
within the life history. Current Biology 21 R701-7. 2011
25. Goldsmith T. On the programmed/ non-programmed aging controversy.
Biochemistry (Moscow) 77-7. 2012. PMID: 22817536
26. Skulachev V. Aging as a particular case of phenoptosis, the programmed death of an
organism (a response to Kirkwood and Melov "On the programmed/non-programmed nature
of ageing within the life history"). Aging (Albany NY). Nov;3(11):1120-3 2011. PMID:
22146104
27. St Poynter J. et al. Statins and the Risk of Colorectal Cancer. New England Journal
of Medicine; 352:2184-2192, May 26, 2005.
28. Goldsmith T. Arguments against non-programmed aging theories. Biochemistry
(Moscow) 78-9 2013. PMID: 24228918
29. Goldsmith T. Aging Theories and the Zero-Sum Game, Guest editorial Rejuvenation
Research 17(1) 2014. PMID: 24438180
30 Villeda S, et al. The ageing systemic milieu negatively regulates neurogenesis and
cognitive function. Nature. 2011 Aug 31;477(7362):90-4. doi: 10.1038/nature10357
31 Katcher HL. Studies that shed new light on aging. Biochemistry (Mosc). 2013
Sep;78(9):1061-70. doi: 10.1134/S0006297913090137. PMID: 24228929
32 Goldsmith TC. Digital genetics, variation, evolvability, and the evolution of
programmed aging. Biochemistry (Moscow) 84 12 1792-1800
doi:10.1134/S0006297919120046
33 Longo VD, et al. 2015. Interventions to Slow Aging in Humans: Are We Ready?
Aging Cell 14, pp497–510
34 De Grey A. (2015) Do we have genes that exist to hasten aging? New data, new
arguments, but the answer is still no. Curr Aging Sci. 8(1):24-33.
35 Kowald A, and Kirkwood T. 2016. Can aging be programmed? A critical literature
review. Aging Cell doi: 10.1111/acel.12510
Introduction to Biological Aging Theory
39
Index
AbbVie .................................................. 32
acquisition issue .................................... 12
Acquisition Trait ................................... 12
Altruism .................................................. 7
American Academy of Anti-Aging
Medicine ........................................... 30
An Unsolved Problem of Biology ............. 8
antagonistic pleiotropy ............................ 9
anti-oxidants ......................................... 16
apoptosis ............................................... 24
Biochemistry (Moscow) ......................... 32
Bio-Identical Hormone Replacement
Therapy (BHRT) ............................... 31
Biological clocks ................................... 20
Bowhead whale ....................................... 1
caloric restriction .................................. 21
Carnes ................................................... 26
Darwin .................................................... 5
Digital Genetics .................................... 21
disposable soma theory ......................... 10
Evolutionary mechanics theory ............... 5
evolvability ........................................... 11
Evolvability .......................................... 10
genomic characteristics ......................... 20
Google Calico Aging Research.............. 31
Group Selection .................................... 10
Hayflick ................................................ 16
Holliday ................................................ 27
Huntington ’s chorea ............................... 9
Immunity .............................................. 12
individual benefit. ................................... 7
Intelligence ........................................... 12
internal immortality ................................ 6
Interventions Testing Program............... 31
Katcher ................................................. 25
Kenyon ................................................. 18
Kin selection ......................................... 10
Kirkwood .............................................. 14
maintenance and repair .......................... 16
Mating rituals ........................................ 11
Medawar ................................................. 8
Moscow State University ...................... 32
naked mole rat ....................................... 23
National Center for Health Statistics ........ 1
natural variation ................................... 11
negligible senescence ............................ 23
Olshansky ............................................. 26
On the Origin of Species.......................... 5
phenoptosis ........................................... 24
phenotypic linkages ............................... 28
pheromones ........................................... 18
population-benefit ................................. 10
Programmed Aging Theories ................... 5
regulation .............................................. 19
Regulation ............................................. 20
Selfish Gene Theory) ............................. 10
Signaling ............................................... 20
Skulachev.............................................. 32
social status .......................................... 12
telomerase ............................................. 16
Telomerase Activation .......................... 31
Telomeres ............................................. 16
Weismann ............................................. 13
Werner syndrome ............................ 17, 22
Williams ................................................. 9
Wodinsky .............................................. 24
