December 25, 2017
"The root cause of aging is not damage accumulation. Rather, in animals with nervous system, aging is permanently enforced on the body by the anti-homeostatic effects of the slight overactivity of countless very weak aversive memories (up to dozens of millions in humans) that develop during the lifetime due to a self-amplification mechanism of aging.
Difficult to believe? This website presents a seamless argumentation for this position, and its validity only depends on two quantitative factors: the number of silent engrams forming during a lifetime and the magnitude of their overactivity resulting from certain properties of neuronal networks."
After a century of intense research, the cause of the process of aging is more than ever before a mystery. For a long time, the evolutionary theories of aging were widely accepted. According to these theories, evolution was not able to optimize certain cellular and tissue maintenance mechanisms. As a result, damage and waste accumulate and ultimately destroy the organism.
But many discoveries made in the last 20 years now question these theories and indicate that aging is to a significant extent "programmed/regulated", i.e. not only an undesired byproduct of evolution but at least partly created by evolution for specific purposes. Additionally, across all animal species, aging seems not only to originate from cellular and tissue-specific mechanisms. Instead, a central mechanism located in the nervous system appears to govern the aging process on a systemic, whole-body level by inducing cellular and tissue aging in a top-down manner.
Particularly perplexing are recent research results [ref2], showing that cells and tissues automatically rejuvenate when those molecular signals are blocked that induce top-down aging. The paradoxical conclusion one must draw from these research results seems to be that "aging is not aging", but rather "blocked rejuvenation". This, in turn, suggests that instead of treating aging, rather unblocking of rejuvenation is the key to better health during getting older - one must find the source of the systemic signals that block rejuvenation and act at this source in the right way in order to prevent the blocking of rejuvenation. Thereafter, tissues and cells will rejuvenate by themselves, automatically, without further intervention. This should work at least to the degree the central aging mechanism was indeed responsible for the extent of cellular and tissue aging at the point of time of unblocking rejuvenation. This means that the effects of cellular aging mechanisms that are not under central control (if such mechanisms exist) will possibly not entirely be reverted by unblocking rejuvenation. Additionally, these mechanisms will possibly continue to induce a certain degree of "real aging". Interestingly, MOHA and the related hypotheses present some inspiring thoughts concerning this point of view.
An analysis of crosstissue coexpression of aging genes (p. 670) points to the hippocampus, a brain region crucial for memory formation, as a source of the top-down aging cascade. To the best of my knowledge, MOHA is the first theory of aging in accordance with this analysis. Basically, MOHA states that in organisms that possess a nervous system (from C. elegans up to H. sapiens) side effects of memory formation create an anti-homeostatic effect that acts permanently on a systemic, whole-body level, and continuously increases over a lifetime. This effect triggers cellular aging mechanisms and ultimately creates the aging phenotype and associated diseases. More specific introductive information about this effect follows below, in the section "The core hypothesis".
MOHA can explain many characteristics of aging as e.g. phenoptosis, fast evolvability of lifespan changes, rejuvenation effects of blocking of specific aging molecules, the apparently very slow pace of aging, the fact that no genes seem to exist that completely abolish aging, the compared to plant species low amount of animal species that exhibit very slow aging, the apparently coordinated aging across tissue boundaries, the conundrum that medical progress heightened average but not maximum lifespan, and many more. For an overview of the very complex science of aging, I recommend the Wikipedia article Evolution of aging and the websites of Joshua Mitteldorf, João Pedro de Magalhães, and Theodore Goldsmith.
The overarching EMD hypothesis develops the concepts on which MOHA is founded. The hypothesis basically argues that a wide range of currently unexplainable medical phenomena develop when "Extinction Memory Damages" (EMDs) amplify the above postulated anti-homeostatic effects of memory formation. The extinction memory is a special kind of memory system that serves to inhibit aversive memories. The postulated anti-homeostatic effect of memory formation actually arises due to damages to the extinction memory. Such damages disinhibit aversive memories, and the resulting overactivity of aversive memories has an anti-homeostatic, disease and aging inducing effect on body and mind (more detailed info follows below). A further article (daccdepot.pdf) completes the EMD hypothesis by presenting the theoretical basis of a memory reconsolidation process that can revert the anti-homeostatic effects of memory formation and therefore should promote cellular and tissue rejuvenation.
