Memory  formation  in  regulatory  systems  as  a​ ​fundamental​ ​source​ ​of​ ​aging​ ​and​ ​disease  by​ ​Rudger​ ​Alexander​ ​Kanding September​ ​8,​ ​2017 Text​ ​version:​ ​0.4 Contact:​ ​emd.as.etiology​ ​at​ ​the​ ​google​ ​mail​ ​service Abstract: The hypothesis presented in this text, partly founded on concepts developed in (Kanding, 2017b), basically states that side effects of memory formation in nervous systems lead to a continuous and during a lifetime ever increasing anti-homeostatic signalling to the body. The multitude of the detrimental effects of this anti-homeostatic signalling, like for instance a pro-inflammatory effect, damage and waste accumulation due to induction of a permanent shift of resources from metabolic to catabolic processes, etc., is thought to ultimately cause the manifestation of aging phenotypes. The main part of this text explores the hypothesis and presents a collection of research data that supports the hypothesis for a multitude of organisms that possess a nervous system, ranging from humans and mice, to honey bees and garden snails, up to simple organisms like the nematode ​Caenorhabditis elegans. ​Subsequently, the article develops a speculative model for an aging-promoting role of memory formation in regulatory systems in general. The model proposes that cellular aging partly originates from tissue-spanning feedback loops with memory capacities and that the immortality of the germ line originates from a wide absence of such feedback loops. Finally the article turns back to complex organisms, and develops a theoretical model for characteristics that a memory reconsolidation process must possess in order to reduce the anti-homeostatic effects of memory​ ​formation​ ​and​ ​consequently​ ​to​ ​decelerate​ ​aging​ ​and​ ​improve​ ​health. Terminology: EMD = extinction memory damage; MO = memory overexpression; BLA = basolateral amygdala; PL = prelimbic​ ​cortex

Introduction  The main text of the EMD hypothesis (Kanding, 2017b) proposes that organisms possessing certain nervous system characteristics develop during a lifetime a persistent and ever increasing collection of aversive memories and counterbalancing extinction-like memories. It was furthermore proposed that this memory collection (termed e/x balance) may exert aging-promoting effects. The hypothesis presented here proposes that specifically the continuous and during a lifetime ever increasing anti-homeostatic signalling exerted by the e/x balance towards the body may explain significant components of aging phenotypes across a multitude of animal species. In order to substantiate on a mechanistic level the proposed anti-homeostatic effects of the e/x balance, the main text developed two fundamental concepts that explain in what way aversive memories may exert detrimental health effects by means of scientifically well established mechanisms of Brain-Body Medicine (Lane and Wager, 2009). The first concept, ‘memory overexpression’ (MO) argued that intrinsic neuronal network activity as well as extinction memory damage (EMD) related memory disinhibition may permanently activate aversive memories, and that the magnitude of this effect slowly, but continuously, increases during the lifetime (see chapter 1 and 2 of the main text). The second concept, ‘functionally identical neuronal engagement’ (FINE) explained in what way MO translates into permanent end organ symptoms and health effects by means of well established brain-body mechanisms (see chapter 3.2 of the

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main text). FINE argues in particular that MO engages brain-body mechanisms similar to the ones engaged by the originally encoded emotional state, and therefore translates into end organ symptoms and health effects similar to those induced by the originally encoded emotional state. The following text presents a first outline of a ‘memory overexpression hypothesis of aging’ (MOHA) on basis of the concepts of the e/x balance, MO and FINE on the one hand, and research data on aging and health psychology on the other. Due to the presence of research data that allows a seamless argumentation, this outline primarily covers mammalian aging. Subsequently, a reasoning is given why this argumentation is generally valid for organisms that possess a nervous system exhibiting certain characteristics. After a discussion of various research data that support MOHA, the speculative part of this article tries to create an account for a role of memory formation in cellular aging. Finally the article develops a theoretical foundation for the application of memory reconsolidation as means to reduce the aging and disease promoting effects of MO (further elaborated in Kanding (2017a)). For an overview on research on the most important aspects of aging, see Lenart and ​Bienertová-Vašků (2017), ​López-Otín et al. (2013), Kirkwood and Melov (2011), Finch (2009), Ljubuncic and Reznick (2009), and Petralia et al. (2014). For a summary of the data supporting the existence of the e/x​ ​balance​ ​in​ ​various​ ​species,​ ​see​ ​chapter​ ​5.5​ ​of​ ​the​ ​main​ ​text.

