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The Inflammatory Reflex - HDW's Learning Log

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#211 HighDesertWizard

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Posted 08 April 2019 - 12:49 PM

Oh sure
very straightforward to stimulate a Vagus Nerve directly; they do this by implanting a device that is in direct contact with the nerve.
Check out the link:
"A stimulator device is implanted under the skin in the chest. A wire from the device is wound around the vagus nerve in the neck."
https://www.epilepsy...stimulation-vns
 
What I am having a hard time understanding is how an electrical current applied to the skin penetrates many layers of tissue and reaches the vagus nerve

  • A stimulator device is implanted under the skin in the chest. A wire from the device is wound around the vagus nerve in the neck.

 
I investigated this GammCore device a bit more over the weekend and learned a few significant things and one puzzling thing.
 
The significant things I learned...

  • I take it to be true, then, that electrical stimulation of specific types can penetration layers of skin in a way that can stimulate the vagus nerve.
     
  • What follows below this bullet represents some current understandings I have. I don't have time at present to provide study link references for each statement below. What I have done is to qualify each statement below with a degree of certainty that I could provide study evidence in support of the statement. That will have to do for now.
    • I accept as fact that, because European authorities and the FDA have approved the GammaCore device, it does do electrical stimulation that can penetrate layers of skin to stimulate the vagus nerve.
    • I know there are studies demonstrating that TENS devices do electrical stimulation that can penetrate layers of skin
    • I know that PEMF (Pulsed Electro-Magnetic Field) therapy devices generate magnetic waves that can penetrate layers of skin that provides healthful benefits.
    • I know Robert Dennis has demonstrated that his ICES device can provide healthful benefit. I believe his ICES device may provide superior healthful benefits than PEMF does.
      •  I believe that PEMF signals penetrate more deeply into tissue than TENS device electrical signals.
    • I know that PEMF provides healthful benefit via, among potentially multiple mechanisms, Heat Shock Protein expression, especially HSP 70.
    • I believe that specific characteristics of the signals generated by these devices--Frequency, Amplitude, Power, Waveform--might have an impact on the effectiveness and nature of the benefit a device can provide.
      • And because a single device, like my new TENS device, provides settings for changing those characteristics, I believe a single device might provide multiple types of benefit.
  • A while back, I established a Longecity Forum Thread to discuss these issues entitled:  Pickin' up Good Vibrations : Leveraging the Science of Frequency-Sensitive Biological Interventions.

 
The thing about GammaCore I'm puzzled about...
 
2015, OC-069 Non-invasive afferent vagus nerve stimulation (nvns) using gammacore (gc) in patients with treatment refractory gastroparesis awaiting enterra gastric neurostimulation
 

Introduction High frequency, low energy gastric neurostimulation (EnterraTM) is indicated for compassionate treatment of patients with refractory gastroparesis. Symptom improvement is reported in 50–60% of patients but not accompanied by improved gastric emptying. It is likely that gastric neurostimulation affects the gut-brain axis influencing autonomic afferents.1GammaCore (electroCore, LLC) is a non-invasive, afferent selective vagus nerve stimulator (nVNS) used for the treatment of migraine and cluster headache.2We report the first use of gammaCore (gC) in patients with refractory gastroparesis.
 

Method 35 consecutive patients with intractable gastroparesis were invited to undergo a course of gC whilst awaiting funding for Enterra. The gC device delivers its stimulus to afferent vagus fibres as they cross the neck adjacent to the carotid arteries and it is programmed to deliver doses of 120 s. Patients were trained to deliver 2 doses (240 secs) to the left and right vagus nerve respectively. This dosing regimen was self-administered 8 hly (12 doses/day) for 2 weeks, increasing in week 3 to 3 doses 8 hly (18 doses/day). Patients were asked to grade their symptoms daily using the 9 item Gastroparesis Cardinal Symptom Index (GCSI) with a 5 point Likert scale. The GCSI was completed for 2 weeks prior and throughout the treatment period. At the end of the treatment period, the mean aggregated GSCI score at baseline was compared with the score of the final week of treatment. Clinically meaningful improvement was defined as a GCSI Likert scale reduction of ≥1.