Functional Somatic Syndromes. Interestingly, the major class of diseases explained by the EMD hypothesis, the so-called functional somatic syndromes (FSS), has a peculiar relationship to aging: In many FSS, brain-aging appears to be accelerated, and conversely, aging is accompanied by a multitude of functional somatic symptoms. The explanation proposed by the EMD hypothesis for the FSS and their relationship to aging is quite straightforward. First, internal and external factors that induce EMDs drive a person's neuroendocrinal and muscular system to a pre-symptomatic state. Usually, this process takes place unnoticed over a long period of time (decades). A typical internal factor that causes EMDs would be chronic subclinical brain-inflammation. Various toxins could constitute external factors. Many other factors exist. Interestingly, traumatization increases the vulnerability to EMDs and amplifies the effects of EMDs. Traumatized persons are therefore prone to reach the pre-symptomatic state more rapidly than non-traumatized persons.
Further occurring EMDs may drive the pre-symptomatic state to a permanent symptomatic state. In this way, the chronic FSS like tension headache or fibromyalgia develop. Moreover, the pre-symptomatic state can easily be shifted by internal and external factors to a transient symptomatic state. In this way, the transient symptoms of the various FSS develop. E.g. in IBS (irritable bowel syndrome), irritating nutrition causes a transient shift to the symptomatic state. And in PMS (premenstrual syndrome), the transient change in hormone levels is the culprit. In what way influences of such distinct nature as nutrition and hormones may trigger one key disease mechanism that can produce the very varied symptoms of the FSS, represents one major innovation provided by the EMD hypothesis. A further major innovation is the above-proposed transit to a pre-symptomatic state via EMDs. Note also the important implication of the EMD hypothesis that a subset of cases of various psychiatric disorders like depression, anxiety disorder, and schizophrenia/psychosis, develop in precisely the same way as the FSS (see chapter 7.3 and 8.2 of emdscientific.pdf). Whether FSS, psychiatric disorders, or other medical phenomena develop from the proposed disease mechanism, and which comorbidities develop, depends on the extremely complex interaction of factors like genotype, main brain location where EMDs occur, memory content, and environmental factors. This is in line with recent research results suggesting a shared, multifactorial etiology for various psychiatric disorders. The Appendix at the end of this page lists further phenomena possibly explainable by the EMD hypothesis.
In the EMD hypothesis, the FSS develop from an effect of EMDs. This effect, a permanent anti-homeostatic signaling to the body, is after MOHA (see above) also the primary cause of aging. This explains the similarity between the FSS and the functional somatic symptoms that accompany aging. Note also that the proposed effect of EMDs exists in all animals with a nervous system and therefore can also explain the occurrence of FSS (and in particular the related phenomenon of trigger points) in animals like cats, dogs, horses and even sharks.
The proposed effects of EMDs arise from malfunction and demise of inhibitory interneurons in the nervous system. Somewhat surprisingly, this implies that the FSS develop similarly (though much slower) to tetanus - a severe disease where the malfunction of inhibitory interneurons in the spinal cord entails extreme muscle cramps. This link of the FSS to tetanus is described in the short version of the EMD hypothesis.
Please find below a brief description of the core hypothesis. It is actually a slightly changed email to a scientist.
The core hypothesis
Dear J,
As my texts are very long, here a very short version of the core of my hypothesis. A "P" in front of a sentence means "postulation", an "F" means "fact".
F: In the hippocampus, a basic spatiotemporal memory of every life event is created and associated with a memory of its emotional quality. Importantly, of these memories in particular the aversive ones are crucial for survival and therefore decay only very slowly.
