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The metabolism -- brain health connection

brain mitochondria neurogenesis insulin depression inflammation alzheimers ketosis metabolism

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#1 StevesPetRat

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Posted 12 July 2018 - 07:09 AM

Warning: speculation to follow.


One of the interesting things in the mathematics of dynamical systems (and consequently in physics, chemistry, biology, etc) is how a few simple rules can end up producing extremely complex dynamical behavior. Check out the Lorenz equations for a great example of this.


If we look at life, then, what are the simple principles governing it? I would argue that life is governed by the drive to consume resources in order to reproduce. These simple constraints produce the incredible variety of living systems that we see around us. (This is a model for life, not a definition. Is fire alive? Well, no, even though it follows the same principles -- though fire is quite a complex dynamical system in and of itself)


Fundamentally, then, the brain is a finely evolved resource-seeking and -conserving mechanism. And cutting-edge research indicates that defects in the mechanisms of metabolism are largely responsible for many neurological pathologies. For example, Alzheimer's disease has been called "type 3 diabetes", Parkinson's disease is now believed to be associated with insulin resistance and mitochondrial dysfunction, and Huntington's disease patients exhibit lower insulin secretion and sensitivity, just to list a few.


As a personal anecdote, I have struggled with depression on and off since I got mono from the Epstein-Barr Virus at the age of 19. On recent reflection, the main thing that I notice about this depression is that, when confronted with a task, I simply don't feel like I have the literal energy available to complete it. That if I were to begin, I'd run out of steam well before completion. Mood and cognitive problems seem to arise secondary to my brain's fundamental under-estimation of the resources available to it.


I wonder if this model of localized insulin resistance / mitochondrial dysfunction / metabolic disruption might not explain other symptoms of depression, and other conditions like ADHD or borderline personality disorder (let alone cases of ME/CFS). Take anhedonia, for instance. "Joy" or "pleasure" are energetically expensive emotions to experience -- we tend to move around a lot more, be more active, make more noise, think more racing thoughts, etc. Yet depressed people still enjoy food enough to eat (until the depression becomes truly severe), oftentimes gaining weight, which is consistent with the prioritization of energy resource accumulation. Loss of libido is somewhat more common in depressed women than men, again consistent with the energy budget idea. Furthermore, inflammation could lead to this scenario as well; after all, it signals our brains to conserve our energy to fight off illness or heal from injury. Trauma also triggers epigenetic responses; I would be utterly shocked if none of these had anything to do with insulin sensitivity / metabolism. Look at all the people who become obese due to eating to feel "safe" after childhood abuse -- this must be driven by such mechanisms.


So, now I ask:

How do we improve our brain's sensitivity to signals about how much energy is available?

What are ways to improve mitochondrial function?

Can these metabolic corrections become "locked in" epigenetically, or do we have to continuously fight against the slide downhill?


I know there are plenty of short threads on the topic, as well as long ones (i.e. the Lostfalco mega thread on intranasal insulin). Maybe I am just somewhat depressed, so my brain is telling me I don't have the energy to go search for all these answers ........

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#2 tunt01

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Posted 13 July 2018 - 05:58 PM

Short message because of time constraints and my original reply got nuked by a lost Internet connection.


1.  I'd look to Mark Mattson/Valter Longo periodic fasting/intermittent fasting to restore insulin sensitivity at the brain.  Mark's work has been centered around neuropathologies (Alzheimer's, Huntington's) and dietary interventions to improve insulin sensitivity.  Some of Mattson's work show that exercising in a fasted state is additive in terms of mitochondrial biogenesis and healthspan.


2.  Consider looking at other non-dietary interventions.  Exercise, quality sleep, blue light circadian rhythm, hyperbaric oxygen therapy (HBOT) that might strengthen your insulin sensivity.


I don't have the time to fully commend on your questions about Epigenetics, and my study of this subject matter is limited.  I think the downhill side you are concerned with is more or less about aging itself and overall epigenetic drift.  


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#3 Dichotohmy

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Posted 13 July 2018 - 06:35 PM

I would call this a detailed way to describe the medical concept of "dauer," which is a persistent hypometabolic state that is highly associated with chronic fatigue syndrome, but I would agree should be associated with other medical conditions that have metabolic deficits as key symptoms. Dauer is thought to be a different concept than cytokine induced sickness behavior, the two being quite similar, and like sickness behavior, dauer is postulated to occur for the ultimate purpose of the body to conserve energy in order to better fight off some sort of underlying infection or to survive. 


On the epigenetic question, I would say that this only matters in cases where the body isn't actually fighting off a persistent and active infection. For instance, perhaps someone had Epstein Barr 10 years ago and, for all intents and diagnostic purposes, there is no measurable trace of the EBV remaining active. In fact, that 10-year old infection could have very well caused an epigenetic change that leads to a persisting dauer state in lieu of the body actually fighting off an infection. If the body is actually fighting an infection, that seems more in line with sickness behavior. Quite honestly, I am 100% confident nobody yet knows the actual answer to the epigenetic question, so all we can do is speculate. Also, nobody has any answers to dauer, so all we can do is speculate.


I think one thing is for sure: once we figure out dauer, and more importantly how to treat it - or even better, make it go away forever - we will finally have an answer and likely a cure to all kinds of diseases. Not just CFS-like illnesses, but chronic depression and other "mental" illnesses, neurodegenerative diseases, and possibly even supposed autoimmune conditions. Maybe medicine won't find the answer to those other things by being able to solve the hypometabolic state of dauer, but the insight, diagnostics, and stumbling blocks along the way to solving dauer will unintentionally lead to answers for a lot of other things.



Edited by Dichotohmy, 13 July 2018 - 06:39 PM.

Also tagged with one or more of these keywords: brain, mitochondria, neurogenesis, insulin, depression, inflammation, alzheimers, ketosis, metabolism

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