 

Results Twenty-three of the 35 patients (65.7%) used the gC as instructed and completed the diary. At 3 weeks, 8 patients (35%) had a ≥1 reduction in the aggregated GSCI score. Two patients who continued stimulation for more than three weeks had a delayed response, giving a total response rate of 43%. The response was evident within 1 week of commencing treatment in 8/10 responders (80%) and there was symptom recurrence within a week of stopping treatment in all the responders. There were no significant adverse events.

 

Conclusion In this group of patients with treatment refractory gastroparesis, 1/3 failed to engage with short term nVNS. In compliant patients,43% recorded a fall of ≥1 in their aggregated GCSI score. As gC stimulates afferent vagus fibres, it is likely that the response is mediated at the level of the gut-brain axis. In refractory gastroparesis, gC might offer a new approach to symptom control. The dosing and duration of nVNS required to obtain an optimal response deserves further consideration.


Notice that I've highlighted the fact that GammaCore influences Afferent (i.e., Sensory) Vagus Nerve Fibers.
 

And now for something completely different than anything I've written about The Inflammatory Reflex in the past...

The Inflammatory Reflex is a reflex in a way comparable to other sensory and motor reflexes. Among the most often cited examples is the Hand-on-a-Burning Stove example.
 
Put your finger or hand on a hot surface and almost immediately, there is a response to pull it away. The Sensory (aka, Afferent) arm of the Reflex senses the extreme heat and a signal proceeds up this Sensory Neuron to an InterNeuron which, first, processes the signal, and then sends the Pull-It-Away signal via Motor (aka, Efferent) Neurons, and the arm is pulled away. See the figure that illustrates the point.
 
8HucmhBh.png
 
Now, up to this time, I've only been posting about the Motor (Efferent) arm of The Inflammatory Reflex. But there is a Sensory (Afferent) arm and Kevin Tracey and his colleagues have recently published a study about the Afferent arm.
 
I summarize a couple points about this new study below, but you'll need to know a few additional facts as background first...

  • There are 80,000 to 100,000 vagus nerve fibers in our bodies. I'll post a study reference link at some point.
     
  • About 80% of these Vagus Nerve Fibers are Sensory (Afferent) and not Motor (Efferent) fibers.
     
  • A good analogy for how this is architected within our bodies: Imagine the broadband network within a city. Large cables carry thousands of smaller wires from the broadband central location out to individual homes. From one point of view, the connection from the central location to the periphery is singular. From another point of view, it's a profound mistake to think about the wire as a single cable. The same is true about the Vagus Nerve and how its presence within us is architected.

 

 
Kevin Tracey says that Anti-Inflammatory action in the Spleen establishing a less inflammatory state in an organism's periphery can be achieved by placing an electrode on the vagus nerve to trigger EFFERENT (Motor) Vagus Nerve Fibers. Efferent Vagus Nerve Activation at the location Tracey specifies is among the ways to trigger, what Tracey calls, "The Inflammatory Reflex".
 
I'm puzzled about how the folks at GammaCore KNOW that they've triggered AFFERENT rather than EFFERENT Vagus Nerve Fibers.


Edited by HighDesertWizard, 08 April 2019 - 12:59 PM.


#212 sub7

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Posted 23 April 2019 - 09:32 PM

  • I take it to be true, then, that electrical stimulation of specific types can penetration layers of skin in a way that can stimulate the vagus nerve.
     
    • I know there are studies demonstrating that TENS devices do electrical stimulation that can penetrate layers of skin

 

You have written a lot of good stuff that is worthy of comment, but just one very simple question:

 

Why not just take a TENS device and place it near the carotid artery on the neck and turn it on?
This should stimulate the Vagus nerve, no?
Would it be dangerous? I really doubt it....

 

How will we know if this is stimulating the Vagus Nerve? That should be simple: Just measure your pulse continuously while you do so (by way of a free cellphone app that reads your pulse through the cellphone camera lens) and if the pulse is slowing down, you are almost certainly stimulating the Vagus Nerve....