F: During memory consolidation, aversive memories are bestowed with inhibitory "extinction memories", which are mainly implemented in inhibitory interneurons. Extinction memories allow the controlled reactivation of aversive memories.
P: Due to these memory formation characteristics, an ever-increasing collection of aversive memories and counterbalancing extinction memories develops during a lifetime. Most of these memories represent very weak negative assessments of very short life events. However, due to an intrinsic self-amplification of aging, the number of such memories lays in the dozens of millions. The cumulative anti-homeostatic force of these memories actually enforces aging on the body (see below for details).
F: Every day about 80000 neurons die in the human cerebral cortex.
F: The inhibitory interneurons that form extinction memories are much more active compared to the principal neurons that form the associated aversive memories. Inhibitory interneurons are therefore more vulnerable to detrimental influences (e.g. neuronal aging, inflammation, toxins, etc.). P: They die therefore at a slightly higher rate than principal neurons. Over time, this leads to slightly defective extinction memories and to a slight, permanent disinhibition of the affected memory traces.
F: The continuously ongoing intrinsic activity of the CNS exploits this disinhibitory effect and produces a slight but continuous overexpression (i.e. overactivity) of the affected memory traces. The effect is referred to as "memory overexpression" or "MO". (Besides the described EMD-induced memory overexpression, the continually ongoing baseline activity in the CNS most probably entails an additional tendency to the very weak overexpression of aversive memories, even when they are extinguished by perfectly healthy extinction memories. Thus, even when the extinction memory stays perfectly healthy, the continually increasing amount of stored memories automatically entails an ever increasing level of MO. However, it is currently challenging to estimate the magnitude of this effect, and it is therefore not explicitly discussed in the EMD hypothesis.)
F: The continuous overexpression of aversive memories has a systemic anti-homeostatic effect. For instance, memory recall (which is similar to memory overexpression) up-regulates NF-κB and stress hormones. Memory extinction has the opposite effect. The sympathetic and the parasympathetic are up- and down-regulated in an analogous manner. See in my articles the related FINE concept, which infers these effects from research results of Brain-Body Medicine [ref2, ref3]. The basic concept of FINE is straightforward: Those physiological effects (e.g. activation of the sympathetic, blood pressure elevation, cytokine and hormone level changes) observed by Brain-Body Medicine during an emotional state, should be permanently re-instantiated when the memory of this emotional state is permanently overexpressed. Thus Brain-Body Medicine allows inferring chronic physiological changes from chronic memory overexpression. These changes are in this introduction referred to as "permanent anti-homeostatic side effect of memory formation". For instance, when an emotional state entails blood pressure elevation and muscle fiber strain, then the permanent overexpression of the memory of this emotional state entails permanent blood pressure elevation and permanent muscle fiber strain (chapter 3.2 of emdscientific.pdf provides a detailed neuroscientific argumentation, showing that these inferences are valid).
P: As memory overexpression is usually a very weak effect (except for traumatic memories), only the added effects of many overexpressed memories produce significant symptoms. The validity of the EMD hypothesis depends therefore crucially on a quantitative factor, the number of silent engrams that are prone to be overexpressed. Silent engrams are neuronal ensembles that form basic entities of memories of life experiences. The EMD hypothesis posits that due to an intrinsic self-amplification of aging (explained here), thousands of silent engrams are formed by day, leading to the accumulation of dozens of millions of silent engrams during a lifetime. The slight MO of these countless silent engrams represents the quantitative factor that pushes the minimal effects of single MOs to a significant anti-homeostatic level.
P: When laying on a natural activity level and when progressing in a natural velocity, then the continuous and during a lifetime ever increasing 24/7 activity of the described systemically acting, anti-homeostatic mechanism creates the molecular microenvironment that promotes cellular aging. This ultimately creates the aging phenotype and associated diseases. On the basis of a chronically elevated activity level of this anti-homeostatic mechanism, functional somatic syndromes (FSS), psychiatric disorders, and other phenomena may develop. See the description of the mechanism in the FSS section above.
