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Medical Hypotheses 119 (2018) 68–78
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Medical Hypotheses
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Aging is an adaptation that selects in animals against disruption of
Anthonie W.J. Muller
Synthetic Systems Biology – Nuclear Organization Group, Swammerdam Institute for Life Sciences/University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The
Evolutionary medicine
During evolution, Muller’s ratchet permanently generates deleterious germline mutations that eventually must
be defused by selection. It seems widely held that cancer and aging-related diseases (ARDs) cannot contribute to
this germline gene selection because they tail reproduction and thus occur too late, at the end of the life cycle.
Here we posit however that by lessening the offspring’s survival by proxy through diminishing parental care,
they can still contribute to the selection.
The hypothesis in detail: The widespread occurrence of aging in animals suggests that it is an adaptation. But
to what benefit? Aging seems to have only drawbacks. In humans, ARDs cause today almost all mortality; they
include heart disease, cerebrovascular disease, Alzheimer’s disease, kidney disease and cancer. Compensation
seems unthinkable.
For cancer, the author proposed in a previous study a benefit to the species: purifying selection against
deleterious germline genes that when expressed enhance intracellular energy dissipation. This multicausal energy
dissipation, posited as the universal origin of cancer initiation, relates to cellular heat generation, disrupted
metabolism, and inflammation. The organism reproduces during cancer’s dormancy, and when approaching its
end of life, the onset of cancer is accelerated in proportion to the cancer-initiating signal. Through cancer, the
organism, now a parent, implements the self-actuated programmed death of Skulachev’s phenoptosis. This “first
death” enhances by proxy the offspring’s chance of “second death” (or “double death”) through diminished
parental care. Repetition over generations realizes a purifying selection against genes causing energy dissipation.
The removal of the deleterious germline gene mutations permanently generated by Muller’s ratchet gives a
benefit. We generalize, motivated by the parallels between cancer and aging, the purifying selection posited for
cancer to aging. An ARD would be initiated in the organ by multicausal disruption of homeostasis, and be followed
by dormancy and senescence until its onset near the end of the life cycle. Just as for cancer, the ARD eventually
enhances double death, and the realized permanent selection gives a benefit to the species through the selection
against germ line genes that disrupt homeostasis.
Given their similarities, cancer and aging are combined in the posited Unified Cancer-Aging Adaptation
(UCAA) model, which may be confirmed by next-generation sequencing data. Also because of the emerging
important role of cellular senescence, the hypothesis may guide the development of therapies against both
cancer and aging.
Introduction: The problem of aging
Aging [1–8] is essentially unexplained. Here we posit, in a nutshell,
as explanation that aging is an adaptation that gives a benefit to the
species—but not to the individual. In the lineage, it would select against
germline genes that disrupt homeostasis. The selection functions in a
circuitous way: during the life span, disruption of homeostasis of an
organ, say the heart, initiates aging of the organ. At old age, after reproduction, dormancy ends and the initiating signal is activated and
amplified. Failure of the organ (heart) is accelerated, causing death.
This death in turn decreases the parental care given to the offspring,
lessening its chance of survival; this decreases the frequency of the
The work was not grant supported.
Address: Swammerdam Institute for Life Sciences, Synthetic Systems Biology – Nuclear Organization Group, Room C2.105, University of Amsterdam, Science
Park 904, 1098 XH Amsterdam, The Netherlands.
E-mail address:
Received 14 June 2018; Accepted 25 July 2018
0306-9877/ © 2018 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
Medical Hypotheses 119 (2018) 68–78
A.W.J. Muller
beneficial to adverse [24]. Cellular senescence can be defined by the
absence of cell division and the occurrence of β-galactosidase and
p16Ink4A activity [13,25]. The long-held idea that senescence protects
against cancer is being abandoned. Gonzalez-Meijem et al. [26]:
adverse germline genes in the population. Both parents and offspring
are therefore affected. The combined overall result is selection against
the pertinent germline genes.
According to the hypothesis, death by disease sometimes gives a
benefit. Moreover, the hypothesis implies an unexpected evolutionary
link between parental care and aging (including cancer). The novel
ideas relate to primitive processes observable in our own lives and
which are considered to be well understood. The ideas are unfamiliar
and not easily taken in—they constitute a new, fundamentally novel
point of view on life, a truly new paradigm.
Hereafter, we substantiate the hypothesis. For cancer we have in the
previous study [9] posited the Cancer Adaption (CA) model1, which
selects against deleterious genes that upon expression enhance energy
dissipation. Detrimental to the individual, cancer would, in a clear case
of individual-species conflict, over many generations give a benefit to
the species. Deleterious genes are permanently added by H.J. Muller’s
ratchet to the mutational load [10], not only in asexual but in sexual
organisms as well [11].
According to Lopez-Otin et al. “At a deeper level, … cancer and
aging share common origins.” [12]. Many similarities and links between cancer and aging exist, for instance in cellular senescence [13].
The etiology of cancer involves inflammation [14], and Age Related
Diseases (ARDs) [15,16] show a similar role for “inflammaging” [17].
Other similarities are polygenicity as shown by GWAS studies [18],
involvement of mitochondria [19] and impediment by physical activity
Here we posit for aging also a selection mechanism, but instead of
selection against multicausal energy dissipation, selection against
multicausal disruption of homeostasis [15,16]. One can therefore similar to the CA speak of the Aging Adaption (AA) model. Parallel
partial processes permit the combination of the CA and AA to the
Unified Cancer-Aging Adaptation (UCAA) model.
Main novelties in the presented hypothesis for cancer and aging are
the roles for (1) Muller’s ratchet, (2) cellular senescence, and (3) protection of the young by (4) parental care, diminished by cancer and
Although senescence has historically been considered a protective
mechanism against tumorigenesis, the activities of senescent cells
are increasingly being associated with age-related diseases, including cancer.
Targeting cellular senescence by senolytics is being investigated as
therapy against aging [27,28].
Many human diseases also occur in other animals [29] and, in
contrast to earlier assumptions, aging occurs in most animals in the
wild [30]. Aging may affect all animal species.
In old age, death is accelerated by organ (tissue) dysfunction
through ARDs (Fig. 1). Almost all present human mortality (∼90%) can
be related to the so-defined aging [31].
After separation of cancer, the multifarious Set of ARDs (SARDs)
comprises cardiovascular disease, cerebrovascular disease, Alzheimer’s
disease, hypertension, obesity, diabetes (pancreas), osteoarthritis, osteoporosis, Parkinson’s disease, kidney disease, liver disease, gallbladder disease, multiple sclerosis, macular degeneration, acute lateral sclerosis and
several other diseases of organs (15 items)—indeed, almost every organ
seems affected [23].
Many of these diseases may eventually contribute to a co-morbidity
linked to “geriatric syndromes” [34] which comprise at least 6 clinical
. . . common conditions that geriatricians treat, including delirium,
falls, frailty, dizziness, syncope and urinary incontinence are classified
as geriatric syndromes. . . . multiple organ systems, tend to contribute
. . . [emphases added]
In the distant past, old age and the geriatric syndromes may have
been rare. Under primitive conditions even a small fitness decrease
must lessen survival through its amplification by competition [3].
Today, humans live longer, and treatment of the SARDs and geriatric
syndromes constitute a significant part of medical practice.
The complexity of aging is illustrated by the mentioned multifariousnesses: (1) many animal species, (2) many affected organs, (3)
many diseases, (4) polygenicity, and (5) at least 6 geriatric syndromes.
Additional multifariousnesses comprise: (6) many theories [7,35], (7)
many physiological changes [35], (8) many non-coding RNAs
[23,36–38], (9) 4 FOXO transcription factors [39,40] with numerous
target genes, and (10) 7 sirtuin proteins [41–43] with numerous effects
on physiology, (11) many exosomes [44,45], and (12) many investigated pharmaceutical therapies [46].