 

Am I off base here? If so, please someone correct me



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#213 HighDesertWizard

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Posted 25 May 2019 - 05:28 PM

You have written a lot of good stuff that is worthy of comment, but just one very simple question:
 
Why not just take a TENS device and place it near the carotid artery on the neck and turn it on?
This should stimulate the Vagus nerve, no?
Would it be dangerous? I really doubt it....
 
How will we know if this is stimulating the Vagus Nerve? That should be simple: Just measure your pulse continuously while you do so (by way of a free cellphone app that reads your pulse through the cellphone camera lens) and if the pulse is slowing down, you are almost certainly stimulating the Vagus Nerve....
 
Am I off base here? If so, please someone correct me

 
sub7... Great question... It's a question I was asking myself just a few months ago. I don't now have a definitive opinion about on the question but I do have a strongly held belief.
  
I've come to the conclusion that TENS stimulation of the Vagus Nerve isn't the optimal approach to triggering The Inflammatory Reflex (TIR).

  • Anecdotal reports suggest that TENS stimulation can impact heart beat in a negative way. This makes sense because, as I understand it, at the point of intervention close to neck, the main trunk of vagus nerve fibers have not yet split into the sub-trunk fibers that head to the spleen and the heart.
    • I have cardiac-related issues and I've decided not to fiddle with TENS intervention.
  • It's important to keep the entire scope of evidence about TIR in mind when thinking about how and where to intervene to trigger it. The Inflammatory Reflex is, after all, the SMILE of Longevity, the Splenic Macrophage Inflammation Limitation Explanation of Longevity.
    • by triggering a change of macrophage phenotype from M1 to M2, that is, from pro-inflammatory macrophage to anti-inflammatory macrophage, in the spleen, inflammation is reduced throughout mammalian organisms because...
      • most inflammatory cytokine macrophage "soldiers" are held in reserve in the spleen
      • the blood circulation flows through the spleen
    • so a question to be asking is this...
    • Are there ways to change the phenotype of splenic macrophages directly without triggering the vagus nerve by ingesting substances or stimulation?
  • Evidently, the answer is Yes.

Another "Tracey study" hot off the press, this time with the full study text more easily available. This study is a game changer. at least for me...   :)
 
 
March 12, 2019, Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation
 

Tools for noninvasively modulating neural signaling in peripheral organs will advance the study of nerves and their effect on homeostasis and disease. Herein, we demonstrate a noninvasive method to modulate specific signaling pathways within organs using ultrasound (U/S). U/S is first applied to spleen to modulate the cholinergic anti-inflammatory pathway (CAP), and US stimulation is shown to reduce cytokine response to endotoxin to the same levels as implant-based vagus nerve stimulation (VNS). Next, hepatic U/S stimulation is shown to modulate pathways that regulate blood glucose and is as effective as VNS in suppressing the hyperglycemic effect of endotoxin exposure. This response to hepatic U/S is only found when targeting specific sub-organ locations known to contain glucose sensory neurons, and both molecular (i.e. neurotransmitter concentration and cFOS expression) and neuroimaging results indicate US induced signaling to metabolism-related hypothalamic sub-nuclei. These data demonstrate that U/S stimulation within organs provides a new method for site-selective neuromodulation to regulate specific physiological functions.

 

ttYNJYG.png
 
 
Of course, we know what the key substances associated with triggering of TIR/CAP, norepinephrine, acetylcholine, and both, splenic- and serum-TNF. Can and does Focused Pulsed Ultrasound impact those independent-variable substances? Figure 2 of the study addresses that question...
 
6NFXzHBh.png
 
 
 
OMG.
 
A Game Changer Study!

 

 

Do you understand why that study is a game changer? It's Tracey, himself, who has put evidence on the table demonstrating that intervention directly vis-a-vis the spleen can achieve comparable anti-inflammatory effects in the circulation that vagus nerve stimulation can achieve.

 

Given that study, here are some questions to ask...

