Visceral Fat Harms Cognitive Function via Inflammatory IL-1β Signaling
It is well known that excess visceral fat tissue is harmful to health over the long term. A sizable amount of this harm stems from mechanisms that act to generate chronic inflammation. These include an accelerated generation of lingering senescent cells, DNA debris from dead fat cells, signaling from normal fat cells that is similar to that secreted by infected cells, and so forth. Researchers here focus on the link between visceral fat and loss of cognitive function, showing that particular inflammatory signal is influential in causing the central nervous system immune cells known as microglia to change their behavior for the worse, thereby harming the function of neurons in the brain. There is a great deal of other evidence pointing towards the importance of inflammatory and senescent microglia in the development of neurodegenerative conditions; chronic inflammation is a noteworthy component of the aging process, and to the extent it can be minimized, such as by maintaining a low level of visceral fat tissue, individuals tend to have a better prognosis.
Scientists have shown one way in which visceral fat is bad for brains is by enabling easy, excessive access for the proinflammatory protein signal interleukin-1 beta. The brain typically does not see much of this interleukin-1 beta, but researchers have found that visceral adiposity generates high, chronic levels of the signal that in turn over-activate the usually protective microglia, the resident immune cells in our brain. A bit like a smoldering pot, this chronic inflammation from visceral fat prompts formation of inflammasome complexes that further amplify the immune response and inflammation. The protein NLRP3 is a core component of the inflammasome complex in the fat, and it's what promotes the production and release of interleukin-1 beta by fat cells, and stokes the inflammation fire. It was known these reactions were causing problems in the body, and now the scientists have evidence they are causing problems in the brain.
To explore brain effects, the scientists knocked NLRP3 out of mice and found the mice were protected against obesity-induced inflammation of the brain and the cognitive problems that can result. They also transplanted visceral adipose tissue from obese mice and obese mice missing NLRP3 into lean mice recipients and found the transplant from the NLRP3 knockout mouse had essentially no effect. But the transplant from the obese but genetically intact mice increased levels of interleukin-1 beta in the hippocampus, a center of learning and memory in the brain, and impaired cognition.
Microglia typically function as watchdogs, constantly surveilling and roaming the brain, eliminating dead cells and other debris as well as a myriad of other tasks like forming and pruning connections between neurons. Microglia also have receptors for interleukin-1 beta, and the protein, whose many actions include promoting inflammation, easily passes through the protective blood brain barrier. Microglia's helpful - or harmful - actions likely result from signals they are exposed to, and another thing interleukin-1 beta appears to do is prompt microglia to wrap around synapses, possibly exerting damaging pressure and/or releasing substances that actually interfere with conversations between neurons. In the absence of disease, microglia also are known to embrace synapses but to release good things like brain-derived neurotrophic factor, which is like fertilizer for these invaluable connections.
Link: https://jagwire.augusta.edu/visceral-fat-delivers-signal-to-the-brain-that-hurts-cognition/
This is yet another interesting area of study, especially as pertaining to the microglia, rather than just the adipiosity as a singular cause of its over-activation.
For some time now, I have been pondering an idea, as far as troubleshooting potential variations in efficacy, once SENS therapies really go into play. This is a bit of a 3-fold, or 4-fold web of intermingled elements of physiology that seem to sway the bar of any given substance, food or drug - natural or unnatural - from efficacious to the other side of the fence, where once helpful results become paradoxical, and full of side effects, rather than therapeutic. (*The 4-folds would be: 1) limbic 2) autonomic 3) mitochondrial 4) microglial - too much sway, and what is good, becomes what is bad; or what is healthy, becomes toxic or taxing)
One of the things I have seen, repeatedly, both through personal experience, and through research(mostly of the anecdotal variety), is that, when there are substantial variations in the activity of the limbic brain, there are correlating deviations in the reactions to substances entering the body. On one end of the spectrum, you have the ME/CFS/Fibro subset, or those on the autistic spectrum, and on the opposite end of limbic sensitivity, you have psychopathy. Both groups seem to have stark variation in how they process and "accept" substances coming in.