The search for the fundamental pattern underlying the observations
is still on. Goldsmith (2014) states in his book The evolution of aging [5]
that popular notions on aging are upon close inspection untenable—for
instance, that aging involves an accumulation of damage similar to the
wear-and-tear processes occurring in machines, or that it involves an
accumulation of somatic mutations.
Is aging programmed? In the late 19th century, Weismann gave two
arguments supporting this idea [1]. For the first argument, I give
Kenyon’s formulation (2002) in a personal communication to Mitteldorf
Muller’s ratchet → deleterious genes ↑→ mutational load ↑ →
(Redistribution over chromosomes by crossing-over; in chromosomes with large load:) →
Cellular senescence ↑→ cancer and aging ↑→ parental death
(phenoptosis) ↑→
Parental care ↓ → protection of offspring ↓→ death of offspring ↑→
mutational load ↓
The model presents a novel point of view on biology and medicine.
During an organism’s lifetime, conservation of the during evolution
acquired genome [21] is considered to be just as important for the
species as the creation of new functionality, which receives so much
attention in Darwin’s Origin of species.
We review aspects of aging pertinent for our hypothesis: its complexity, including its fuzziness, and the question whether aging is programmed. Aging is ill-defined [4]. Fremont-Smith wondered [22]:
“What, indeed, do we mean by ‘ageing’?” We consider aging’s effects in
the lineage, and we make it more definite by relating aging to the large
set of linked non-communicable, often chronic, ARDs that plausibly
affects all human organs. Thum [23]: “Age-related diseases [affect] all
organs in our body.”
ARDs are often preceded by senescence, a deterioration with age
that lets organs remain functional and that gradually turns from
The range of time scales for senescence across the biosphere extends
from hours to thousands of years. No physical process of deterioration could act with such a variable rate, spanning six orders of
magnitude; therefore the rate of aging must result from a biological
program under evolutionary control.
In addition to the rate of aging [47], other attributes of aging such
as fertility, mortality and survival vary strongly with the species [48].
The second argument has been formulated as “The old must die to make
room for the young” [49]. One may therefore speak of the AA—and in
We distinguish (1) the theoretical model, explanation or process, such as say
the Cancer Adaptation (CA), and (2) the clinically observable phenomenon, say
cancer; the posited AA is similarly distinguished from the clinically observed
Medical Hypotheses 119 (2018) 68–78
A.W.J. Muller
Fig. 1. A. Distinction of non-age related disease and “Age-Related Disease” (ARD) by different incidence with age during the life cycle. B. Mortality due to aging
follows Gompertz Law: mortality µ (x) = a ebx, with x the age, and a and b parameters [32,33]. The mortality vs age curve is linear on a semi-log plot:
log µ (x) = log a + (b log e) x.
Similarly, Passarino has stated [60]:
particular of Weismann’s programmed AA, a simple theory based on
only two arguments, with much room for extension.
Since Weismann, little progress has been made in the fundamental
issue whether aging is an adaptation [5,7,47,50]. A benefit that compensates for its large drawback has not been identified. Gladyshev
concludes his objections to the adaptation idea as follows [7]:
Before the 1990ies [the idea] was largely spread . . . that aging is
ineluctable and that genetics does not control it. It was important, . .
.that aging occurs after reproduction, and then there is no need, but
also no opportunity, for selection to act on genes that are expressed
during this late period of life . . .[emphasis added]
Thus, while some elements of the programmed aging theory seem
logical, . . .it is unclear how it can be maintained during evolution or
how it can be universal in the biology of aging.
At present, the programmed AA remains controversial. Some notable proponents are V.P. Skulachev, T. Goldsmith, J. Mitteldorf, C.
Kenyon, V. Longo, and J.P. de Magalhaes, and some notable opponents
T. Kirkwood, A.D. De Grey, V.N. Gladyshev, and M.V. Blagosklonny.
The UCAA counters the argument that living into old age would
occur too late to have a role in evolution, by supposing a requirement in
the offspring for parental care given during old parental age. Parental
care thus makes selection possible (Fig. 2). We now formulate an
overall mechanism for the UCAA that combines Muller’s ratchet, cellular senescence, parental care and Skulachev’s phenoptosis:
During evolution, Muller’s ratchet continuously generates mutations. Most are deleterious and therefore increase the mutational load,
which in turn may accelerate cellular senescence. After reproduction,
the parents’ phenoptosis system checks for physiological “wrongness”
and correspondingly accelerates self-actuated death by phenoptosis.
More specifically, the CA links errors in metabolic inefficiency, and the
AA errors in homeostasis, to Skulachev’s wrongness. The parental death
diminishes parental care to the offspring, enhancing its mortality by
proxy—the double death. Thus the deleterious mutations are permanently selected against, and this continuous activity of the UCAA removes them ultimately, over generations, from the population. The
benefit of cancer and aging is therefore identified as their permanent
battle with the output of Muller’s ratchet.
Hereafter we consider the introduced concepts in further detail.
Chapter 2 examines the posited AA and the UCAA. Chapter 3 considers
extreme longevity. Chapter 4 considers verification of the UCAA, and
Chapter 5 implications for therapies. We end with the Discussion in
Chapter 6.
In analogy to the well-known apoptosis process, programmed cell
death, Skulachev has proposed the notion of phenoptosis [51–54],
programmed death of the individual that gives an advantage to the
species and/or group, often effected by failure of an organ [52]:
It is suggested that injury accumulation is monitored by[a] special
[phenoptosis] system sending a death signal to actuate a phenoptotic
program when the number of injuries reaches some critical level.
[In] the system . . .the lethal case appears to be a result of phenoptosis long before occasional injuries make the functioning of the
organism impossible. [emphasis added]
Phenoptosis has been related to cancer and to aging; the “special
[phenoptosis] system” would be activated when the organism senses
that “something is wrong” [55]:
. . . . living systems from organelles to organisms use a principle that
can be formulated as “It is better to die than to be wrong.
and as a result:
Thus phenoptosis of old individuals may be considered as a tool to
purify the population from those whose genomes are badly damaged.
Skulachev and Mitteldorf have looked for benefits of aging for animals [8,51,54]. A similar combination as in phenoptosis—disadvantage to the individual and advantage to the lineage—is found in the
controversial theory of group selection [56–59], which has been related
to altruism. Whereas in the absence of groups, altruism beats egoism
inside a population, when individuals form groups, altruistic groups
beat egoistic groups.
Mitteldorf’s latest book [8] Aging is a group-selected adaptation considers several possible benefits of aging. He proposes for instance that
animals may practice “ecological homeostasis”—animals with the aging
trait would avoid “population overshoot”, “chaotic population dynamics” and thus “local extinction”. According to Skulachev and Mitteldorf, the benefit of aging lies in the areas of biochemistry or ecology.
An argument against aging given a benefit is that aging would come
too late in the life cycle, as reproduction precedes it. Comfort [2]:
The aging adaptation hypothesis
We assume a similarity between cancer and aging, and propose a
new top-down model for the AA similar to the theoretical CA model
posited in the previous study, wherein accelerated death by cancer
implements a purifying selection against deleterious germ line genes.
We now invoke Muller’s ratchet and the interference with parental care
[61] from the CA as the—compared to Weismann’s programmed
AA—key novel components in the presented new AA hypothesis. Muller’s ratchet [62,63] is the well-known issue in evolutionary biology
that the number of deleterious genes, the mutational load [10,64,65],
increases with each generation. When not somehow checked, it is easy
to see that this increase should in asexual species eventually lead to a
catastrophic mutational meltdown [11,63], causing extinction of the
What happens . . .in the postreproductive period, is theoretically
outside the reach of selection, and irrelevant to it.