  • Can we determine the biological mechanism of action underlying the focused ultrasound reduction of inflammation in the spleen?
     
  • Are there ways we can, today, trigger this mechanism to reduce inflammation in the spleen?

I believe the answers are Yes and Maybe-Yes, ...

 

:)


Edited by HighDesertWizard, 26 May 2019 - 05:49 AM.


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#214 HighDesertWizard

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Posted 26 May 2019 - 06:58 AM

Seven years ago, yesterday, I created the thread post that evolved to become this thread. It had a different name at the time and I had no idea where the content of the science of The Inflammatory Reflex was headed.
 
It's turned out to be more important than I possibly could have imagined.
 
This is my first post to celebrate the date...
 
:)
 
 
Valentin Pavlov, one of Kevin Tracey key team members, recently published a literature review of The Inflammatory Reflex. It's a worthwhile read...
 
May 2019, Collateral benefits of studying the vagus nerve in bioelectronic medicine
 

Studies on the role of the vagus nerve in the regulation of immunity and inflammation have contributed to current preclinical and clinical efforts in bioelectronic medicine. In parallel, this research has generated new insights into the cellular and molecular mechanisms underlying the immunoregulatory functions of the vagus nerve within the inflammatory reflex. The vagus nerve and other cellular components of the inflammatory reflex are implicated in the regulation of bleeding, cancer, obesity, blood pressure, viral infections and other conditions. This collateral benefit broadens scientific horizons and provides new rationale for technological advances and therapeutic implications.

 

HgIQGsVh.png


Edited by HighDesertWizard, 27 May 2019 - 02:12 PM.


#215 Oakman

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Posted 26 May 2019 - 03:18 PM

Kudos HighDesertWizard for your thread efforts on this anniversary. All hail the vagus nerve, such an important, yet misunderstood and often neglected health mechanism and marker. I discovered your thread not so long ago, yet it has been extremely helpful. Nine months ago I started tracking my daily HRV, which led me to try to figure how to improve it, that led to the vagus nerve, that led to spermidine, and so to making my own spermidine fermented wheat germ extract, and to oxytocin, another vagus nerve stimulator, and so to a DIY yogurt with L reuteri, yet a further VN stimulator.  Finally I have found cholinergic supplements offer effective results for overall fitness. The combination of these has brought marked improvements in my recovery strategies and lowered inflammation to improve aerobic exercise performance. Haven't been able to incorporate bioelectricity yet, but I'm sure more practical advancements will be made in that realm too.

 

So many connected functions and effects, with the vagus nerve intimately involved in each. I'm thrilled that these strategies have allowed me to lower my resting HR, raise my HRV and improve consistency in heart health and exercise performance. It's esp. helpful that I can easily measure these metrics to validate I am getting stronger and my body more efficient over time.


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#216 HighDesertWizard

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Posted 26 May 2019 - 08:01 PM

The key prescription for achieving radical personal longevity can be thought of simply like this: Do what's necessary not to die of any specific thing over the long term while in a health crisis context...

This is the second post to mark my seven year obsession with the science of The Inflammatory Reflex (TIR)...

 
I appreciate the work of Tracey and his colleagues, including Valentin Pavlov, and their frequent reviews of the literature about The Inflammatory Reflex. But I've decided that their judgment has been less than stellar in one respect in their more recent reviews of the literature.

The most recent TIR-related literature reviews have all included references to the fact that triggering TIR increases Survival Probability, even in the context of lethal inflammation administration. But, to my knowledge, the larger meaning of this Triggering-TIR-Impact on survival probability has not been summarized in a serious way by...

  • intervention types (e.g., acupuncture, ingested substance, electrode placement)
  • intervention frequencies by intervention type
  • dosing strategies taking into account intervention type and frequency
  • addressing the relevance of the studies for present day humans in the wild
  • graphical means that make the complexity intelligible

The closest TIR-related overview diagram concerned with survival probability is the one shown below. It's now old, published in 2012, and doesn't begin to integrate the study data of The Inflammatory Reflex / Survival Probability by the dimensions I've listed above.