P: This mechanism is responsible for the observed relationship between lifetime adversities and reduced lifespan (put simply: more aversive memories --> more aversive memory overexpression --> more aging).
F: Supercentenarians possess an extraordinary efficient anti-inflammatory network. P: This protects them from a major source (i.e. neuronal inflammation) of interneuron demise and the ensuing overexpression of aversive memories. The resulting reduced overexpression of aversive memories is thought to be responsible for their increased lifespan.
P: The most common sign of the described mechanism is surprisingly the facial wrinkles that are treated with botulinum toxin. Explanation: Aversive memories are usually associated with a muscular reaction that generates a facial expression of the aversiveness. The continuous activation of such muscular reactions by overexpressed memories causes quasi-permanent muscular contractions that ultimately contract the overlying skin and cause wrinkles. Epigenetic reprogramming resulting from permanent muscle cell activation leads to sarcomere shortening and increases the described effect.
That's the core of my hypothesis. I found supporting data for all postulations. In particular, the anti-homeostatic effect of the continual overexpression of aversive memories can be demonstrated experimentally in mice (via optogenetic deactivation of those interneurons that form the extinction memory, see emdscientific.pdf, chapter 1.1).
Thus there is no doubt that overexpression of aversive memories and the postulated anti-homeostatic effects really exist. Additionally, the existence of extinction memories has been demonstrated in a wide range of species, including honey bees and garden snails. The postulated anti-homeostatic effect that results from defective extinction memories could therefore be the root of the aging cascade in many species.
After my research, the remaining question is only if the effect is strong enough to induce aging/diseases or if evolution found a way to keep the strength of the effect below the detrimental level.
Best wishes, Rudger
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If interested, please find further introductive information on the page "Physical versus psychosomatic". Or switch directly to the Scientific Version.
Possibly the EMD hypothesis has explanatory power also for:
Some states of chronic focused and widespread pain
Some states of chronic muscle tension and shortening as e.g. frozen shoulder syndrome
Complex regional pain syndrome
Metabolic syndrome
A subset of cases of high blood pressure
A subset of cases of functional neurological syndromes
Various diseases that are characterized by epigenetic dysregulation of cellular mechanisms. The main example is cancer. Note here that epigenetic changes realize physiological adaptions to life experiences. Consequently, overexpression of memories of life experiences should indeed be able to induce overshooting, disease-causing epigenetic changes.
The worldwide epidemic of shortsightedness. Current research results indicate that time spent outdoor reduces the risk for shortsightedness. My (speculative) idea is that several indoor related factors cause EMDs which in turn induce chronic muscle tensions in the eyeball musculature and accommodation musculature. These muscle tensions trigger adaptive reactions that eventually create the eyeball elongation that is responsible for shortsightedness. This idea is supported by the fact that shortsightedness is often accompanied by symptoms typical of the FSS (e.g. fatigue, headache). This indicates that possibly shortsightedness is a functional somatic syndrome and develops like described above in the FSS section. A description of the indoor factors that putatively cause EMDs follows later. One obvious factor is the chemical compounds prevailing indoor (e.g. printing ink compounds transpired from book pages, plastic softener, etc.). These compounds are inhaled and may pass the blood-brain barrier and cause EMDs. This idea seems to contradict research results that suggest that daylight exposure of the retina protects against shortsightedness. But frankly, if this is the main factor, shouldn't there exist a strong link between shortsightedness and wearing sunglasses??? I would rather suggest that daylight exposure protects against EMDs in two ways. First, EMD-causing indoor factors are usually missing when exposed to daylight. Second, recent research suggests that too much exposure to dim light has a strong negative effect on neuronal wiring in the brain. This profound effect of light exposure to the brain suggests that additional effects may exist. Speculatively, i would suggest that daylight may has an anti-inflammatory and therefore neuroprotective, EMD reducing, effect due to the entailed positive mood and the related hormonal changes.