Medical Hypotheses 119 (2018) 68–78
A.W.J. Muller
Fig. 2. Comparison of the basic stages of the life cycle during natural selection (A), and in humans and animals, first in the absence (B), and next in the presence (C) of
a parental care requirement in the offspring. A. The Darwinian Model. The basic steps of evolution by natural selection involve variation in the genome. Interaction of
the new genome with the environment (Gen. × Env.) may change the mortality, which affects the following reproduction and results in a change in the number of
offspring. These four stages implement the adaptation of a species to the environment. Parental care is not involved. B. In humans today, most mortality occurs after
reproduction: mortality and reproduction have been exchanged (for the purpose of this study mortality before reproduction is ignored). Because this late mortality
follows reproduction, it has been stated that it cannot have a selective effect, and since cancer and aging occur mostly during this late stage, they also would have no
selective effect. The model cannot explain cancer and aging. C. The UCAA model. A parental care requirement in offspring permits cancer and aging—since they
interfere with parental care— to effect a selection of the offspring against those genes that initiate cancer and aging. The ‘first death’ of the parent enhances by proxy
the chance of the ‘second death’ in the offspring. The selection implemented by cancer and aging gives a benefit to the lineage and makes them adaptations.
(6) During adulthood, the mentioned group selection, which is based
on competition between groups of individuals. In humans, warfare
with its high mortality has been linked to group selection [73];
(7) During the end of the life-cycle, while approaching death: the
posited UCAA.
population. Even in sexual species, Muller’s ratchet could cause extinction [11].
H.J. Muller has pointed out that the recombination during sexual
propagation—since it can remove deleterious genes using crossing-over
in chromosomes2—can diminish the mutational load [62].
A strong filtering of deleterious mutations that lowers the mutational load seems needed to avoid mutational meltdown. It would also
permit an increase in mutation rate [66], which in turn would yield the
benefit of faster evolution. In the past, studies of the mutational load in
humans were mainly theoretical, but presently the observational data is
increasing [65], making these previous studies practically relevant.
Agrawal et al. have considered several causes of a mutational load
decrease [64]. By the addition of the UCAA operating in old age, all stages
of the life cycle participate in selection against the mutational load:
Parental care (we ignore grand parental care [74], which can similarly be accounted for) includes maternal and paternal care; the
former is typically much larger than the latter. Parental care is receiving
increasing attention in biology [61,75]. During the post-reproductive
period it can be important for successful reproduction [76], making the
term “post-reproductive period” a misnomer: significant care to the
offspring during this time-span turns it into a reproductive period.
Parental old age may be vital for children [1]: “by protecting, feeding,
or instructing them.” Parental care embraces many activities and has
been called intergenerational transfer [77]. It is often taken for granted
and easily overlooked [69].
The previously posited CA model for cancer comprises: (1) universal
and multicausal initiation during the life cycle by intracellular heat
generation, (2) dormancy, (3) onset, delayed to old age, but then accelerated to the extent of the initiating signal, (4) first death in the
individual, who is a parent: fatal amplification of the initiating signal,
(5) diminished (interfered) care transfer to offspring, (6) second death
in this offspring by proxy: resulting in (7) a weak selection in the
lineage by this death, resulting in turn in (8) purifying selection against
germ line genes linked to initiation. Germ line genes and somatic genes
that enhance energy dissipation when expressed are thus selected
against. This selection in the lineage effects energy conservation, the
posited benefit of cancer.
In addition to energy conservation, homeostasis is also important in
animal physiology [78,79]. Its emergence during evolution seems often
difficult to model. We link aging to disorganization and disruption of
In 1952, a review was published on the aging of homeostasis [78].
The somewhat mundane observations involved the temperature, blood
sugar, oxygen consumption, exercise rate, blood pressure …More
(1) During fertilization, selection for energetic mitochondria based on
sperm cell speed [67];
(2) During pregnancy, miscarriage. Early miscarriage occurs in 50% of
pregnancies [68];
(3) During infancy, infant death [69]. Enhanced offspring mortality
upon maternal death has been observed in rural Gambia, an undeveloped country where conditions may still resemble the conditions of natural environments [70]. Concerning more developed
countries, Van den Berg et al. similarly state [71]:”infant mortality
can be considered a proxy for maternal health”;
(4) During adulthood, the selection during interaction with the environment, or what Darwin called “ordinary selection”;
(5) During propagation, roughly half of adults produce offspring [72].
Sexual selection and Muller’s recombination mechanism occur at
this stage;
During crossing-over, parts of homologous chromosomes are exchanged in a
random way: the resulting chromosomes may contain all, some (most plausible), and even none of the deleterious mutations from both parent chromosomes. Subsequent selection would favor those chromosomes with the fewest
deleterious mutations, and thus lessen the mutational load.
Medical Hypotheses 119 (2018) 68–78
A.W.J. Muller
similar somatic mutation accumulation has been proposed [4,50,84].
These mutation accumulation theories are the current standard models
for cancer and aging; we combine them in the Somatic Mutation-based
Standard Model for Aging and Cancer (SM2AC), in which cancer and
aging do not have an evolutionary function, as mainly somatic cells are
In the UCAA, in contrast, dysfunction in the aging soma affects the
offspring through diminished transferred parental care. The purifying
selection of deleterious germline genes is the fundamental, evolutionary
beneficial process that drives the UCAA’s emergence and function.
The SM2AC and UCAA therefore strongly differ. The SM2AC interprets cancer and aging as diseases that result from dysfunction of the
organism, possibly related to interaction with the environment or faults
in the predisposed or acquired genetic mark-up: the occurrence of
cancer and aging indicate an error of the machine that disturbs the
physiology, whereas in the UCAA, cancer and aging cause activation of
the first part of a selection mechanism (first death) against deleterious
germ line genes. The UCAA involves error detection by the machine.
In the long term, the UCAA results in the removal by purifying selection of deleterious germline mutations, and improves the population’s fitness—deleterious genes are selected against, and their removal
may be observable. Verification of the UCAA may require the tracking
of genotypes in the population, and is considered in Chapter 4.
In the short term, the incapability to initiate cancer and aging may
give an advantage to the individual—absence of suffering due to absence of ARDs.
recently (2016), disturbance of organ homeostasis has been proposed as
initiator of the innate immune response that relates to inflammation
and disease, in particular during metabolic processes such as obesity
and diabetes. Colaço and Moita [15]:
Interestingly and significantly, substantial and continued deviations to
homeostasis have been proposed to be a root cause of chronic debilitating conditions that invariably are accompanied by inflammation,
including obesity, type 2 diabetes, and atherosclerosis. [emphases
and—a citation that we emphasize in its entirety because it is
principal to this study:
A homeostasis disruption model of immune response initiation and
modulation has broad implications for pathophysiology and treatment of
disease and might constitute an often overlooked but central component
of a comprehensive conceptual framework for innate immunity.
Antonelli and Kushner (2017) link inflammation to disturbed
homeostasis as well [16]:
Inflammation has been defined for many years as the response to
tissue injury and infection. We are now forced to reconsider this
definition by the avalanche of reports that molecules and cells associated with inflammation are activated or expressed in high concentration in a large variety of states in the absence of tissue injury or
infection. Modest increases in concentration of C-reactive protein, a
circulating marker of inflammation, have been reported to be associated with an astounding number of conditions and lifestyles felt to be
associated with poor health; these conditions represent or reflect
minor metabolic stresses. In recent years we have learned that inflammation is triggered by sentinel cells that monitor for tissue
stress and malfunction—deviations from optimal homeostasis—and
that molecules that participate in the inflammatory process play a
role in restoring normal homeostasis. [emphases added]
Extreme longevity
As any adaptation, the UCAA may be affected by mutation. We
distinguish two types of mutations: (1) mutations that code for the
UCAA, which we call Type U mutations, which interfere with (affect) the
UCAA, and (2) mutations involving other physiological processes which
are detected and selected against by the UCAA; we call these Type R (after
ratchet) mutations.
