Medical Hypotheses 119 (2018) 68–78 Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy Aging is an adaptation that selects in animals against disruption of homeostasis☆ Anthonie W.J. Muller T ⁎ Synthetic Systems Biology – Nuclear Organization Group, Swammerdam Institute for Life Sciences/University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands A R T I C LE I N FO A B S T R A C T Keywords: Aging Gerontology 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: email@example.com. ⁎ https://doi.org/10.1016/j.mehy.2018.07.020 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 (http://creativecommons.org/licenses/BY-NC-ND/4.0/). Medical Hypotheses 119 (2018) 68–78 A.W.J. Muller beneﬁcial to adverse . 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. : 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  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 , not only in asexual but in sexual organisms as well . According to Lopez-Otin et al. “At a deeper level, … cancer and aging share common origins.” . Many similarities and links between cancer and aging exist, for instance in cellular senescence . The etiology of cancer involves inﬂammation , and Age Related Diseases (ARDs) [15,16] show a similar role for “inﬂammaging” . Other similarities are polygenicity as shown by GWAS studies , involvement of mitochondria  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 aging: 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  and, in contrast to earlier assumptions, aging occurs in most animals in the wild . 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 . 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 . Many of these diseases may eventually contribute to a co-morbidity linked to “geriatric syndromes”  which comprise at least 6 clinical conditions: . . . 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 . 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 , (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 . The search for the fundamental pattern underlying the observations is still on. Goldsmith (2014) states in his book The evolution of aging  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 . 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  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 . Fremont-Smith wondered : “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 : “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 , other attributes of aging such as fertility, mortality and survival vary strongly with the species . The second argument has been formulated as “The old must die to make room for the young” . One may therefore speak of the AA—and in 1 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 aging. 69 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 : 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 : 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 : 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” : . . . . 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  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 : 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  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. 70 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 ; (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 . 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 . 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 , 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 , making these previous studies practically relevant. Agrawal et al. have considered several causes of a mutational load decrease . 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 , 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 , 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 : “by protecting, feeding, or instructing them.” Parental care embraces many activities and has been called intergenerational transfer . It is often taken for granted and easily overlooked . 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 homeostasis. In 1952, a review was published on the aging of homeostasis . 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 ; (2) During pregnancy, miscarriage. Early miscarriage occurs in 50% of pregnancies ; (3) During infancy, infant death . 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 . Concerning more developed countries, Van den Berg et al. similarly state :”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 . Sexual selection and Muller’s recombination mechanism occur at this stage; 2 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. 71 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 considered. 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 : 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 added] 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 : 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” . 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 . 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 . For aging, a Here, we link these mutants, that Gladyshev claims are absent, to individuals that show “successful aging”  (also called “healthy aging”), deﬁned as : 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 : 72 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 ). 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). 73 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 . A similar tail (“mortality plateau”) at high age has been reported in many animal studies . 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 . A linked SNP (rs2802292) decreases the risk of cardiac disease . Davinelli et al. remarked on the family : 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 , 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. : 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 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 , 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 74 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 . 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 , or data from electronic health records . Much genetic data has been gathered in Iceland . Reconstructing of ancestor genomes  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 , including miRNA and lncRNA  aﬀect aging. Investigation of the functionality of non-coding RNA is still in progress. Kour : 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 . Common partial mechanisms  explain the numerous observations that drugs eﬀective in one disease can be eﬀective in another : Recent pertinent RNA studies on aging of organs have been done on the heart  and on the kidney . 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. Therapy “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 . A recent (2017) book on anti-aging drugs  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 : 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 : 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]. Exosomes 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  and is therapeutically applied . 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 : “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 75 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 selection. 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. : 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 . Conﬂict of interest Cellular senescence None. 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 [26–28,119]. Moreover, chemo- and radiotherapy of cancer induces senescence, which in turn is involved in the relapse of cancer : this suggest the feasibility of the application of senolytics as protection against relapse. 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