The​ ​memory​ ​overexpression​ ​hypothesis​ ​of​ ​aging​ ​(MOHA) It is well known that psychosocial stress induces systemic low-grade inflammation (Rohleder, 2014). Consequently, on the basis of FINE, overexpression of memories of psychosocial stress events will likewise stimulate systemic low-grade inflammation. Life is accompanied by tens of thousands of psychosocial stress events, which assumedly all enter the e/x balance. Thus, even when the EMD hypothesis holds on to only a very low quantitative level, there can be little doubt that at least in old age, when many memories of psychosocial stress events have accumulated, the permanent overexpression (mainly driven by aging-related EMDs) of these memories has a significant effect, and significantly stimulate systemic low-grade inflammation (again on the basis of FINE). It is therefore possible that the systemic low-grade inflammation that invariably accompanies aging (termed ‘inflammaging’; Franceschi and Campisi, 2014; Salminen and Kaarniranta, 2009) and whose source is currently unknown, originates from permanently overexpressed memories of psychosocial stress events. Intriguingly, the research lines linking aging and inflammation provide convincing arguments that inflammation is not a mere epiphenomenon of aging, but rather the main force that causally drives the aging process (reviewed for the “master regulator of inflammatory responses” NF-κB in Salminen and Kaarniranta, 2009). Taken in conjunction with the here presented possible causal link between MO and inflammation, this implies that aging may be significantly driven by MO, specifically by the overexpression of memories of psychosocial stress events. This argumentation, which will in a future article version be detailed and extended to other types of stress, is the basis of the statement in the short version of the EMD hypothesis, that aging is in a certain sense a psychosomatic phenomenon (and it is also the counterintuitive implication​ ​of​ ​FINE,​ ​mentioned​ ​in​ ​chapter​ ​3.2​ ​of​ ​the​ ​main​ ​text). Interesting in this context is the conclusion of Huang et al. (2011) from their analysis of cross-tissue gene expression changes in aging, that “age-related immune dysfunction is not intrinsic to the immune cells but arises as a result of age-related defects in other neuroendocrine functions” (p. 670), and that “... the aging of hippocampus caused some kind of cascade of aging in other tissue” (p. 670). These conclusions, taken together with the recent finding that contextual memories have a very long lifetime in the hippocampus (e.g. Moscovitch et al., 2016, pp. 115-119) and taken together with the fact that contextual memory activation co-activates related emotional memories (Maren et al., 2013), renders aging-related EMDs in hippocampus and the resulting MO of aversive memories an intriguing candidate for the “defect in other neuroendocrine function” proposed by Huang et al. (2011) and therefore for the central force that drives age-related gene expression changes, possibly including those gene expression changes that cause inflammaging. On a mechanistic level, this view on hippocampus damage driven MO as origin of aging is corroborated by findings that fear renewal is gated by ventral hippocampus neurons that project to the PL and BLA to regulate the expression of fear after extinction (Jin and Maren, 2014). EMDs resulting in an overactivity of these

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neurons could therefore mimic diffuse renewal of extincted memories of fear and other aversive events. As this diffuse aversive memory renewal will continuously activate a wide range of deregulating brain-body mechanisms, therefore specifically damage of extinction memory aspects that are stored in the ventral hippocampus may indeed represent the central mechanism that drives the aging cascade. Please take here into account that the two theoretical vicious cycles that accelerate the onset of the disease mechanisms posited by the EMD hypothesis (developed in chapter 3.2 and 3.1, respectively, of the main text) also accelerate the process of aging. Both cycles could therefore be​ ​a​ ​target​ ​for​ ​non​ ​memory​ ​reconsolidation​ ​based​ ​interventions​ ​to​ ​decelerate​ ​aging. Please note also that the e/x balance and the related aging-promoting phenomena like EMDs and MO already exist in simple animals as e.g. the garden snail ​Helix aspersa ​and the honey bee ​Apis mellifera (see chapter 5.5 of the main text). Thus, although it appears quite curious in the first place, possibly even in these relatively simple animals the continuous intrinsic and EMD-related MO of aversive memories and the resulting continuous anti-homeostatic signalling to the body represents the origin of the aging cascade. Even though this point is not further investigated here on a mechanistic level, this suggests that MOHA may explain the occurrence of aging phenotypes across a wide range of phyla in the animal kingdom. Besides chapter 5.5 of the main text, further research data and theoretical deliberations support this apparently daring hypothesis. More specifically the chapters 5.1 to 5.3 of the main text argue that in mammals the amount of aversive memories accumulating during a lifetime and forming an e/x balance is unexpectedly high. Furthermore, chapter 5.4 advances theoretical arguments for the idea that persistent memory inhibition and the resulting formation of persistent entries in the e/x balance is much more prevalent than usually expected and maybe very deeply rooted in evolutionarily ancient memory formation processes. Corroborating these theoretical ideas, a research data driven paradigm shift seems to take place in neuroscience, stating that (in mammals) memories in general have a much more longer lifetime than previously thought (see Poo et al., 2016, pp. 1-5; Moscovitch et al., 2016, pp. 115-119). This suggests a widespread presence of persistent inhibitory mechanisms responsible for the control of memory accessibility, a constellation that strongly supports the idea of a persistent e/x balance. In order to better appreciate that the impact of memories in the e/x balance is indeed substantial, one must also consider quantitative aspects of memory formation arising from the fact that the pace of evaluation of sensory cues (intrinsic and extrinsic), and consequently the pace of memory trace formation, is quite fast, laying in the range from tens of seconds, up to a few seconds (-). Therefore as even during exploration of an ideal environment, the evaluation of sensory cues frequently generates a weak aversiveness, i.e. a slight negative prediction error (-), even an e/x balance that formed during life in an ideal environment, contains high amounts of slightly aversive memories the accumulated MO of which may lead to a substantial and continuous anti-homeostatic signalling to the body. Furthermore note that due to a feedback mechanism in MOHA, aging is to a certain extent self-amplifying, i.e. the aging promoting effects of MO i) enhance the extent of MO, and ii) increase the aversiveness of life events and the respective memories. As a consequence, after a certain point of time in life, aging by itself continuously ‘fills’ the e/x balance with high amounts of weakly aversive memories (for details see the two feedback mechanisms described in chapter 3.2 of the main text; note that research data is only presented for mammals, however, the mechanisms underlaying the feedback mechanisms are evolutionarily ancient and related to memory and immune system functioning, suggesting that variations or rudimentary forms exists in all animals that exhibit a nervous system). Taken together this data suggest that in organisms possessing a nervous system the presence of a persistent e/x balance with the potential to generate a significant and continuous anti-homeostatic signalling to the body, is a well founded construct, rendering the above delineated aging-promoting effects of the e/x balance an uncommon and surprising, but nevertheless plausible, construct for the explanation of aging phenotypes across a multitude of species. A final noteworthy point is the argumentation advanced later in this text, stating that especially in simple nervous systems as e.g. the one of ​C. elegans​, where a persistent e/x balance seems only partly present, memory formation​ ​per​ ​se​ ​may​ ​exhibit​ ​anti-homeostatic,​ ​thus​ ​aging-promoting​ ​effects.