Interference with the UCAA would result in enhanced suffering in
the long term (i.e., over generations) because of the non-removal of
acquired deleterious Type R mutations, but in the short term (during a
life span) it would lessen suffering, due to lessened cancer and ARDs.
According to Gladyshev, aging cannot be an adaptation, since
otherwise absence of aging due to mutation would have been observed
Evolution, conflict, homeostasis and inflammation would be mutually related:
It is apparent that the ultimate purpose of inflammation in response
to tissue injury or infection is to ultimately return tissues to their
normal state, including tissue repair and regeneration, which are the
anatomic equivalent of metabolic homeostasis; [emphases added]
Their last sentence states:
The ultimate function of inflammation, in any case, is to restore the
optimal homeostatic state, as, per Claude Bernard, is true of all the
body’s mechanisms. [emphases added]
. . . while the undisputed role of genes in regulating aging does
imply genetic, and therefore, program like features, there is currently no evidence of any gene or process that evolved specifically to
stimulate aging or eliminate older individuals, and no mutants in any
organism have been found in which such genes/processes are disrupted
aborting the aging program. [emphasis added]
The posited AA is identified as one of these body’s mechanisms for
returning to homeostasis.
Fig. 3 illustrates how this AA can be derived from the previously
posited CA by extension of Fig. 1 in the previous study with the addition
of disruption of homeostasis [79,80] as initiating factor.
The AA implements a pre-emptive removal of germ line genes that
negatively affect the homeostasis of pertinent organs and thus cause
organ dysfunction.
Can one call the CA and AA diseases when they give a benefit? We
reconsider the opposite setting of adaptation and disease in the previous study: instead, the CA and AA are named diseases since “disease
… is… about suffering” [81]. As they work over the evolutionary time
scale of generations, cancer and aging comprise a distinct class of pathology, different from infection diseases or trauma. They are truly
“evolutionary diseases”, diseases with an evolutionary component, the
implementation of selection and therefore the subject of evolutionary
medicine [82].
Programmed and non-programmed theories for aging have been
compared by Goldsmith. The Somatic Mutation Theory (SMT) links
cancer to somatic mutations accumulated with age [83]. For aging, a
Here, we link these mutants, that Gladyshev claims are absent, to
individuals that show “successful aging” [85] (also called “healthy
aging”), defined as [85]:
We define successful aging as including three main components: low
probability of disease and disease-related disability, high cognitive and
physical functioning capacity, and active engagement with life.
[emphasis added]
We also link both categories to individuals having Type U mutations.
Due to the diminished incidence of ARDs, individuals with Type U mutations would live longer. Whereas in a first approach (“Regular curves” in
Fig. 4A) disease incidence monotonously increases with age, and survival
monotonously decreases, in a small fraction of the population (“Extreme
longevity” in Fig. 4B) the curves change direction. A small part of the
human population indeed shows an inherited enhanced survival to old age,
a phenomenon that occurs in animals as well and is named deceleration of
aging or mortality plateau [86,87]. A recent review states [71]:
Medical Hypotheses 119 (2018) 68–78
A.W.J. Muller
Fig. 3. System flow chart of the posited Unified Cancer-Aging Adaptation (UCAA) which implements in the species a drive for perfection by a selection based on
“double death”. From the genes that enter the gene pool (by mutation including transposons) the UCAA removes by a purifying selection either—through cancer—deleterious genes that cause enhanced cellular energy dissipation (red), or—through aging—genes that cause organ (tissue) dysfunction (green) (modified and
extended from Fig. 1 of the previous study [9]). The UCAA comprises acceleration of parental death by the aging adaptation (AA) and the cancer adaptation (CA); (a)
the overall function of the UCAA: gene removal from the new genes that during evolution enter the gene pool continuously; (b) entered genes to be selected against
by aging. Start of the aging branch, which is followed first (b → d → e → f); (c) entered genes that are removed by cancer. The cancer branch consists of the trajectory
(c → k → l → m); Aging branch (d) aging initiation in an organ. This initiation is effected by dysfunction of the organ, the disturbance of organ homeostasis. Disease.
Aging initiation is eventually followed by dormancy, onset and progression of the ARD. Inflammation is an intermediate partial process. The ARD is less complex than
cancer: the disease tends to remain limited to the organ. The ARD shares however several attributes with cancer; (e) terminal phase. The “first death” of the double
death is accelerated; (f) death by aging shortens post-reproductive life; Shared cycle (g) the shortening diminishes the parental care given to the offspring, and
consequently the care it receives; (h) the diminished received parental care accelerates the “second death” of the double death; (i) over many generations the multiple
life cycles result in a purifying selection of the carcinogenic gene or the gene that causes organ dysfunction; (j) the purifying selection results in the removal of the
gene from the gene pool; Cancer branch (k) cancer initiation in an organ. This multicausal initiation can be effected by many processes that cause enhanced heat
generation and dissipation, in particular disturbed metabolism. This can in turn be the result of distortion of the genetic machinery, such as by viruses. Somatic
mutations may cause cancer as well. Disease. Cancer initiation is eventually followed by dormancy, onset and progression; inflammation is involved. Progression
involves a prolonged and complex process. The cancer may metastasize; (l) terminal phase. The end of the cancer progression. The “first death” of the double death is
accelerated; (m) death by cancer shortens post-reproductive life. The same shared cycle (g → j) as during aging is followed, and eventually results in removal of the
carcinogenic gene from the gene pool (j).
Medical Hypotheses 119 (2018) 68–78
A.W.J. Muller
Fig. 4. A. The regular curves of disease incidence and survival with age. The relation between the incidence of an ARD and age, depicted in Fig. 1A, and shown here as
well, results in the shown convex curve. Survival monotonously decreases with age in the Kaplan-Meier plot. B. Extreme longevity of a small fraction of the population.
Above an age of say about 85 years, the curve of disease incidence shown in A often becomes concave instead of convex, both in cancer and ARD (“deceleration of
aging”); the survival vs age curve shows an inflexion point. This phenomenon is linked to “extreme longevity,” the survival of a small fraction of the population into
very old age, such as centenarians [71]. A similar tail (“mortality plateau”) at high age has been reported in many animal studies [87]. Here, we relate this tail to a
disturbance—such as by mutation—of the UCAA in a small fraction of the population, which would delay death.
Sirtuins . . . deacetylate histones and several transcriptional regulators . . . regulate fat and glucose metabolism in response to
physiological changes in energy levels, thereby acting as crucial
regulators of the network that controls energy homeostasis and as
such determines healthspan. [emphases added]
Around 1950, even the oldest old (age 85 or older) started to show a
pattern of extended life expectancy and today they are the fastest
growing segment of older people, This means that populations not
only survive to higher ages than in the past, they also have a lower
mortality rate, during their young and middle years. Remarkably,
the survival of a select few persons stands out of an otherwise aging
population, These persons were extremely long-lived and, most of
all, showed little to no signs of age-related disease, allowing them to
have extremely long and healthy lives. . . . first-degree relatives . . .
also had extremely long and healthy lives . . . Hence, the familial
component, including both genetic and environmental contributions, seemed to play a key role in gaining more knowledge about
factors involved in healthy aging and in the capability to survive
into extreme old ages (often called longevity). [emphases added]
SIRT1 stimulates the lifespan-enhancing FOXO3 transcription factor
that has been linked to several ARDs [40]. A linked SNP (rs2802292)
decreases the risk of cardiac disease [98]. Davinelli et al. remarked on
the family [99]:
FoxOs are involved in a myriad of cellular processes and programs
including energy metabolism, cell cycle regulation, apoptosis, autophagy, immunity, inflammation, resistance to oxidative stress,
stem cell maintenance and appear to play a conserved “prolongevity”
role observed in worms through to human beings. [emphases added]
According to the SM2AC point of view, the healthy-agers have less
aging-causing genes, i.e. have a better genetic mark-up, and have been
positively affected. According to the UCAA, the healthy-agers are negatively affected: the pre-emptive gene purifying selection would not
function, as the genes sustaining the UCAA are mutated, and Type R
mutations increase, and enhance the mutational load.
