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A novel hypothesis on aging and Alzheimer. Part 1:
A novel hypothesis on aging and Alzheimer. Part 1:
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A novel hypothesis on aging and Alzheimer. Part 1:
14/05/2019 17:47:49 »
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.
PART 1: 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:
- Existing memory traces are constantly slightly activated by both incoming and intrinsic neuronal activities that take place within memory systems (see e.g. Pubmed-Ids: 18319728 and 10980021).
- In particular, aversive memories tend to lose small proportions of their inhibitory control over time, leading to their slight, permanent overactivity (more details below).
I call this tiny basic activity of memory traces generated by the above 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 influence of emotions on physical health.
The basic argument underlying this claim is that if a negative emotion has a proven anti-homeostatic effect, then the overexpressed memory of that emotion will have the same effect, only much weaker (see e.g. Pubmed-Id: 19524045; more follows also below).
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: The now increased 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”). Vicious, 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 a lot 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 IN THE LONG RUN, MAINLY BY INHIBITING CELLULAR 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 ...)
Short note: for the sake of brevity, instead of using the complicated phrase:
"the overexpression of the aversive memories created by the VC induce effect X ...",
I will use in the following the phrase:
"the VC-memories induce effect X ...",
or even more simply, "the VC induces effect X ...".
HOW DOES THE VC INHIBIT REPAIR MECHANISMS?
Before I go into the exact mechanisms by which the VC inhibits repair mechanisms, let me first explain how the VC generally activates physiological mechanisms.
According to my hypothesis, as briefly explained in point 2, the VC-memories generate their anti-homeostatic effect by triggering a series of brain-body mechanisms.
As also briefly explained in point 2, the basic argument behind this assertion is that if a negative emotion has a proven negative physiological effect, then the overexpressed memory of that emotion has the same physiological effect, only weaker.
The following quotes from a fundamental review article of brain-body medicine support this argument:
First of all, the following quote briefly summarizes the data situation that motivates an independent brain-body medicine:
“... what this juxtaposition [of scientific papers] reveals is that there is a remarkable commonality of brain areas and brain mechanisms that appear again and again in these [brain-body neuroimaging] papers. This commonality, which exceeded our expectations, suggests that there is a coherent field of neurobiology that relates emotion, emotion regulation and stress on the one hand to systemic medical disorders and peripheral physiological processes on the other.” (Lane and Wager, 2009, p. 1135)
The next quote demonstrates the harmful physiological effects of negative emotions:
„the field of Brain–Body Medicine has ... unequivocally demonstrated that negative emotional states such as depression and stress have deleterious effects on physical health“ (Lane and Wager, 2009, p. 1135)
The following decisive quote demonstrates the negative physiological effect of continuously active brain-body mechanisms triggered by negative emotions or permanent negative emotional states.
„Since these [brain-body] mechanisms related to [negative] emotion are in continuous operation, their integrated influences across months or years are likely to have clinically important effects on disease processes and outcome. Indeed, that is what the epidemiological evidence indicates ...“ (Lane and Wager, 2009, p. 1135)
The important conclusion now is:
SINCE THE MEMORIES GENERATED BY THE VC ARE PERMANENTLY, 24/7, OVEREXPRESSED AND CONTINUOUSLY TRIGGER THE CORRESPONDING DELETERIOUS BRAIN-BODY MECHANISMS, THEY EXERT A SIGNIFICANT NEGATIVE PHYSIOLOGICAL EFFECT, SIMILAR TO THE EFFECT POSTULATED IN THE ABOVE QUOTE BY LANE AND WAGER FOR NEGATIVE-EMOTION RELATED BRAIN-BODY MECHANISMS THAT ARE IN CONTINUOUS OPERATION.
This, in turn, leads directly to the conclusion that the VC can trigger all diseases which, according to brain-body medicine, can be triggered by negative emotions: cardiovascular diseases, high blood pressure, chronic pain, etc.
(Please note here that the validity of this conclusion depends only on quantitative factors, since the phenomenon of overexpression of memories, as well as the resulting effects on brain-body mechanisms, certainly exists to some extent. The only question is whether the phenomenon of memory overexpression is strong enough to exert a significant activating influence on brain-body mechanisms.)
These were the explanations on how the VC generally triggers brain-body mechanisms. In order to substantiate that the VC produces the aging phenotype, it remains to be shown that among the brain-body mechanisms activated by aversive memories there are also those that inhibit repair mechanisms. In this case, the VC would generate the characteristics of the aging phenotype, such as accumulation of cell and tissue damage and molecular waste products, by inhibiting repair mechanisms.
The available literature on brain-body mechanisms shows that the VC achieves the postulated inhibitory effect on repair mechanisms mainly because overexpressed aversive memories activate brain-body mechanisms that deregulate the neuroimmunoendocrine system (i.e., ANS, immune, and endocrine systems).
The main result of this deregulation (examples follow below) is a tendential shift of cellular mechanism from anabolic to catabolic. This shift inhibits repair mechanisms, including stem cell activity necessary for tissue regeneration.
The main conclusion of my hypothesis is therefore that the inhibitory effect of the VC on repair mechanisms, acting over decades, eventually leads to the accumulation of molecular waste products and cell and tissue damage, thereby _allowing_ the onset of the aging phenotype. This means that the VC is not directly but causally responsible for the aging process.
As an example, I would like to describe here one brain-body mechanism that is triggered by aversive memories and actually gives the VC an inhibitory effect on repair mechanisms.
According to brain-body medicine aversive experiences trigger the release of stress hormones:
—> It follows that overexpressed memories of aversive experiences lead in the same way to the release of stress hormones.
—> This also applies to the aversive memories generated by the VC.
—> Since VC-memories are continuously overexpressed, this means that the VC triggers a continuous release of stress hormones. (And, indeed, the level of stress hormones in the blood increases steadily as you get older.)
—> Since stress hormones have a catabolic effect (see e.g., PMID 6365973, or Wikipedia on „Catabolism“), it follows that the VC has a permanent catabolic effect and therefore permanently inhibits cellular repair mechanisms. Q.E.D.
Since the results of brain-body medicine are very extensive and include a variety of brain-body mechanisms, further mechanisms that give the VC inhibitory effects on repair mechanisms can easily be derived. An example of how the VC inhibits repair mechanisms by means of the autonomous nervous system follows below.
To better understand the central importance, scope, and detail of brain-body medicine, I strongly recommend reading the abstracts and introductions to the following review articles:
The new field of Brain-Body Medicine: what have we learned and where are we headed?
Lane and Wager, 2009; PMID 19524045
Brain-Body Pathways Linking Psychological Stress and Physical Health.
Gianaros PJ, et al., 2015; PMID 26279608;
The rebirth of neuroscience in psychosomatic medicine, Part I: historical context, methods, and relevant basic science., Lane RD, et al., 2009; PMID 19196808
The rebirth of neuroscience in psychosomatic medicine, Part II: clinical applications and implications for research., Lane RD, et al., 2009; PMID 19196806
Part 2 follows
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