2012, Reflex Principles of Immunological Homeostasis

 

The reasoning that neural reflexes maintain homeostasis in other body organs, and that the immune system is innervated, prompted a search for neural circuits that regulate innate and adaptive immunity. This elucidated the inflammatory reflex, a prototypical reflex circuit that maintains immunological homeostasis. Molecular products of infection or injury activate sensory neurons traveling to the brainstem in the vagus nerve. The arrival of these incoming signals generates action potentials that travel from the brainstem to the spleen and other organs. This culminates in T cell release of acetylcholine, which interacts with α7 nicotinic acetylcholine receptors (α7 nAChR) on immunocompetent cells to inhibit cytokine release in macrophages. Herein is reviewed the neurophysiological basis of reflexes that provide stability to the immune system, the neural- and receptor-dependent mechanisms, and the potential opportunities for developing novel therapeutic devices and drugs that target neural pathways to treat inflammatory diseases.


nNiGayfh.png


Edited by HighDesertWizard, 27 May 2019 - 02:10 PM.


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#217 HighDesertWizard

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Posted 27 May 2019 - 07:53 PM

The content of this post has long been on my mind. It's the third post marking the 7th anniversary of my 1st post about The Inflammatory Reflex (TIR)...
 
In a post to follow, I'll provide an overview of the most significant TIR-related, survival probability experiments along with study graphic images.
 
This post is my attempt to summarize the larger scientific and human context within which this TIR-related-science is emerging.
 
:)
 
 
We find ourselves in a strange context...
 
Hundreds of scientists in hundreds of studies have designed and performed experiments about TIR and published descriptions of its physiology and biology. Many of those studies have also documented the benefits of triggering it for relief and resolution of a multitude of debilitating disorders and to increase survival probability in organism life threatening contexts.
 
Nevertheless, these scientific teams, publishing astounding Survival Probability findings, have not...

  • identified themselves with the Longevity Science Movement (LSM)
  • summarized the potential impacts on human lifespan of global, human TIR-triggering

The most recent TIR-related literature reviews have all included references to the fact that triggering TIR increases Survival Probability, even in the context of lethal inflammation administration. But, to my knowledge, the larger meaning of this Triggering-TIR-Impact on survival probability has not been summarized in a serious way by...

  • intervention types (e.g., acupuncture, ingested substance, electrode placement)
  • intervention frequencies by intervention type
  • dosing strategies taking into account intervention type and frequency
  • addressing the relevance of the studies for present day humans in the wild
  • graphical means that make the complexity intelligible

 
Meanwhile...

  • billions of humans around the globe spend their lives without knowledge that a mechanism already exists within them that could be leveraged for benefit if they only knew that it existed and learned how to trigger it
  • LSM Thought Leaders claim that health and lifespan benefits are in store for peoples around the globe, but none I know of has bothered to acquaint her-/him-self with the lifespan-impacting science of TIR, let alone think through and organize to educate these billions about how to leverage that science

In fact, these LSM Thought Leaders are doing the opposite. The LSM and Transhumanist Thought Leader I most respect has explicitly argued that our task is to "outsmart evolution".

... never mind that evolution established this incredible TIR mechanism within us that we've just figured out exists and, as you will see, has already been demonstrated to have positive effects in humans

 

As you review the survival probability studies and curves in a post to follow, consider the larger context described above...
  
:)


Edited by HighDesertWizard, 29 May 2019 - 04:39 PM.


#218 Ovidus

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Posted 05 June 2019 - 04:58 PM

HighDesertWizard,

This is all very good information and a lot of high quality work. As of this moment, is there any practical, actionable results from this all? -at least from your personal perspective?

I will be trying to stimulate the vagus nerve via a TENS device sometime soon. As mentioned, I will be monitoring my pulse during this process to gauge the effects and I will be very careful. 

 

As far as increasing acethycholine, can we take Cholinesterase Inhibitors? Is that a potentially viable step?

If the Cholinesterase Inhibitor does not sound like a good idea, is there anything else you are planning to do in order to put the lessons in this thread to practical use?