Numerous causes of death exist, best known causes being infection
diseases and trauma, but many processes are also known that increase
lifespan and delay death. Outright starvation leads to marasmus and
kwashiorkor, which may do permanent damage [88], and obviously
may be fatal. A limited food intake may however increase lifespan, a
phenomenon called Caloric Restriction (CR) [89–93]. CR has been
correlated with extreme longevity and healthy aging [40,94].
CR is widely observed in the animal kingdom, including rodents,
which allows experimentation. These studies have demonstrated the
relevance of the sirtuin proteins [41–43,95,96] and the FOXO transcription factors, in particular FOXO3 [39,40,97]. The sirtuins, especially SIRT1, were shown to play a role in numerous other processes as
well. Houtkooper et al. [41]:
The sirtuins [39,96,100] link aging to homeostasis. The reported
mutual links between disturbed/disrupted homeostasis, sirtuins, tissue
stress, tissue malfunction, inflammation, innate immunity and general
poor health are consistent with the posited AA and UCAA.
Mimicking extreme aging, i.e., inducing it artificially, might yield a
therapy for cancer and aging.
Verification of the essence of the UCAA, the implemented selection,
would require tracking gene frequency changes in all the genomes of
entire populations over many generations. This seems feasible only for
quickly propagating vertebrates such as the turquoise killifish [101],
but not for humans.
The model for extreme aging seems easier to verify in humans: we
predict that in some of the individuals concerned the UCAA is impeded
by Type U mutations.
The UCAA may be verified by elucidating partial processes, and
Medical Hypotheses 119 (2018) 68–78
A.W.J. Muller
in disease, it is helpful to consider —in just a slight twist—the concept
of Physical Inactivity (PIA) instead of the PA, as the effects of PIA are
not always simply the converse of the effects of PA [20]. According to
Booth et al. “Physical inactivity is an actual cause of over 35 chronic
diseases/conditions, …”: heart disease, myocardial infarction, congestive
heart failure, stroke, hypertension, obesity, type 2 diabetes, insulin resistance, metabolic syndrome, osteoarthritis, osteoporosis, hemostasis, endothelial dysfunction, atherosclerosis, peripheral artery disease, deep vein
thrombosis, sarcopenia, disuse atrophy, cognitive dysfunction, depression,
anxiety, breast cancer, endometrial cancer, polycystic ovary syndrome, gestational diabetes, pre-eclampsia, erectile dysfunction, nonalcoholic fatty
liver, colorectal cancer, diverticulitis, constipation, rheumatoid arthritis,
pain, balance, and fracture/falls. The large overlap of the SARDs with
this even longer list shall be clear. Moreover: “Remarkably, physical
inactivation speeds biological aging”.
From the AA point of view, PIA can be interpreted as an implementation of Lamarck’s evolution mechanism: the AA processes a
signal given by an organ about its homeostasis. Reception of a signal of
incorrectness would accelerate aging/the ARD, but this acceleration
may also occur if the organ is inactive or its functioning is redundant.
check whether their functions agree with the overall function of the
UCAA: an example would be the activation of cancer/aging stem cells,
and check whether the activation eventually gives the benefit of a selection against deleterious genes.
Support for the UCAA may also be obtained from analysis of other
types of genetic data, for instance data on disease incidence, such as by
GWAS studies, data on genetic traits and disease [102], or data from
electronic health records [103]. Much genetic data has been gathered in
Iceland [104]. Reconstructing of ancestor genomes [105] that go a few
generations back may in combination with recorded causes of death
verify the UCAA’s selection. DNA sequences of DNA taken from graves
of ancestors might assist in such reconstructions.
DNA and RNA [106], including miRNA and lncRNA [36] affect
aging. Investigation of the functionality of non-coding RNA is still in
progress. Kour [36]:
Recently, the discovery of pervasive transcription of a vast pool of
heterogeneous regulatory noncoding RNAs (ncRNAs), . . . have
provided an alternative way to study and explore the missing links in
the aging process, its mechanism(s) and related diseases in a whole
new dimension.
. . . Many lncRNAs have been implicated in age-related diseases such
as cardiovascular, neurological, immunological and metabolic diseases along with many types of cancer . . . [emphasis added]
Serendipity in pharmacy
In the UCAA, cancer and aging share mechanisms such as inflammation. Many unexpected mutual correlations among the SARDs
have been found, such as metformin targeting cancer stem cells or a
commonality between cancer and cardiovascular disease [112,113]:
this sometimes fuzzy demarcation substantiates their unification. Comorbidity occurs especially in aging [34]. Common partial mechanisms
[5] explain the numerous observations that drugs effective in one disease can be effective in another [114]:
Recent pertinent RNA studies on aging of organs have been done on
the heart [107] and on the kidney [108]. More generally, many reports
on links between RNA & cancer, RNA & aging, and RNA & cancer &
aging have recently been published. The complexity of aging may be
related to the complexity of RNA and its mutual interactions which
should be further explored.
“the same drug can be employed for multiple diseases . . . . The
scientific basis for serendipitous findings comes from the fact that
quite different diseases share common molecular pathways and
common targets in the cell. [emphasis added]”
Many therapies for aging are nowadays being investigated [109]. A
recent (2017) book on anti-aging drugs [46] gives pertinent reviews on
numerous intracellular systems. We consider therapy from the viewpoint of the UCAA.
Interference with aging using RNA
Physical activity as therapy, and its relation to Lamarckism
If aging is indeed an adaptation, it may be easily interfered with,
which may simplify therapies and allow the extension of extreme
longevity to a larger part of the population. Skulachev and Skulachev
state [115]:
In biology, Lamarck (1809) stated that disuse of an organ leads to
atrophy, not only during an individual’s life span, but also in the species
over a larger time scale. Organisms would be capable to (1) decrease in
size organs which are too large, or even to (2) remove redundant organs. Lamarck [110]:
If aging is the inevitable result of deterioration of such a complex
system as the organism, its repair is possible only by replacing the
worn-out organs with new organs. If it is a program in our genome,
then it can be broken (or, as programmers say, “hacked”).
Obviously, it is easier to break the aging program than to build a
new organism out of young or artificial organs.
Firstly, a number of known facts proves that the continued use of
any organ leads to its development, strengthens it and even enlarges
it, while permanent disuse of any organ is injurious to its development, causes it to deteriorate and ultimately disappear if the disuse
continues for a long period through successive generations. Hence
we may infer that when some change in the environment leads to a
change of habit in some race of animals, the organs that are less used
die away little by little, while those which are more used, develop
better, and acquire a vigour and size proportional to their use.
[translation Hugh Elliot]
They therefore consider interfering with the adaptation program as
a cure, similar to the methods used by hacking computer programmers.
Molecular biologists may similar interfere with the information-carrying RNA to which aging has been linked [23,36,38,116].
Such a vanishing of an organ over many generations by disuse is
easily explained in Darwinian terms; disuse implies redundancy, and
disrupting mutations that diminish the organ’s size and functioning will
because of the redundancy not be removed by selection during evolution, but will instead be kept, leading to the disappearing of the organ.
