Rudger

Hello Forum, I would like to present you a novel hypothesis about the origin of aging and aging-related medical phenomena, possibly including Alzheimer‘s disease. The hypothesis sounds even more than crazy at first. So please keep in mind that many scientific innovations initially sounded blasphemous or even crazy. Also, take into account that the hypothesis is possible AND unique. You will not find it anywhere else, and you yourself, believe me, would never get the idea ... it is just too weird. THE HYPOTHESIS The hypothesis is based on the following 4 premises: 1 A memory trace, once formed in the neuronal networks of the brain, is never fully inactive. Rather it is permanently active to a tiny extent (let’s say around a micro-percent) compared to its activity during memory recall. The mechanisms causing this phenomenon are: - Permanent, incoming as well as intrinsic neuronal activities in memory systems slightly activate existing memory traces (see e.g. Pubmed-Ids: 18319728 and 10980021). - Some types of memory traces tend to lose low levels of their inhibitory control over time, resulting in a slight persistent activation of the memory trace (see below). I call the tiny baseline activity of a memory trace resulting from these mechanisms the “OVEREXPRESSION” of a memory. 2 The overexpression of an _aversive_ memory, e.g. a pain memory, has an extremely weak, anti-homeostatic effect on body and brain. This follows from research results of Brain-Body medicine, which investigates the impact of negative emotions on physical health (see e.g. Pubmed-Id: 19524045). The underlying argument is that if a negative emotion has been shown to have some anti-homeostatic effect on a biological system, then the overexpressed memory of that emotion will have the same effect, only much weaker. 3 Now the completely crazy part: The normal memory perception mechanisms that exist in all animals with nervous system, lead to the unconscious perception of the OVEREXPRESSED EMOTIONAL COMPONENTS of aversive memories ... ... AND TO THE CONTINUOUS AND UNCONSCIOUS RE-MEMORIZATION of these overexpressed emotional components as part of the emotionality of the normal, ongoing autobiographical events ... followed by their RE-OVEREXPRESSION, ... and subsequent re-memorization ... and so on ... moment by moment, the whole life long. Ok, that sounds really weird. Therefore again step by step: Step 1: All memories of aversive events of your life are permanently a little bit active (i.e., „overexpressed“), thereby slightly shifting your state of mood towards negativity. Step 2: This (consciously imperceptible) slightly negative state of mood is re-memorized as an aversive emotional memory along with the current autobiographical event. As this newly formed memory is also overexpressed, this step increases the number of aversive memories that are overexpressed. Step 3: This higher number of overexpressed aversive memories in turn increases to a tiny extent the negativity of your state of mood, which is again re-memorized as in step 2 ... and so on, moment by moment, the whole life long. In this way, the number of aversive memories that are overexpressed, and likewise their combined anti-homeostatic effect (remember point 2 above), increases constantly in an unstoppable manner. This is obviously a vicious cycle (hereafter just called “VC”). Viscous, because it induces a steadily increasing anti-homeostatic effect in the body, which may react with potentially dangerous health problems (see below). Since a new autobiographical event is generated and memorized roughly every second (actually when a new visual scene occurs after an eye movement), overexpressed memories are re-memorized also roughly every second. The VC creates therefore during a human life about one BILLION of very, very, very slightly aversive memories - and every single one of them exerts a very, very, very slight anti-homeostatic effect on the body. (Yes, you read that right, one BILLION, 10 ^ 9, 1000 MILLIONS of memories ... no joke.) A side note: It sounds a bit ridiculous, but the VC basically works like the mechanism „compound interest with contributions” in the financial sector. It starts as soon as the first aversive memory has been formed. Aversive memories, which are subsequently formed by negative life experiences, are "contributions". And like compound interest, the VC has enormous effects over a longer period of time. Another side note: Since the future relevance of aversive memories can not be predicted, they remain memorized for a lifetime and never completely decay (proved in animal experiments; in humans, traumatic memories are an example for the long lifetime of aversive memories). Therefore, the VC really creates the postulated high number of aversive memories. But many of them lose much of their contextual information throughout life. For background information, google „silent engram“. 