 

Thanks a ton


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#219 HighDesertWizard

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Posted 18 June 2019 - 04:43 PM

This is my fourth post marking the 7th anniversary of my posts about The Inflammatory Reflex... 

 

We find ourselves in a strange context...
 
Hundreds of scientists in hundreds of studies have designed and performed experiments about TIR and published descriptions of its physiology and biology. Many of those studies have also documented the benefits of triggering it for relief and resolution of a multitude of debilitating disorders and to increase survival probability in organism life threatening contexts.
 
Nevertheless, these scientific teams, publishing astounding Survival Probability findings, have not...

  • identified themselves with the Longevity Science Movement (LSM)
  • summarized the potential impacts on human lifespan of global, human TIR-triggering

 
 
What, then, have they been up to? What's been driving them to do survival probability studies if their motivation hasn't been related to the LSM objective of discovering knowledge to increase lifespans?
 
In this post, I summarize what I believe was on their minds and a few of their study experiment objectives...
 
 
In the 1990s, Kevin J. Tracey was involved in scientific study teams attempting to reduce inflammation in patients, especially with sepsis. Over time, he and his various team members realized that Tumor Necrosis Factor (TNF) was a (the) key inflammatory cytokine in the blood circulation (aka, "in the serum") that drove negative health outcomes, oftentimes death.

TYIxVXR.png

  • Later, in the 1990s, by accident, he and colleagues discovered that a micro-dose of a TNF-inhibiting substance in the brain dramatically reduced TNF expression in rodents' serum.
  • Over time, they figured out that the Vagus Nerve was a required component of whatever mechanism was triggered in the brain that inhibitied inflammation throughout the organism and in the serum.

 
They had discovered something remarkable...
 
Evolution had established a mechanism in rodents...

  • providing a means for inflammation inhibition throughout the organism by means of
    • receptors in the brain
    • the vagus nerve
    • the blood circulation system
  • potent enough to dramatically increase survival probability in the face of lethal inflammation administration

But in the early 2000s, Tracey and his colleagues didn't yet know what Other Biological Objects were required for the mechanism to be effective in inhibiting inflammation. So he and colleagues around the world embarked on a decade of studies to figure out what these required objects were...
 
Their research strategy was relatively simple because they already knew the few facts above highlighted in red...

They determined to perform experiments that would...

  • remove the function of the specific biological components believed to be a part of the mechanism
  • trigger the anti-inflammatory mechanism in the brain
  • inject the lethal inflammatory substance
  • see if the animals without the biological function survived in significantly fewer numbers than the control animals with the biological function intact

If a significantly greater number of animals survived with the biological component intact than those without...
 
--> then the biological component had to be considered a critical and required component of the mechanism...
 
Right?
 
:)
 
 
Early on, Tracey believed that the Brain-Vagus-Serum mechanism that inhibited inflammation in rodents was just one Arm of a larger Reflex Mechanism having to do with inflammation. The image below depicts the kind of biological objects that make up a Reflex Mechanism and the concepts important for understanding it. (There are many versions of the image below online that can be easily found.)

 

I've posted a tiny bit about the concept of Reflex Mechanisms, including the image below, in a post up thread here
 
8HucmhBh.png
 
 
Tracey published a first study sketching his hypothesis in 2002 in a study entitled, The Inflammatory Reflex.
 
Notes about that study...

  • Tracey imagined (in Figure 3) that the mechanism was a Reflex, hence, the name of the Mechanism, with a Sensory ("afferent") Arm and a Motor ("efferent") Arm.
     
  • Tracey imagined that the Substances inhibiting Inflammation throughout the organism were/are Agonists of Brain Interneurons triggering the Motor Arm of The Inflammatory Reflex.
    • ​It's worth taking time to understand that sentence with reference to the images above and below. If you do understand it, you'll understand what Tracey and his colleagues were really up to...
      • figuring out To Hack an ancient, evolutionary conserved mechanism in mammals
  • In 2002, by means of Figure 1, we know that Tracey already understood that Acetylcholine was the key neurotransmitter of the Motor Arm of The Inflammatory Reflex.
    • The label Cholinergic Anti-Inflammatory Pathway is a synonym for the Motor Arm of The Inflammatory Reflex.
  • He also anticipated means to trigger the mechanism at a high level in Figure 4, including attaching an electrode to the Vagus Nerve to reduce inflammation throughout the organism.