Arguments​ ​and​ ​speculations​ ​supporting​ ​MOHA

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The brain drives soma aging in a top-down manner. Several lines of research demonstrated that aging is a process originating in the brain, governing systemic physical aging in a top-down manner by the physical consequences of a hypothalamic inflammation (Zhang et al., 2013; Satoh and Imai, 2014). This is in line with MOHA, where a brain-related inflammatory process induces systemic physical aging in a top-down like manner. This is particularly intriguing, because an hypothalamic inflammation could theoretically be induced by brain regions that are known to exert neuronal and endocrinal influences on the hypothalamus during aversive memory expression (e.g. amygdala, paraventricular nucleus of the thalamus; see Do Monte et al., 2016). The ever increasing MO of aversive memories during the lifetime, taking advantage of these links, could therefore indeed be at the root of aging by inducing​ ​the​ ​ever​ ​increasing​ ​hypothalamic​ ​inflammation​ ​observed​ ​during​ ​aging. Cellular aging specifically in interneurons modulates organismal aging: Of high importance is the implication of MOHA that the process of aging possibly contains an element that may severely complicate the interpretation of research results on cellular aging. Background is that MO is strongly modulated by the activity of extinction memory neurons, in particular of the highly energized and stress vulnerable parvalbumin expressing (PV​+​) interneurons (Courtin et al., 2014; Kann, 2016; see also Introduction of the main text). As a consequence, cellular level mechanisms could modulate organismal aging not only through cell autonomous effects that affect soma cells to a comparable extent. Additionally, cellular level mechanisms could modulate organismal aging through effects predominantly targeting extinction memory neurons, thus by modulating the extent of MO. Experimental results on cellular level mechanisms could therefore give the impression of supporting entropic theories of aging (ROS, DNA damage, etc.), whilst the observed effect actually occurred predominantly through modulation of MO. Interestingly, Alcedo et al. (2013) conclude in their review on neuronal influences on aging that “... it is amply clear today that aging and longevity are profoundly influenced by neuronal activities” (p. 9). One factor in this posited neuronal influence on aging​ ​may​ ​be​ ​indeed​ ​the​ ​dysregulating​ ​effects​ ​of​ ​MO​ ​(or​ ​the​ ​more​ ​general​ ​‘MESS​ ​effects’,​ ​introduced​ ​below). Antagonistic pleiotropy of the e/x balance. ​As those genetic mechanisms that entail the strong early life benefits of the e/x balance (the option to reuse outdated, extinguished experiences), are the same genetic mechanisms that entail strong late life costs (the detrimental effects of overexpression of extinguished memories), these genetic mechanisms are a prime example for the concept of antagonistic pleiotropy (i.e. genes with early life benefits and late life costs). MOHA fits therefore very well with the antagonistic pleiotropy theory of aging (Ljubuncic and Reznick, 2008). Programmed aging. Aging-related gene expression analyses suggest that aging is a deterministic, somehow ‘programmed’ process, that deregulates the expression of a set of genes in a chronologically coordinated manner (Podolskiy et al., 2015; Kogan et al., 2015). The epigenetic effects of an ever increasing overexpression of aversive memories​ ​during​ ​aging​ ​predicts​ ​such​ ​a​ ​picture​ ​of​ ​gene​ ​expression​ ​change. Lack of PV​+ interneurons in turtles: ​PV​+ interneurons are fast spiking, highly energized, and highly stress vulnerable interneurons that are implicated by research in the cognitive impairments seen during aging (Kann, 2016). Furthermore, they play an important role in the EMD hypothesis and MOHA, because their involvement in the control of fear expression (see Introduction of the main text) viewed in conjunction with their stress vulnerability suggests that they are an important source of EMDs in elderly individuals. Thus aging-related PV​+ interneuron demise or function impairment could be an important source of aversive memory overexpression that drives after MOHA the process of aging. Interestingly, turtle species in general seem not to possess PV​+ interneurons (mentioned in Naumann et al., 2015, p. 317, unfortunately without reference). This phenomenon, viewed in the context of Gibbons’ (1987) remarks about aging in turtles that “among vertebrates, turtles are near the top in the number and proportion of species that have been known to live more than 50 years in captivity.” (p. 262) and “extended longevity appears to be widespread among turtles, rather than limited to a few species.” (p. 263), motivate the question whether the general lack of PV​+ interneurons in turtles may be related to their longevity not only through the entailed general protective effect to the brain,​ ​but​ ​by​ ​specifically​ ​protecting​ ​this​ ​animal​ ​order​ ​from​ ​an​ ​important​ ​source​ ​of​ ​aging-promoting​ ​EMDs.