In the ME/CFS/Fibro group, as well as the autism catalog, there is microglial over-activation, as well as limbic over-activation(as well as autonomic issues). In psychopathy, there is limbic under-activation, and often, a parallel in autonomic response(*altered stress response).
When the stress response is altered - "neurons that fire together, wire together" - there is often immune correlation, such as the microglia in the brain. Once in overactivation, a simple ingestion of a vitamin C tablet can cause dizziness, headache, pain etc, due to the central sensitization effect, which microglia play a big part in(as does the limbic brain). This is where Vitamin C goes from "Kill a cold", to "Causes an autoimmune reaction". It's not the Vitamin C, it's the brain, the nervous system, and the balance of the immune activation.
So with that central sensitization theme in mind, this troubleshooting idea that keeps circulating in my mind, is : "If the limbic brain/ANS/microglia/mitochondria(*insufficiency), can turn a helpful Vitamin C tablet into neuroimmune disarray, how much more could that skew the data when the "SENS cocktail" is administered to go to work on many systems simultaneously? And how important could it be, to gauge this level of activation, prior to accepting patients into an efficacy study? Also, how would it be adjusted for in populations on either side of the activation bell curve?" Sure, the ME/CFS/Fibro/Autism and Psychopathy populations are the extremes, but rate of efficacy might not need extremes to produce unfavorable deviations as proof of concept - not to mention the prevalence of side effects by percentage as well. Small variations in activation could theoretically lead to large deviations in outcomes.
I have come across massive interplay when it comes to the microglial overactivation groups when it comes to correlations in ANS dysfunction, limbic overactivation, and mitochondrial insufficiency, as pertains to adverse reactions to innocent substances - or, even in the absence of adverse reactions, substances that would otherwise be effective to control populations, seem to have no effect on turning those populations into better health.
Here's the kicker: this seems to be the case until the limbic brain and microglia are no longer exciting the ANS via stress hormone production (or negative feedback loops once exhausted), which in turn, leads to restoration of mitochondrial function and a shift from glycolysis, back to aerobic respiration and sufficient ATP production. I suspect this could be a game changer for anti-aging therapetics, seeing as ME/CFS is a spectrum, and, with old age, comes many of the signs of CFS, including dimished mitochondrial capacity and ANS regulation In producing desired results, then that little bit could go a long way in troubleshooting the dreaded question of, "Why is this working on this subset, but not the other?" - and then chasing the tail of singular biomarkers, when it is more of a systems default in the software of the brain, rather than hardwired physiology or gene expression.
Here is the quote from an interview with a psychopath, which I found interesting. I am used to researching the complete opposite end of the spectrum, but seeing similar reactions on the opposite end, I have to consider the significance of the involvement, which makes me also wonder about the microglial activity of psychopaths, and if lowered microglial activation can cause just as much of an issue as does overactivation in sensitized populations.
"And you don't take any medication for it, right?
No. It's just a variant brain structure. And actually we respond very differently to medications as well, because our chemistry is different, so you can expect strange medication reactions. I've been dealing with that. Whenever a doctor prescribes the medication, I can pretty well expect it to not work as intended."
Source: https://www.thecut.com/2018/08/my-life-as-a-psychopath.html
I've had all of this circulating in my head for quite a while, so I needed to put this out there into open space, in case it is a lead or clue for anyone - and thanks to the mention of the over-activation of microglia due to adiposity, it spurred me into actually blurting it out. Like most on here, I just want to see these therapies work - and given some of the skepticism out in mainstream society, proving efficacy in absence of toxicity(or side effects), is going to be a huge area of boom or bust(not to mention cash investment influx vs "Interesting, but I'll watch a little longer from the sidelines").
Fine tuning could be the difference. Prime the brain and the body, then administer the therapy.