In medicine, use and non-use of organs are important as well. The
benefits of occupational therapy are well known, just as the benefits of
more strenuous PA. Many ARDs are tempered by PA, which may include exercise [111] and is therapeutically applied [20]. We follow
Booth et al. who have argued that for understanding the role of exercise
Klimenko has recently pointed to the importance in physiology of
small non-coding RNA (sncRNA) in exosomes [117]:
“now, non-coding oligonucleotides are known to play key roles in
the . . . regulation of cellular function. . . . these molecules often
participate in intercellular communication as passengers in exosomes. sncRNAs are small non-coding regulatory molecules.”
The diverse roles of sncRNAs in gene expression suggests that these
molecules are indeed the architects of eukaryotic complexity from
Medical Hypotheses 119 (2018) 68–78
A.W.J. Muller
The hypothesis yields a new general, unifying and fundamental
principle that relates numerous medical and biological phenomena. The
list of multifariousnesses comprises the mutational load, animal species,
animal organs, stages of the life cycle, ARDs, geriatric syndromes,
polygenicity, diseases treatable by physical activity, RNAs of many
types, exosomes, therapies based on many pharmaceuticals. We can add
effects on the FOXO transcription factors and sirtuins (which are intertwined with components of physiology through their target genes),
homeostasis, inflammation, phenoptosis, cellular senescence, extreme
longevity, healthy aging, caloric restriction, Lamarckism and group
In summary, an adaptation model for cancer and aging is presented
with a wide explanatory power. The increase in mutational load by
Muller’s ratchet is neutralized by selection against the generated deleterious genes; the complex mechanism based on cancer and aging involves enhanced offspring death through diminished parental care. The
hypothesis unifies notions from the disciplines of medicine, evolutionary medicine and biology. Also because of the emerging role of
cellular senescence, confirmation of the hypothesis may result in application in therapies for cancer, including its relapse, and for aging.
an evolutionary point of view. . . . Processes such as RNA interference, gene silencing, imprinting, co-suppression, methylation,
acetylation, position-effect related variegation and paramutation are
cyclically related pathways through which sncRNA is affected. .
[emphasis added]
Lately a cancer therapy was described based on miRNA packaged in
exosomes [44,118]. We cite Di Rocco et al. [44]:
Extracellular vesicles (EVs), including exosomes and microvesicles,
are critical mediators of cell-to-cell communication in tissue
homeostasis and repair, both in physiological and pathological
conditions. Recently, progress has been achieved in their use in regenerative medicine as transfer agents for active biomolecules.
Specifically, EVs are natural carriers of microRNAs (miRNAs) protecting their cargo from plasma ribonuclease . . .
Such existing RNA-based cancer therapies using exosomes seem
easily modifiable to RNA-based therapies against aging by replacing the
RNAs effective against cancer by RNAs effective against aging. For
example, diabetic necropathy, an ARD, is stimulated by the lncRNA
MALAT1, which is impeded by miR-23c [108].
Conflict of interest
Cellular senescence
In contrast to the subsequent ARD, cellular senescence has little
impact on evolution. For therapy or protection against ARDs it may be
however highly relevant. Recent experimental work suggest the feasibility of rejuvenation by removal of senescent cells by senolytics
Moreover, chemo- and radiotherapy of cancer induces senescence,
which in turn is involved in the relapse of cancer [120]: this suggest the
feasibility of the application of senolytics as protection against relapse.
The UCAA model may enable a better understanding of these therapies.
For discussions during the writing of this paper I thank Hans Crezee,
Lukas Stalpers, Peter Roessingh and Paul Fransz; for discussions at the
end stage, I thank Steph Mencken, and William Beckman and other
members of SSB-NOG, including Hans Westerhoff, who questioned the
magnitude of the role of selection in a previous version.
[1] Weismann A, Poulton EB, Schönland S, Shipley AE. Essays Upon Heredity and
Kindred Biological Problems. Oxford: Clarendon Press; 1891.
[2] Comfort A. The Biology of Senescence. New York: Rinehart; 1956.
[3] Williams GC. Pleiotropy, natural selection, and the evolution of senescence.
Evolution 1957;11:398–411.
[4] Curtis HJ. Biological mechanisms underlying the aging process. Science
[5] Goldsmith TC. The Evolution of Aging: How New Theories Will Change the Future
of Medicine. Crownsville, Maryland: Azinet Press; 2014.
[6] MacNee W, Rabinovich RA, Choudhury G. Ageing and the border between health
and disease. Eur Respir J 2014;44:1332–52.
[7] Gladyshev VN. Aging: progressive decline in fitness due to the rising deleteriome
adjusted by genetic, environmental, and stochastic processes. Aging Cell
[8] Mitteldorf J. Aging is a Group-Selected Adaptation: Theory, Evidence, and Medical
Implications. Boca Raton, Florida: CRC Press; 2017.
[9] Muller AWJ. Cancer is an adaptation that selects in animals against energy dissipation. Med Hypotheses 2017;104:104–15.
[10] Muller HJ. Our load of mutations. Am J Hum Genet 1950;2:111–76.
[11] Lynch M, Conery J, Bürger R. Mutational meltdowns in sexual populations.
Evolution 1995;49:1067–80.
[12] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of
aging. Cell 2013;153:1194–217.
[13] Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol
[14] Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet
[15] Colaço HG, Moita LF. Initiation of innate immune responses by surveillance of
homeostasis perturbations. FEBS J 2016;283:2448–57.
[16] Antonelli M, Kushner I. It's time to redefine inflammation. FASEB J
[17] Kennedy BK, Berger SL, Brunet A, et al. Geroscience: linking aging to chronic
disease. Cell 2014;159:709–13.
[18] Dudbridge F. Polygenic epidemiology. Genet Epidemiol 2016;40:268–72.
[19] Wallace DC. A mitochondrial bioenergetic etiology of disease. J Clin Invest
[20] Booth FW, Roberts CK, Thyfault JP, Ruegsegger GN, Toedebusch RG. Role of inactivity in chronic diseases: evolutionary insight and pathophysiological mechanisms. Physiol Rev 2017;97:1351–402.
[21] Maklakov A, Immler S. The expensive germline and the evolution of ageing. Curr
Darwin’s theory of evolution deals with the origin (i.e., emergence)
of species. Although the genome obviously undergoes changes during
the progression towards a new species, plausibly most of its genome
must remain conserved. The permanent attack on the genome by
Muller’s ratchet demonstrates that this conservation of the bulk is not
guaranteed; it requires permanent selection as a countervailing force.
We posit that at all stages of the life cycle, intense selection counteracts the increase in mutational load. Cancer and aging do so at the
end of the life cycle by self-actuated phenoptosis that enhances the
chance of offspring death through diminished parental care; they are
major adaptations, passed on by the species. The ARDs would be initiated upon observation of the proper error detection signal, and would
late in the life cycle be accelerated according to the signal’s size.
Aging is not only a most important pathological process in medicine
that causes suffering of individuals, but is also posited to be a major
selection mechanism in biology that gives a benefit. Cancer and aging
are commonly seen as passive, destructive, pathological, and secondary
processes in medicine, but the derived UCAA is also posited to be an
active, constructive, regular and fundamental process in biology that
accounts for much of the complexity of life.
In the hypothesis, the interests of the individual and the species
conflict. What is good or bad, beneficial or deleterious, depends on the
context and the temporal scale: just as fever, a fatal disease may give a
benefit. As a result, significant parts of medicine and biology may require careful reanalysis and reevaluation.
The relation between disease and evolution is the subject of the
emerging discipline of evolutionary medicine. Why do some diseases
remain extant when their extinction would give a benefit? Wallace’
question, “Why can’t we understand and cure the common diseases?”
[121] is answered by blaming lack of recognition of the UCAA.
Medical Hypotheses 119 (2018) 68–78
A.W.J. Muller
[62] Muller HJ. The relation of recombination to mutational advance. Mutat Res
[63] Gabriel W, Lynch M, Bürger R. Muller's ratchet and mutational meltdowns.