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Mating related disinhibition of stress memories as cause of phenoptosis. ​In some species, individuals undergo rapid phenoptosis, i.e. fast aging and death, after mating (Skulachev and Skulachev, 2014). This phenomenon seems to have independently evolved in several species, including salmons and marsupials (Skulachev and Skulachev, 2014), and seems to be driven by high levels of stress hormones, as suggested by the fact that ablation of the adrenal gland after mating prevents phenoptosis. It is commonly thought of having evolved from an evolutionary advantage of freeing the biological niche of adult subjects that otherwise would compete with the offspring for resources(-), and, at least in salmons, from an evolutionary advantage of “... fertilization of streams by carcasses of spent adults …” that “enrich rearing habitat for juveniles” (Crespi and Teo, 2002, p. 1016). However, an additional factor may play an important role in the evolution of phenoptosis. On the precondition of a given, low, zero, or negative contribution of after-mating individuals to species survival, evolution was allowed to select for traits that can ‘push’ an animal to support extremely high levels of stress (and ignore respective alarm signals) for the purpose of reproduction. In this case, the arsing detrimental, stress-related health effects, if postponed to after the mating period, do not endanger species survival, and evolution is therefore allowed to accept the possibly severe detrimental effect of an extremely elevated e/x balance evolving from this trait (i.e. very strong stress memories or high amounts of stress​ ​memories​ ​in​ ​the​ ​e/x​ ​balance). In order to support the high levels of stress during the pre-mating period, it is probable that stress protective mechanisms operate during this period. It is further probable that these mechanisms include ways to prevent overexpression of stress memories (which otherwise would produce stress by activating the usual brain-body mechanism). Such mechanisms would be particularly relevant in case the pre-mating period exhibits reduction of sleep, since this would reduce sleep related memory depotentiation and inhibition, thereby aggravating the stress memory overexpression problem. In case these stress memory inhibiting mechanisms stop working after mating, an overexpression of countless stress memories (possibly unconsolidated and therefore exerting strong intrinsic MO effects) will provoke by means of usual brain-body mechanisms a flooding of the organism with stress hormones, thereby possibly causing a rapid decline in health and even death, thus, phenoptosis. It is important to note, that stress hormones probably do not only drive the aging process on the level of the soma. Rather they keep the whole phenoptosis process active in a top-down manner, because after their humoral secretion, they readily enter the brain and therein facilitate aversive memory expression (as evidenced by their facilitation of fear memory expression, see Miracle et al., 2006), which in turn provokes the release of stress hormones. This may be the reason why ablation of the adrenal gland after mating stops the whole MO driven phenoptosis process in salmons, and does not spare other effects of MO as e.g. sympathetic bias, as it would be in the first place predicted by an MO driven phenoptosis. Interestingly, such a strong dependence of the phenoptosis process on a single mechanisms implies dependence on only a low amount of genes and therefore an easy evolvability (Goldsmith, 2008) of this kind of phenoptosis. Note that further mechanisms possibly driving phenoptosis can be derived from the two aging and disease promoting vicious​ ​cycles​ ​developed​ ​in​ ​chapter​ ​3.2​ ​of​ ​the​ ​main​ ​text. This idea is speculative and I am currently trying to find supporting data. I include this speculation in this text version, because it provides a possibility to test the EMD hypothesis: As mentioned, ablation of the adrenal gland after mating prevents phenoptosis. If stress hormone release in the adrenal gland is driven by stress memory overexpression, e.g. by means of the sympathetic, than the equivalent of a cingulotomy (which will affect the brain region that decisively drives aversive memory expression), performed after mating, should likewise prevent phenoptosis (or possibly only reduce it, because aspects of aversive memories, stored in deeper brain regions such as the PAG [Buhle et al., 2013],​ ​may​ ​exert​ ​a​ ​dACC-independent​ ​overexpression). Skulachev (2014) proposes that normal aging is a kind of slow phenoptosis, thus programmed aging. The major problem of programmed aging theories is to explain how a trait that is disadvantageous for an individual can survive selection pressure (Skulachev, 2014). Skulachev proposes as one possible explanation for this problem that phenoptosis could evolve from a bifunctional mechanism with a vital, indispensable part that cannot be eliminated by evolution, and a detrimental part that can be used to drive phenoptosis. Intriguingly, the e/x balance exhibits this demanded property because i) it cannot be eliminated by evolution because it is a vital, indispensable mechanism and ii) it can, in case of a strong elevation, exert lethal effects. Within the concept of MOHA, aging can therefore be