Jij1Prrh.png
 
uGlqs1Jh.png
 
gtFKB6mh.png


Edited by HighDesertWizard, 18 June 2019 - 05:33 PM.

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#220 HighDesertWizard

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Posted 20 June 2019 - 03:52 AM

This is my fifth post marking the 7th anniversary of my posts about The Inflammatory Reflex... 

 

 They [Tracey and his colleagues] had discovered something remarkable...

 
Evolution had established a mechanism in rodents...

  • providing a means for inflammation inhibition throughout the organism by means of
    • receptors in the brain
    • the vagus nerve
    • the blood circulation system
  • potent enough to dramatically increase survival probability in the face of lethal inflammation administration

But in the early 2000s, Tracey and his colleagues didn't yet know what Other Biological Objects were required for the mechanism to be effective in inhibiting inflammation. So he and colleagues around the world embarked on a decade of studies to figure out what these required objects were...
 
Their research strategy was relatively simple because they already knew the few facts above highlighted in red...

They determined to perform experiments that would...

  • remove the function of the specific biological components believed to be a part of the mechanism
  • trigger the anti-inflammatory mechanism in the brain
  • inject the lethal inflammatory substance
  • see if the animals without the biological function survived in significantly fewer numbers than the control animals with the biological function intact

If a significantly greater number of animals survived with the biological component intact than those without...
 
--> then the biological component had to be considered a critical and required component of the mechanism...

 

To grasp the meaning of the experiments performed reviewed below that show increased survival probability, it helps to visualize the biological objects implicated in the experiments.

  • This post contains 4 images of the biological objects implicated in those experiments copied from several Tracey studies. I've posted most of them before with a reference link and I will get around to posting links to them in this post.
     
  • Some objects are shown more than once and are depicted in more than one size.
    • The objects in the images are shown out of proportion to their actual size.
  • I may be updating this pic with additional explanation notes over time.

 

 

 

I'll be referencing biological objects in the images shown below in a future post about TIR and survival probability.

 

1W01TNgh.png


Edited by HighDesertWizard, 20 June 2019 - 04:02 AM.

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#221 Phoebus

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Posted 28 June 2019 - 05:04 PM

 

  • He also anticipated means to trigger the mechanism at a high level in Figure 4, including attaching an electrode to the Vagus Nerve to reduce inflammation throughout the organism.

 

 

 

 

cool, so how do we do that? 

 

lets make this happen 



#222 Oakman

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Posted 30 July 2019 - 03:37 PM

'Tickling' the ear with a small electrical current could 'help you stay healthier as you get older and slash your risk of deadly heart disease'

https://www.dailymai...der-people.html

 

16664042-7300435-image-a-2_1564474163384

 

 

Using an electrical device to send 'tickling' impulses into someone's ear could help them stay healthier into old age, scientists say.

Stimulating the vagus nerve through the skin of the head may kick-start a person's resting nervous system and vital digestive processes which get weaker with age.

And doing this may reduce the risk of high blood pressure, heart disease or an irregular heartbeat, according to researchers.

Just 15 minutes per day proved long enough to have the desired effects on over-55s in a study, which the scientists called a 'great response'.

-----------------

 

Study > Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity


Edited by Oakman, 30 July 2019 - 03:43 PM.


#223 HighDesertWizard

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Posted 24 July 2020 - 03:36 PM

I've begun research about a question related to the topic of this forum thread, the SMILE as an Explanation of Longevity, NF-kB Inhibition, Telomerase Expression, and HRV. I hope research about the question and my posts about it here can contribute to the case for getting an experiment done to answer the question in a definitive way.
 