4 Now the last and decisive statement of the hypothesis: THE COMBINED ANTI-HOMEOSTATIC EFFECTS OF THE VERY, VERY, VERY SLIGHT OVEREXPRESSION OF ALL THE MEMORIES FORMED BY THE VC, CREATE, MAINLY BY BLOCKING REPAIR AND REJUVENATION MECHANISMS, THE AGING PHENOTYPE AND RELATED DISEASES. (To keep you on the hook, I'd like to reveal that a gene expression study indeed suggests that the most important brain area of human memory, the hippocampus, actually causes a cascade of physical aging in some tissue. In addition, there is a study showing that the skin of mice is AUTOMATICALLY REJUVENATED as soon as a particular pro-inflammatory molecule is blocked whose activity is driven by the VC. More below ...) CONSEQUENCES OF AN AMPLIFIED VISCOUS CYCLE This was a description of the VC how it is running in its normal velocity in _every_ animal with a nervous system. In this „normal“ velocity, the VC has after my hypothesis already a strong deleterious effect and causes or promotes in humans, mainly through its pro-inflammatory action, all the major aging-related diseases: cancer, type 2 diabetes, cardiovascular disease, etc. This is already bad news. But unfortunately, since the VC has several intrinsic positive feedback loops, various influences are able to shift the VC into an amplified state, where it has an even stronger disease inducing effect. In this amplified state, it creates significantly stronger aversive memories, ranging in number from dozens to hundreds of millions, depending on when in life the amplifying event took place. The consequences of an amplified VC are disastrous in several ways: - All aging-related diseases may occur up to decades earlier. - Existing health problems of any kind, occurring at any age, are amplified by the significant anti-homeostatic effect of an amplified VC. - A whole range of new health problems specific to an amplified VC may occur (see the second part of the Introduction page on my website). INITIATING EVENTS The major initiating events that lead to an amplified VC are: - The formation of traumatic memories. Its overexpression and re-memorization significantly increases the strength of memories created by the VC, and, consequently, their anti-homeostatic effects. - The induction of a chronic, subclinical brain inflammation due to various factors, like strong infections, concussion, toxic events, etc. This amplifies the VC in two, quite astonishing, ways: A) The cytokines released during a brain inflammation induce a subclinical „sickness behavior” (see google), which entails a slightly aversive state of mood. This reinforces the VC, since from now on the memories generated by the VC are slightly more aversive. B) Brain inflammation indirectly disinhibits aversive memories by increasing the cell-death rate among a special type of very stress-sensitive neurons that control aversive memories (the so-called „PV+ interneurons“, see more on my website, or google “Interneuron Energy Hypothesis” and PMID 24256726). This leads to an increased overexpression of the affected aversive memories, which in turn reinforces the VC. The process B is, in my hypothesis, also to a certain extent induced by normal brain aging, and therefore represents the second general mechanism — besides the persistent neuronal activity in memory systems mentioned in premise 1 — which leads to memory overexpression. Influences that take advantage of this second mechanism of memory overexpression are in my opinion the most important and most dangerous entry points into an amplified VC. Furthermore, aversive memories, especially traumatic ones, most probably promote brain inflammation (for mechanisms, see my website). This would additionally reinforce the VC by inducing two further positive feedback loops into the VC via the two mechanisms described in the preceding paragraphs. THE VICIOUS CYCLE MUST BE DISTINGUISHED FROM CLASSICAL DISEASE MECHANISMS The VC is basically a natural process that slowly drives many biological regulatory systems in body and brain out of their state of equilibrium. This implies several specific properties for the VC that distinguish it from classical disease mechanisms: - THE VC-INDUCED DISEASES HAVE A COMMON ORIGIN. BUT THEY NEVERTHELESS APPEAR TO BE COMPLETELY DIFFERENT MEDICAL PHENOMENA BECAUSE EVERY BIOLOGICAL REGULATORY MECHANISM DEREGULATED BY THE VC, PRODUCES ITS OWN COMPLEX OF SYMPTOMS. - IT IS DIFFICULT TO PREDICT WHICH DISEASES THE VC WILL CREATE IN AN INDIVIDUUM, BECAUSE THE WAY THE VC DEREGULATES BIOLOGICAL REGULATORY MECHANISMS DEPENDS IN AN EXTREMELY COMPLEX WAY ON GENETICS, EARLY LIFE EPIGENETIC PRIMING, LIFESTYLE, AND AUTOBIOGRAPHICAL MEMORY CONTENT. - SINCE THE VC GENERALLY DEREGULATES NOT ONE, BUT SEVERAL BIOLOGICAL REGULATORY MECHANISM, THE VC-INDUCED DISEASES HAVE A HIGH CO-MORBIDITY. The main similarities of the VC-induced diseases are: - They are driven by chronic inflammation (since the main detrimental effect caused by the VC is chronic inflammation in brain and body, and chronic inflammation has multiple tissue-damaging effects). - Their main risk factor is aging (since in general, the VC's