Evolution 1993;47:1744–57.
[64] Agrawal AF, Whitlock MC. Mutation load: the fitness of individuals in populations
where deleterious alleles are abundant. Annu Rev Ecol Evol Syst 2012;43:115–35.
[65] Henn BM, Botigue LR, Bustamante CD, Clark AG, Gravel S. Estimating the mutation load in human genomes. Nat Rev Genet 2015;16:333–43.
[66] Sniegowski PD, Gerrish PJ, Johnson T, Shaver A. The evolution of mutation rates:
separating causes from consequences. Bioessays 2000;22:1057–66.
[67] Reinhardt K, Dobler R, Abbott J. An ecology of sperm: sperm diversification by
natural selection. Annu Rev Ecol Evol Syst 2015;46:435–59.
[68] Schwartz D. The pathology of pregnancy. In: Strayer D, editor. Rubin’s Pathology.
Philadelphia: Wolters Kluwer; 2015. p. 535–62.
[69] Volk T, Atkinson J. Is child death the crucible of human evolution? J Social Evol
Cult Psych 2008;2:247–60.
[70] Sear R, Steele F, McGregor IA, Mace R. The effects of kin on child mortality in rural
Gambia. Demography 2002;39:43–63.
[71] van den Berg N, Beekman M, Smith KR, Janssens A, Slagboom PE. Historical demography and longevity genetics: back to the future. Ageing Res Rev
[72] Lumley AJ, Michalczyk Å, Kitson JJN, et al. Sexual selection protects against extinction. Nature 2015;522:470–3.
[73] Lopez AC. The evolutionary psychology of war: offense and defense in the adapted
mind. Evol. Psychol. 2017;15. 1474704917742720.
[74] Coall DA, Hertwig R. Grandparental investment: past, present, and future. Behav
Brain Sci 2010;33:1–19.
[75] Fernandez-Duque E, Valeggia CR, Mendoza SP. The biology of paternal care in
human and nonhuman primates. Annu Rev Anthropol 2009;38:115–30.
[76] Brown JS, Aktipis CA. Inclusive fitness effects can select for cancer suppression
into old age. Philos Trans R Soc Lond B Biol Sci 2015;370:20150160.
[77] Lee R, Intergenerational transfers, social arrangements, life histories, and the elderly, In: LM Weinstein M, editor. Sociality, Hierarchy, Health: Comparative biodemography: A Collection of Papers. Washington, DC: National academies press;
2014, p. 223–246.
[78] Shock NW. Ageing of homeostatic mechanisms. In: Lansing AI, editor. Cowdry's
Problems of Ageing. Baltimore: Williams and Wilkins; 1952. p. 415.
[79] Kotas M, Medzhitov R. Homeostasis, inflammation, and disease susceptibility. Cell
[80] Chovatiya R, Medzhitov R. Stress, inflammation, and defense of homeostasis. Mol
Cell 2014;54:281–8.
[81] Duffin J. Discovery and disease: history, philosophy, and medicine in the year
2000. Pubbl Stn Zool Napoli 2001;23:75–85.
[82] Gluckman P, Beedle A, Buklijas T, Low F, Hanson M. Principles of Evolutionary
Medicine. Oxford University Press; 2016.
[83] Vaux DL. In defense of the somatic mutation theory of cancer. Bioessays
[84] Kirkwood TB. Evolution of ageing. Nature 1977;270:301–4.
[85] Rowe JW, Kahn RL. Successful aging. Gerontologist 1997;37:433–40.
[86] Charlesworth B, Partridge L. Ageing: levelling of the grim reaper. Curr Biol
[87] Maklakov A. Aging: why do organisms live too long? Curr Biol 2013;23:R1003–5.
[88] Strayer DS, Rubin E. Environmental and nutritional pathology. In: Strayer DS,
Rubin E, Saffitz JE, Schiller AL, editors. Rubin's pathology. Philadelphia: Wolters
Kluwer; 2015. p. 327–66.
[89] Comfort A. Nutrition and longevity in animals. Proc Nutr Soc 1960;19:125–9.
[90] Lee CK, Klopp RG, Weindruch R, Prolla TA. Gene expression profile of aging and its
retardation by caloric restriction. Science 1999;285:1390–3.
[91] Masoro EJ. Overview of caloric restriction and ageing. Mech Ageing Dev
[92] López-Otín C, Galluzzi L, Freije JP, Madeo F, Kroemer G. Metabolic control of
longevity. Cell 2016;166:802–21.
[93] Most J, Tosti V, Redman LM, Fontana L. Calorie restriction in humans: an update.
Ageing Res Rev 2017;39:36–45.
[94] Webb AE, Kundaje A, Brunet A. Characterization of the direct targets of FOXO
transcription factors throughout evolution. Aging Cell 2016;15:673–85.
[95] Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Ann Rev Path Mech Dis 2010;5:253–95.
[96] Vachharajani VT, Liu T, Wang X, Hoth JJ, Yoza BK, McCall CE. Sirtuins link inflammation and metabolism. J Immunol Res 2016;2016:8167273.
[97] Eijkelenboom A, Mokry M, Smits L, Nieuwenhuis E, Burgering BT. FOXO3 selectively amplifies enhancer activity to establish target gene regulation. Cell Rep
[98] Willcox BJ, Morris BJ, Tranah GJ, et al. Longevity-associated FOXO3 genotype and
its impact on coronary artery disease mortality in Japanese, whites, and blacks: A
prospective study of three American populations. J Gerontol A Biomed Sc Med Sc
[99] Davinelli S, Maes M, Corbi G, Zarrelli A, Willcox DC, Scapagnini G. Dietary phytochemicals and neuro-inflammaging: from mechanistic insights to translational
challenges. Immun Ageing 2016;13:16.
[100] Yu J, Auwerx J. The role of sirtuins in the control of metabolic homeostasis. Ann N
Y Acad Sci 2009;1173:E10–9.
[101] Harel I, Brunet A. The African Turquoise Killifish: a model for exploring vertebrate
aging and diseases in the fast lane. Cold Spring Harb Symp Quant Biol
[102] Timpson NJ, Greenwood CMT, Soranzo N, Lawson DJ, Richards JB. Genetic
Biol 2016;26:R577–86.
[22] Introduction Fremont-Smith F. Cowdry's problems of ageing: Biological and
medical aspects. Baltimore: Williams & Wilkins; 1952. p. xxi.
[23] Thum T. Non-coding RNAs in ageing. Ageing Res Rev 2014;17:1–2.
[24] He S, Sharpless NE. Senescence in health and disease. Cell 2017;169:1000–11.
[25] Childs BG, Durik M, Baker DJ, Van Deursen JM. Cellular senescence in aging and
age-related disease: from mechanisms to therapy. Nat Med 2015;21:1424–35.
[26] Gonzalez-Meljem JM, Apps JR, Fraser HC, Martinez-Barbera JP. Paracrine roles of
cellular senescence in promoting tumourigenesis. Br J Cancer 2018;118:1283–8.
[27] Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16 Ink4a-positive senescent
cells delays ageing-associated disorders. Nature 2011;479:232–6.
[28] Gurău F, Baldoni S, Prattichizzo F, et al. Anti-senescence compounds: a potential
nutraceutical approach to healthy aging. Ageing Res Rev 2018;46:14–31.
[29] Natterson-Horowitz B, Bowers K. Zoobiquity: The Astonishing Connection
Between Human and Animal Health. New York: Vintage; 2013.
[30] Nussey DH, Froy H, Lemaitre J, Gaillard J, Austad SN. Senescence in natural populations of animals: widespread evidence and its implications for bio-gerontology. Ageing Res Rev 2013;12:214–25.