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regarded as slow phenoptosis driven by MO. However, I would call it rather ‘assisted aging’ than programmed aging, because​ ​the​ ​inevitable​ ​negative​ ​effects​ ​of​ ​the​ ​e/x​ ​balance​ ​‘assist’​ ​evolution​ ​to​ ​generate​ ​phenoptosis. Further​ ​aging​ ​phenomena​ ​explainable​ ​by​ ​MOHA​ ​(for​ ​the​ ​sake​ ​of​ ​briefness,​ ​only​ ​with​ ​explanation​ ​hints): Coordinated aging of the soma: ​MO-induced epigenetic deregulation affects through autonomic and neuroendocrinal​ ​signals​ ​all​ ​types​ ​of​ ​tissues. Malleability of aging by evolution ​(Kenyon, 2005): ​changes in many MO-related parameters (e.g. frequency and intensity of emotion generation, memory inhibition/decay, MO intensity, etc.) simultaneously increase early life benefits and late life costs. For instance, increasing emotional reactivity accelerates e/x balance elevation and therefore aging, but simultaneously increases early life survival chances. Note that therefore the individual benefit requirement for evolvability of aging (Goldsmith, 2008) is met. Thus, in particular accelerated aging is, if under positive selection pressure, easy to select by evolution by modulating these parameters. Additionally, as MO is strongly modulated by oxidative damage in interneurons, aging can easily be modulated by modulating oxidative damage​ ​in​ ​interneurons. Phenoptosis:​ ​by​ ​allowing​ ​extreme​ ​MO​ ​effects. No observation of gene mutations “that abolishes ageing altogether” (Kirkwood and Melov, 2011): ​the e/x balance is a complex system, depending on many genes -> spontaneous elimination too improbable. The e/x balance is indispensable -> cannot be eliminated by evolution. The e/x balance is deeply rooted within evolutionary ancient memory systems -> elimination would entail too much detrimental perturbations (see also chapter 5.4 of the main text and​ ​the​ ​Hocking​ ​hypothesis​ ​in​ ​the​ ​short​ ​version​ ​of​ ​the​ ​EMD​ ​hypothesis). Lack of TRPV1 pain receptor increases lifespan ​(Riera et al., 2014): The researchers ascribe this result to a peripheral mechanism that maintains metabolism in aging TRPV1 mutant mice. But intriguingly, TRPV1 mutant mice show also a strong change in e/x balance related parameters, such as reduced anxiety, reduced conditioned fear, and reduced hippocampal long-term potentiation (Marsch et al., 2007). As these parameter changes suggest deccelerated e/x balance elevation throughout lifetime, and therefore deccelerated aging (after MOHA), deleting the TRPV1 receptor may modulate aging through modulation of MO. It would therefore be of high interest, if deletion of the​ ​TRPV1​ ​receptor​ ​exclusively​ ​in​ ​hippocampus​ ​likewise​ ​increases​ ​lifespan. Aging related DNA methylation ​(Hernandez et al., 2011) points to increased maintenance of transcriptional programs not related to DNA damage repair: MO of aversive memories should upregulate catabolic programs, MO of extinction memories should upregulate anabolic programs -> overall upregulation of transcriptional programs despite no​ ​increased​ ​need​ ​for​ ​DNA​ ​damage​ ​related​ ​regulation. Only a few aging related mRNA (gene expression) show linear association to aging ​(Hernandez et al., 2011): this research group therefore hypothesized that “... the accumulation of DNA methylation may be important in maintenance of ​consistent ​gene expression patterns with age.” (p. 1168, emphasis added): This pattern is to be expected in case MO of aversive memories activates one set of transcriptional programs, and simultaneous MO of extinction memories activates a counteracting set of transcriptional programs. It can be expected that the fight and flight associated, sympathetic activating aversive memories activate a set of transcriptional programs which in turn is deactivated by the resting-related, parasympathetic activating extinction memories. Thus, the picture of elevated DNA methylation​ ​with​ ​comparatively​ ​few​ ​mRNA​ ​changes​ ​is​ ​consistent​ ​with​ ​the​ ​influence​ ​of​ ​MO​ ​on​ ​DNA​ ​methylation. Aging is related to sympathetic bias ​(Lee et al., 2004): After the EMD hypothesis, activation of the sympathetic is one​ ​of​ ​the​ ​two​ ​major​ ​effects​ ​of​ ​aging-related​ ​EMDs​ ​(see​ ​main​ ​text​ ​chapter​ ​3.2).

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Aging appears to be programmed: ​MO deregulates transcriptional programs by interfering at the beginning of the regulatory chain, the transcription factors, not at the endpoint of the regulatory chain, the protein products. This has non-stochastic​ ​effects. Aging appears to be stochastic: ​MO-related upregulation of catabolic processes impairs repair mechanisms. Debris​ ​and​ ​damage​ ​accumulates,​ ​giving​ ​impression​ ​of​ ​stochastic​ ​aging. Genome stability in long-lived animals ​(Kogan et al., 2015; Podolskiy et al., 2015): if evolution somehow downregulated MO effects in order to slow down aging, then MOHA predicts increased genome stability. However, as the e/x balance is indispensable, and MO not completely avoidable, it is mysterious how evolution could reduce MO effects to a level where extreme longevity (centuries) as in the Greenland shark (Nielsen et al., 2016) is possible, when mice putatively die of MO effects already at the average age of 2 years. It would therefore be of interest to examine aging-related DNA methylation changes in long-lived animals such as naked mole rat (Lewis et al., 2012) turtles (Congdon et al., 2003), or wandering albatross (Lecompte et al., 2010). This could indicate, where in the regulatory chain aging is blocked. High methylation would point to a prevention of detrimental MO effects, low methylation would point to reduced MO. It is interesting to note here, that the living conditions of many long-lived animals, e.g. low extrinsic mortality (i.e. low mortality from predators, accident, etc) protected habitat, etc., seem to provoke lower amounts of aversive life events, thus lead to a lower e/x balance compared to other animals. Furthermore such living conditions allow evolution to select for traits that lead to a lower e/x balance, traits such as e.g. less reactivity, less emotionality, weaker emotional memory recall (probably reducing MO), etc. It is noteworthy here, that decay of old aversive memories has much less adverse effects under low than under high extrinsic mortality living conditions. Possibly memory decay and the resulting reduced MO of aversive memories is therefore an important aging-delaying factor in long-lived animals. This should lead to measurably reduced long-term fear conditioning retention in long-lived animals. Thus, under conditions of low extrinsic mortality, evolution is allowed to relax the rigid relationship between the adverse and beneficial effects of antagonistic pleiotropic genes that is normally​ ​demanded​ ​by​ ​the​ ​antagonistic​ ​pleiotropy​ ​theory​ ​of​ ​aging​ ​(-). Brain​ ​size​ ​correlates​ ​positively​ ​with​ ​lifespan​ ​(Gonzalez-Lagos​ ​et​ ​al.,​ ​2010)​: The theoretical basis for the explanation of this relationship is developed in the next chapter. Speculatively, as larger brains are more complex, they probably contain a lower amount of ‘overlapping systems’ and therefore express lower amounts​ ​of​ ​aging​ ​inducing​ ​memory​ ​storage​ ​side​ ​effects.