anti-homeostatic effects take decades to rise to a disease-inducing level). (It is worth mentioning at this point that most of the aging-related diseases are indeed driven by chronic inflammatory processes. See https://harvardmagazine.com/2019/05/inflammation-disease-diet) SUPPORTING RESEARCH DATA The hypothesis is supported by the following research findings: GENE EXPRESSION ANALYZES SUGGEST AN IMPORTANT HUMAN MEMORY SYSTEM TO CAUSE AGING IN SOME TISSUE A 2011 study of Huang et al. about aging-related gene expression in various tissues (https://www.ncbi.nlm.nih.gov/m/pubmed/21751870/), concludes that „the aging of hippocampus caused some kind of cascade of aging in other tissue“. The hippocampus is the area of the brain responsible for autobiographical memory. The hippocampus is also known for its decisive role in inhibiting aversive memories. Damage to the hippocampus would, therefore, disinhibit aversive memories. The (after my hypothesis) thereby resulting brain-wide increased level of inflammation would in turn predominantly damage the hippocampus, because it is one of the most sensitive structures of the brain. This would further disinhibit aversive memories, and so on, and so on. This means that the hippocampus could be an area of the brain that is simultaneously the origin and target of one of the mechanisms that form and amplify the VC. This possible role of the hippocampus as a major source and target of the VC, and therefore as a major _causal_ source of an aging-promoting influence on the body, could be the reason why Huang et al., 2011 found the hippocampus as the _causal_ source of the aging-related gene expression changes in some tissues of the body. MICE SKIN AUTOMATICALLY REJUVENATES WHEN BLOCKING A MOLECULAR MECHANISM WHICH IS DRIVEN BY THE VC My hypothesis postulates that the VC creates aging in all animals with nervous system by blocking repair and rejuvenation mechanisms (for exact mechanisms, see my website). Interestingly, a study shows that a molecular mechanism (the pro-inflammatory activity of the NF-κB molecule), actually exists in the skin of mice, that a) becomes more and more active as the mice grow older, and b) THE BLOCKING OF WHICH LEADS TO AUTOMATIC SKIN REJUVENATION. This, in fact, suggests that aging, as postulated by my hypothesis, arises from the blockage of repair and rejuvenation mechanisms. In this case, the blocking of repair and rejuvenation mechanisms is due to the overactivity of NF-κB (for details see PMID 18055696). In addition, because the VC is highly pro-inflammatory and therefore strongly potentiates the activity of NF-κB (see e.g. PMID 19408108), the VC might be responsible for the aging-related increased activity of NF-κB and, thus, also for the resulting skin aging through the NF-κB-induced blockage of repair mechanisms. The VC could therefore indeed represent the origin of the skin-aging process in mice. A CAUSAL CHAIN FROM THE VC, TO THE AUTONOMOUS NERVOUS SYSTEM, TO AGING A research line (see PMIDs (29932493 and 30303708) found, that a major source of tissue aging, the decline of stem cell proliferation during growing older, is caused (at least in vitro) by an imbalance in the activity of the two branches of the autonomous nervous system, the sympathetic (SNS) and the parasympathetic (PNS) (see e.g. https://www.fightaging.org/archives/2018/10/neurotransmitters-envisaged-as-controllers-of-stem-cell-activity/ ). As already mentioned, one major deleterious effect of the VC is a deregulation of the ANS, i.e. an ever-increasing imbalance in SNS and PNS activity during aging. Thus, through this deregulation, the VC could be the causal source of the declining stem cell proliferation occurring during aging, and because of this property actually represent the origin of the aging process. ALZHEIMER CHARACTERISTICS SUGGEST A CAUSATION BY THE VC Now, why do I consider Alzheimer as caused by the VC? Recently, I read this article (https://www.nytimes.com/2019/04/08/health/alzheimers-dementia-stroke.html), which states that Alzheimer is, except for the cases caused by specific Alzheimer genes, mainly an aging-related disease. Alzheimer could, therefore, be a consequence of the VC when it was running in a subject over decades in a specific, „Alzheimer generating“ state. Thus, when it slowly deregulates a set of regulatory mechanisms in a way that the Alzheimer phenotype emerges. Supporting this idea is the fact that the VC _always_ causes, and Alzheimer _always_ is accompanied by chronic brain inflammation. The article states also, that Alzheimer is frequently accompanied by hippocampal atrophy. Since the VC possibly runs predominantly in the hippocampus and damages it, hippocampus atrophy and the causally associated Alzheimer, could both be a consequence of the VC. The hypothesis is described (sorry, unfortunately somewhat cumbersome) in more detail here: https://sites.google.com/site/emdhypothesis/notes Hope, you had a little bit of fun (at least, it would decelerate the VC ;-)) Kind regards, Rudger