[31] de Grey AD. Life span extension research and public debate: societal considerations. Studies Ethics Law Technol 2007;1.
[32] Gompertz B. On the nature of the function expressive of the law of human mortality, and on a new mode of determining the value of life contingencies. Phil Trans
Royal Soc London 1825;115:513–83.
[33] Makeham WM. On the law of mortality and construction of annuity tables. J Instit
Actuaries 1860;8:301–10.
[34] Inouye SK, Studenski S, Tinetti ME, Kuchel GA. Geriatric syndromes: clinical, research, and policy implications of a core geriatric concept. J Am Geriatr Soc
[35] da Costa JP, Vitorino R, Silva GM, Vogel C, Duarte AC, Rocha-Santos T. A synopsis
on aging—Theories, mechanisms and future prospects. Ageing Res Rev
[36] Kour S, Rath PC. Long noncoding RNAs in aging and age-related diseases. Ageing
Res Rev 2016;26:1–21.
[37] Kim J, Kim KM, Noh JH, Yoon J, Abdelmohsen K, Gorospe M. Long noncoding
RNAs in diseases of aging. Biochim Biophys Acta 2016;1859:209–21.
[38] Beermann J, Piccoli MT, Viereck J, Thum T. Non-coding RNAs in development and
disease: background, mechanisms, and therapeutic approaches. Physiol Rev
[39] Eijkelenboom A, Burgering BMT. FOXOs: signalling integrators for homeostasis
maintenance. Nat Rev Mol Cell Biol 2013;14:83–97.
[40] Morris BJ, Willcox DC, Donlon TA, Willcox BJ. FOXO3: a major gene for human
longevity – A mini-review. Gerontology 2015;61:515–25.
[41] Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and
healthspan. Nat Rev Mol Cell Biol 2012;13:225–38.
[42] Morris BJ. Seven sirtuins for seven deadly diseases of aging. Free Rad Biol Med
[43] Poulose N, Raju R. Sirtuin regulation in aging and injury. Biochim Biophys Acta
[44] Di Rocco G, Baldari S, Toietta G. Exosomes and other extracellular vesiclesmediated microRNA delivery for cancer therapy. Transl Cancer Res
[45] Takasugi M. Emerging roles of extracellular vesicles in cellular senescence and
aging. Aging Cell 2018;17:e12734.
[46] Vaiserman AM, Lushchak V. Anti-aging drugs: Where are we and where are we
going? In: Anonymous Anti-aging drugs. : Royal Society of Chemistry; 2017. p.
[47] Lenart P, Bienertová-Vašků J. Keeping up with the red queen: the pace of aging as
an adaptation. Biogerontology 2016:1–17.
[48] Jones OR, Scheuerlein A, Salguero-Gómez R, et al. Diversity of ageing across the
tree of life. Nature 2014;505:169–73.
[49] Mitteldorf J, Sagan D. Cracking the Aging Code: The New Science of Growing Oldand What It Means for Staying Young. New York: Flatiron Books, MacMillan; 2016.
[50] Gavrilov LA, Gavrilova NS. Evolutionary theories of aging and longevity. Scient
World J 2002;2:339–56.
[51] Skulachev VP. 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 (Moscow) 1997;62:1191–5.
[52] Skulachev VP. The programmed death phenomena, aging, and the samurai law of
biology. Exp Gerontol 2001;36:995–1024.
[53] Skulachev V. What is “phenoptosis” and how to fight it? Biochemistry (Moscow)
[54] Skulachev M, Skulachev V. Programmed aging of mammals: Proof of concept and
prospects of biochemical approaches for anti-aging therapy. Biochemistry
(Moscow) 2017;82:1403–22.
[55] Skulachev VP. Mitochondria in the programmed death phenomena; a principle of
biology:“it is better to die than to be wrong”. IUBMB Life 2000;49:365–73.
[56] Wilson EO. Sociobiology. Harvard University Press; 1975.
[57] Sober E, Wilson DS. Unto others: The Evolution and Psychology of Unselfish
Behavior. Harvard University Press; 1999.
[58] Wilson DS, Wilson EO. Rethinking the theoretical foundation of sociobiology. Q
Rev Biol 2007;82:327–48.
[59] Pinker S. The false allure of group selection. Edge Jun 2012;19:2012.
[60] Passarino G, De Rango F, Montesanto A. Human longevity: Genetics or lifestyle? It
takes two to tango. Immun Ageing 2016;13:12.
[61] Royle NJ, Smiseth PT, Kölliker M. The Evolution of Parental Care. Oxford
University Press; 2012.
Medical Hypotheses 119 (2018) 68–78
A.W.J. Muller
architecture: the shape of the genetic contribution to human traits and disease. Nat
Rev Genet 2017;19:110–24.
Wolford BN, Willer CJ, Surakka I. Electronic health records: the next wave of
complex disease genetics. Hum Mol Genet 2018;27(R1):R14–21.
Gudbjartsson DF, Helgason H, Gudjonsson SA, et al. Large-scale whole-genome
sequencing of the Icelandic population. Nat Genet 2015;47:435–44.
Jagadeesan A, Gunnarsdottir ED, Ebenesersdottir SS, et al. Reconstructing an
African haploid genome from the 18th century. Nat Genet 2018;50:199–205.
Shiels PG, Stenvinkel P, Kooman JP, McGuinness D. Circulating markers of ageing
and allostatic load: a slow train coming. Practical Lab Med 2017;7:49–54.
Greco S, Gorospe M, Martelli F. Noncoding RNA in age-related cardiovascular
diseases. J Mol Cell Card 2015;83:142–55.
Li X, Zeng L, Cao C, et al. Long noncoding RNA MALAT1 regulates renal tubular
epithelial pyroptosis by modulated miR-23c targeting of ELAVL1 in diabetic nephropathy. Exp Cell Res 2017;350:327–35.
Kaeberlein M, Rabinovitch PS, Martin GM. Healthy aging: The ultimate preventative medicine. Science 2015;350:1191–3.
Lamarck J. Philosophie Zoologique. Paris: Baillière; 1809.
Daskalopoulou C, Stubbs B, Kralj C, Koukounari A, Prince M, Prina A. Physical
activity and healthy ageing: a systematic review and meta-analysis of longitudinal
cohort studies. Ageing Res Rev 2017;38:6–17.
Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets
cancer stem cells, and acts together with chemotherapy to block tumor growth and
prolong remission. Cancer Res 2009;69:7507–11.
Tall AR, Levine RL. Cardiovascular disease: commonality with cancer. Nature
Prasad S, Gupta SC, Aggarwal BB. Serendipity in cancer drug discovery: rational or
coincidence? Trends Pharmacol Sci 2016;37:435–50.
Skulachev VP, Holtze S, Vyssokikh MY, et al. Neoteny, prolongation of youth: from
naked mole rats to “naked apes” (humans). Physiol Rev 2017;97:699–720.
Gupta SK, Piccoli MT, Thum T. Non-coding RNAs in cardiovascular ageing. Ageing
Res Rev 2014;17:79–85.
Klimenko OV. Small non-coding RNAs as regulators of structural evolution and
carcinogenesis. Non-Coding RNA Res 2017;2:88–92.
Hannafon BN, Ding W. Intercellular communication by exosome-derived
microRNAs in cancer. Int J Mol Sci 2013;14:14240–69.
Baar MP, Brandt RMC, Putavet DA, et al. Targeted apoptosis of senescent cells
restores tissue homeostasis in response to chemotoxicity and aging. Cell 2017;169.
Demaria M, O'Leary MN, Chang J, et al. Cellular senescence promotes adverse
effects of chemotherapy and cancer relapse. Cancer Discov 2017;7:165–76.
Wallace DC. A mitochondrial etiology of common complex diseases. 2017; https:// (23/7/2018).
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