Memory​ ​as​ ​a​ ​fundamental​ ​source​ ​of​ ​aging​ ​(speculative) Memory may modify a regulatory system. ​Starting from the central role that MOHA emphasizes for memory in the process of aging, an interesting line of thought can be developed that ascribes memory formation within regulatory systems in general a deeply fundamental role in aging. After MOHA, the overexpression of memories lying within the e/x balance may change nervous system and tissue function to such an extent that death of the organism occurs. This process of deterioration can be viewed as a special case of a more general phenomenon. Not only those nervous systems related to the e/x balance, but nervous systems in general play a critical role in the regulation of vital homeostatic mechanisms of organisms. However, in many cases the very same nervous system that governs homeostasis also serves as memory system for the adaptive regulation of homeostatic mechanisms. Since memory storage events results in permanent molecular changes within the nervous system, therefore the continuously ongoing storage of memories of life events within the nervous system progressively changes the nervous system. It is inevitable that such changes deregulate the continuously ongoing baseline homeostatic mechanisms that are implemented within the nervous system; thus, MEmory Storage Side effects arise (MESS effects, see also chapter 5.4 of the main text). Such deregulation effects, it significant, impair homeostatic functioning, and in the long run may lead to organism deterioration and death. This view may be valid also for simple nervous systems as e.g. the one of c. elegans, where an e/x balance, the probably most potent creator of MESS effects, is not yet entirely developed. (Extinction is possible, but recovery of extinguished aversive memories seems not yet to be shown, see Amano and

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Maruyama, 2011). Taken to the extreme, all physiologic regulatory mechanisms that simultaneously constitute a memory system, even those lying on a pure cellular level, appear to be prone to aging causing MESS effects. A single cell employs a multitude of regulatory mechanisms, and the underlying regulatory machinery, the genome, simultaneously constitutes a memory system (e.g. through transcriptional circuits and epigenetic changes, see Istrail et al., 2007, p. 190). Thus, this system as a whole, or parts of it, is prone to deregulatory MESS effects that could lead​ ​to​ ​cellular​ ​aging. The core germline has no memory. ​This general view on aging as a side effect of memory storage allows an interesting speculation why in complex animals the germline is immortal and the soma ages (c.f. Smelick and Ahmed, 2005; Jones, 2007). Due to the very complex representation of life events within even simple nervous systems, the mind-body system (hereafter termed ‘soma’, to contrast it with the germline) of animals is during a lifetime exposed to an extreme and unpredictable richness of possible anti-homeostatic events. Many of these events have to be memorized in order to create adaptive reactions that serve survival and its ultimate goal, the transport of the germline to the next generation. Thus, due to the ever increasing MESS effects of countless memories that are continuously stored in a wide array of memory systems, the soma-related homeostatic mechanisms progressively get deregulated. The effects of this deregulation manifests where memory systems influence homeostatic regulation, i.e. on a cellular level (due to transcriptional and epigenetic memories), and on the level of tissues the function of which is regulated by​ ​a​ ​nervous​ ​system.​ ​As​ ​a​ ​consequence,​ ​the​ ​soma​ ​ages​ ​on​ ​a​ ​cellular​ ​and​ ​tissue,​ ​i.e.​ ​whole​ ​body​ ​level. As evolution dedicated the responsibility for solving the complex problem of survival entirely to the soma, and thereby created for the germline an environment (the stem cell niche, see Scadden, 2014) that is free from complex influences, the mechanisms that maintain the core of the germline (i.e. germline stem cell viability and self renewal capacity, hereafter termed ‘GEM mechanisms’ to contrast them to the general germline-related homeostatic mechanisms) are only responsible to deal with a comparatively extremely restricted set of anti-homeostatic events (ionizing radiation, DNA damaging chemicals, stochastic events, etc.). Thus only a very restricted set of regulatory systems and pertaining memory systems is needed to deal with this restricted set of anti-homeostatic events. The reduced complexity of germline anti-homeostatic events also increases predictability of necessary reactions, which further reduces the need for memory systems. This line of thought can be further developed when considering a peculiar, general characteristic of stem cell lines, that is related to complexity and regulation. Several observations suggests, that even a single stem cell is able to provide the full functionality of a stem cell line. For instance, Scaddens notes in his general review of the various stem cell niches (Scadden, 2014), that the niche integrates information at the organismal level and the stem cell “ ‘reads-out’ on a single cell level the needs of the organism” (p. 47). The single cell read-out and functioning of stem cells is impressively demonstrated by the study of Holstege et al. (2014) which found that at the moment of death of a 115 years old women, about two thirds of the white blood cells remaining in her body originated from only two blood stem cells. This view of a single cell or low amount cell ‘read out’ is further supported by the finding of Kozar et al. (2013), that only five ‘working’ stem cells are present in intestinal crypts (tiny depressions in the gut lining). The fact that such a low amount of functional stem cells is sufficient to maintain the functionality of a stem cell line implies that the regulatory signals form a stem cell line to the soma depend only to a very small extent on complex interactions between stem cells. Moreover, the above mentioned finding of only two hematopoietic stem cells producing two third of the white blood cells suggests that probably only a single remaining stem cell would be able to generate the necessary regulatory signals to the soma (most probably first amplified by the stem cell niche before relayed to the soma). By contrast, the regulatory signals generated by a complex tissue (e.g. liver, kidneys, etc.) depend on extremely complex interactions between large amounts of cells of various functionality. Thus, compared to the regulatory signals generated by a complex tissue, the regulatory signals generated by a stem cell line are of extremely reduced complexity. Consequently, concerning interactions between the soma and stem cell lines, the stem cell lines are much more a target than a source of regulatory signals. The stem cell lines are therefore compared to complex tissues only to a restricted extent engaged in regulatory feedback circuits and pertaining memory systems. Furthermore, such feedback circuits not only interfere with memory systems, they actually constitute by themselves memory systems, because on exposure to events, they are able to permanently shift into new states of altered (and possibly detrimental) feedback circuits, that can be

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considered as memories of the state shifting events (Krakauer et al., 2016, p. 8). Thus, due to the low amount of such memory representing feedback circuits, the stem cell lines are compared to complex tissues much more protected from​ ​MESS​ ​effects​ ​related​ ​to​ ​such​ ​circuits. This general constellation in stem cell lines is even more pronounced in the germline, because compared to soma-related stem cell lines, the regulatory signals generated by the germline, when viewed in an abstract way, target only to a restricted extent the current soma but largely target the next soma, therein manifesting as accurate genotype and as adjusted epigenetic, transgenerational acting parameters. The germline exhibits therefore an even lower involvement in regulatory feedback circuits than other stem cell lines. Thus, compared to soma stem cell lines, the germline is even less affected by MESS effects that result from germline-soma regulatory circuits. As in hematopoietic stem cells even a single cell seems to be able to maintain functionality, this suggests that also a single germline cell could maintain the germline functionality. This suggests, that at least the GEM mechanisms can be completely built on the single cell level (provided the presence of a functional germline niche), again reducing complexity​ ​and​ ​related​ ​intrinsic​ ​memory​ ​systems. Therefore, the GEM mechanisms that need to deal with the above mentioned anti-homeostatic events (ionizing radiation, etc.) can also completely be built on the single cell level. Creating such mechanisms outside the single cell level, or memorizing anti-homeostatic events for the adaptive adjustment of GEM mechanisms is not necessary during the pre-replication period. This constellation of a cell-autonomous functioning of the GEM mechanisms implies a complete lack of higher level memory systems within these mechanisms and a low amount of implicit memory systems that would arise from the involvement in soma-germline spanning feedback loops. This markedly low amount of adaptive, memory based system within GEM mechanisms protects these mechanisms from deregulating, intrinsic MESS effects, that would otherwise arise. This is here thought to be the fundamental reason why the GEM mechanisms are not permanently deregulated during the pre-replication period and the germline never ages (or ages so slowly that other mechanisms [Kirkwood and Cremer, 1982, p. 112] can preserve genome integrity). (Regulatory signals from the soma to the germline epigenome, which is a memory system and therefore changes therein could deregulate GEM mechanisms, are here thought only to target transgenerational (see Kelly, 2014) and not soma-lifetime​ ​related​ ​regulatory​ ​mechanisms). This discussion of germline immortality may appear only to represent an altered perspective on the fact that the germline has restricted functionality and the thereby entailed restricted complexity allowed evolution to confer it with more robustness and perfectness, which in turn prevents aging. However, after my internet research, the aspect of deregulation by memory formation is not yet covered by research data and therefore might be of interest in order to elucidate where and how in the course of cell differentiation cellular aging is introduced. Moreover, since memory formation is intrinsic to feedback loops and feedback loops are utilized at all levels of biological regulatory systems (Krakauer et al., 2016, p. 8), deregulation by memory formation could provide a unifying explanatory concept for aging phenomena across the different levels of physiologic processes. In particular theories of programmed/regulated aging have been criticized because of their failure to provide a specific mechanism that may be able to program/regulate aging (Kirkwood and Melov, 2011). Memory, through its persistence and accumulation over time, and through the resulting ever increasing directional influence on regulatory systems, may be a prime candidate for such​ ​a​ ​mechanism. Please note that the developed picture of GEM mechanisms does not mean that these mechanisms do not possess adaptive capacities. It only means that these mechanisms completely revert to their previous state after exposure to a trigger of such mechanisms ceased to persist. For instance a weak toxic event in the soma will leave a permanent memory trace in the soma memory systems, whereas a weak toxic event in the GEM mechanisms will transiently trigger homeostatic mechanisms and after their cessation no trace whatsoever of the toxic event will remain. No long-term memory is formed. Perhaps this view is somewhat too restricted, because a certain amount of memory formation may be advantageous, in case the resulting weak MESS effects can be counterbalanced by means of special mechanisms (see Kirkwood and Cremer, 1982, p. 112). Please note also, that the presented model of aging

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does not predict that all aspects of aging are driven by MESS effects, rather it predicts that aging in the soma has intrinsic,​ ​MESS​ ​effect​ ​driven​ ​components.

Memory  transfer  makes  perhaps  somewhat  SENS  (theoretical,  but​ ​not​ ​speculative)  [Here starts the part related to memory consolidation. ‘MESS effects’ means ‘MEmory Storage Side effects’ and they are​ ​here​ ​hypothesized​ ​to​ ​promote​ ​aging.] Memory transfer may reduce MESS effects. ​The presented model has several implications concerning the question whether SENS (Scientifically Engineered Negligible Senescence, i.e. blocking the aging process) or rejuvenation (de Grey, 2008; Rose, 2008) is theoretically possible. First, the dichotomy of immortality and aging in the germline versus soma suggests that a complete segregation of a regulatory mechanisms from memory storage prevents MESS effects, that could cause an aging phenotype in the regulatory system. However, a complete segregation of long-term memory and regulatory system is not possible in the soma, since for adaptive purposes, soma memory systems must have access to soma regulatory systems through sensors and effectors. This seems to set a minimal theoretical level for MESS effects in the soma being the minimal achievable MESS effects of the soma memory systems. Thus, if in an individual the level of MESS effects is significantly higher than the minimum level (a point that is discussed in chapter 5 of the main text and answered positively for the average adult), then reducing MESS​ ​effects​ ​should​ ​significantly​ ​improve​ ​aging​ ​phenomena​ ​and​ ​health. But how can reduction of MESS effects be achieved? Ideas to answer this question can be developed when considering that possibly the amount of overlap between a regulatory system and the pertaining memory system significantly influences the amount of arising MESS effects. To give an example, it seems probable that due to the low neuron number (302) in c. elegans (Amano and Maruyama, 2011) the neuron groups that govern food intake largely overlap with the neuron groups that govern food related learning. Several arguments suggest that MESS effects in such a system (hereafter termed ‘overlapping system’) are stronger than in a system where regulation and memory are physically segregated, but connected by sensor/effector mechanisms (hereafter termed ‘segregated system’). First, intrinsic overexpression of memories due to intrinsic network activity contributes to MESS effects and such intrinsic activity is stronger in overlapping systems due to parallel ongoing regulatory activity. Through the sensors of the segregated memory system, ongoing regulatory activity in the regulatory system is also injected into the segregated memory system, and therein induces MO which can in turn deregulate the regulatory system (see chapter 2 of the main text for a discussion of this kind of ‘intrinsic’ MO). But the segregated memory system can concentrate on information aspects of the signals coming from the regulatory system and reduce the MO inducing influences of quantitative aspects (signal strength). MO in the segregated memory system should therefore be lower than in the overlapping system. Second, a memory that lays within the regulatory system deregulates this system through its molecular representation and through its overexpression. By contrast, a memory that lies entirely in the memory division of a segregated system does not possess a molecular representation in the regulatory system and therefore deregulates the regulatory system only through memory overexpression. Despite these disadvantages, overlapping systems have one advantage that will turn out below to be of outstanding importance: as signal transmission between memory system and regulatory system is much faster in overlapping systems, they allow a much faster generation of memory based adaptive reactions than segregated systems. These points are not developed further here. I include them despite their speculative character, because they appear to be testable by means​ ​of​ ​computational​ ​simulation​ ​in​ ​biologically​ ​realistic​ ​neuronal​ ​networks. When taking together the arguments that a segregated system has significantly less MESS effects than an overlapping system, this introduces an intriguing theoretical possibility to advance SENS or rejuvenation, or in general to improve health: erasing a memory trace from an overlapping system and a parallel transfer into a segregated memory system, where the adaptive potential of the memory is preserved through a sensor/effector

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connectivity to the overlapping system, should reduce MESS effects of the transferred memory trace and therefore positively influence aging-related phenomena and health. This effect has two major components. First, nervous system generated deregulation commands to tissues should reduce, thereby slowing or blocking aging or diseases. Second, and of great importance, if the reduction of deregulation commands to tissue and cells leads to a return towards baseline of tissue and cellular regulatory mechanisms, and frees repair capacities, then even cellular and tissue rejuvenation could take place. This sounds like science fiction, but the transfer of memories from one to another memory system is actually a common procedure in higher animals (during memory consolidation, see e.g. Do Monte et al., 2016) and it is here hypothesized that such procedures may be applicable for health improvement, aging reduction, or rejuvenation purposes. It is in particular hypothesized that in order to enable animals (including humans) to generate extremely fast reactions on the basis of aversive memories, the suffering part of aversive memories is still now, after more than 500 million years of nervous system evolution stored in an overlapping system, and that transfer of only the suffering part of an aversive memory into a non-overlapping, higher level memory system is sufficient in order to greatly reduce MESS effects of such memories, and in consequence to reduce aging and improve health. This idea is further developed in chapter 8.3 of the main text and in the accompanying article Kanding (2017a). Brief summary of the three articles that comprise the EMD hypothesis. ​Life is continuous adaption to changing but similar conditions, rendering memory an indispensable tool for survival. But by its very nature of being stable over time, memory contains an element of stasis. This element, if too intensively imprinted on an organism, impairs adaptation and may cause disease and death. Basically, this is nothing new. For instance, the dangerous effects of traumatic memories are a well known example of stasis effects of memories. And even the idea that accumulated memories of many minor adverse events may cause long-lasting problems is sometimes expressed in the psychological literature (personal remembering). But new are the neuroscientific formulation (MO and FINE as developed in the main text) of the mechanisms underlying these observations and insights, and the development of a mechanistic concept that may help improve the more than 500 million years old problem of memory stasis effects: the concept of memory transfer from an overlapping to a segregated system (as developed in this text) by means of an existing,​ ​possibly​ ​unique​ ​to​ ​humans,​ ​memory​ ​reconsolidation​ ​process​ ​(as​ ​developed​ ​in​ ​Kanding,​ ​2017a).

Predictions​ ​and​ ​research​ ​ideas  This​ ​chapter​ ​will​ ​be​ ​elaborated​ ​in​ ​a​ ​separate​ ​article.​ ​Here​ ​is​ ​a​ ​brief​ ​and​ ​informal​ ​list​ ​of​ ​the​ ​most​ ​important​ ​points. 1) 2)

MOHA predicts that lifetime adversities (childhood adversities, chronic stress traumatization, etc.) reduce, the​ ​lifespan.​ ​To​ ​the​ ​best​ ​of​ ​my​ ​knowledge,​ ​this​ ​is​ ​reflected​ ​in​ ​the​ ​current​ ​research​ ​state​ ​on​ ​this​ ​issue. Importantly, because easy to test in ​C. elegans​, MOHA predicts that modulation of memory formation modulates​ ​aging.​ ​In​ ​particular,​ ​the​ ​erasure​ ​of​ ​long-term​ ​memories​ ​should​ ​exert​ ​aging-reducing​ ​effects.

Conflict​ ​of​ ​interest​ ​statement. The​ ​author​ ​declares​ ​no​ ​conflict​ ​of​ ​interest. Acknowledgements. Many​ ​thanks​ ​to​ ​Sulayman​ ​J.​ ​for​ ​his​ ​extensive​ ​work​ ​in​ ​typing​ ​and​ ​correcting​ ​this​ ​manuscript. Author information: RA Kanding is the pen name of a german computer scientist with lifelong interest in neurosciences.

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