I've taken a first stab below at what the question looks like and written out a general hypothesis about what an experiment would find the answer to be. In posts to follow, I'll provide the rationale and study links context that explains why the general hypothetical answer is a reasonable one given the evidence available at this date (2017-07-03). I'll also provide a restatement of that first draft hypothesis answer that is testable and a draft list of specific experiments that would falsify that testable answer.
 
Your feedback about this process is greatly appreciated!
 
:)
 
The Question...
 
In various studies, TA-65 has been shown to increase Telomere Length without increased cancer incidence and one study has it that a MAPK related pathway is implicated as a micro-level explanation of the mechanism of action.
 
But what is the larger biological context Mechanism of Action of TA-65's Telomere Lengthening Effect without causing cancer?
 
My hunch below about the answer to the question can be formulated as a falsifiable hypothesis.
 
Vagus Nerve signaling, via the Cholinergic Anti-Inflammatory Pathway, is the larger biological context Mechanism of Action underlying the experiment observation that TA-65 can increase Telomere Length without causing cancer.
 
cc: Steve H

 
 

About the hypothesis I formulated last July...
 
Astragaloside IV Prevents Obesity-Associated Hypertension by Improving Pro-Inflammatory Reaction and Leptin Resistance
 

Low-grade pro-inflammatory state and leptin resistance are important underlying mechanisms that contribute to obesity-associated hypertension. We tested the hypothesis that Astragaloside IV (As IV), known to counteract obesity and hypertension, could prevent obesity-associated hypertension by inhibiting pro-inflammatory reaction and leptin resistance. High-fat diet (HFD) induced obese rats were randomly assigned to three groups: the HFD control group (HF con group), As IV group, and the As IV + α-bungaratoxin (α-BGT) group (As IV+α-BGT group). As IV (20 mg·Kg-1·d-1) was administrated to rats for 6 weeks via daily oral gavage. Body weight and blood pressure were continuously measured, and NE levels in the plasma and renal cortex was evaluated to reflect the sympathetic activity. The expressions of leptin receptor (LepRb) mRNA, phosphorylated signal transducer and activator of transcription-3 (p-STAT3), phosphorylated phosphatidylinositol 3-kinase (p-PI3K), suppressor of cytokine signaling 3 (SOCS3) mRNA, and protein-tyrosine phosphatase 1B (PTP1B) mRNA, pro-opiomelanocortin (POMC) mRNA and neuropeptide Y (NPY) mRNA were measured by Western blot or qRT-PCR to evaluate the hypothalamic leptin sensitivity. Additionally, we measured the protein or mRNA levels of α7nAChR, inhibitor of nuclear factor κB kinase subunit β/ nuclear factor κB (IKKβ/NF-KB) and pro-inflammatory cytokines (IL-1β and TNF-α) in hypothalamus and adipose tissue to reflect the anti-inflammatory effects of As IV through upregulating expression of α7nAChR. We found that As IV prevented body weight gain and adipose accumulation, and also improved metabolic disorders in HFD rats. Furthermore, As IV decreased BP and HR, as well as NE levels in blood and renal tissue. In the hypothalamus, As IV alleviated leptin resistance as evidenced by the increased p-STAT3, LepRb mRNA and POMC mRNA, and decreased p-PI3K, SOCS3 mRNA, and PTP1B mRNA. The effects of As IV on leptin sensitivity were related in part to the up-regulated α7nAchR and suppressed IKKβ/NF-KB signaling and pro-inflammatory cytokines in the hypothalamus and adipose tissue, since co-administration of α7nAChR selective antagonist α-BGT could weaken the improved effect of As IV on central leptin resistance. Our study suggested that As IV could efficiently prevent obesity-associated hypertension through inhibiting inflammatory reaction and improving leptin resistance; furthermore, these effects of As IV was partly related to the increased α7nAchR expression.

 

That study doesn't directly address the hypothesis but, IMO, it does strongly suggest that the hypothesis is on the right track...
  • The a7 nAchR is implicated in Astragaloside supplementation.
  • The effects are felt in the Hypothalamus and in the Periphery.
  • NF-kB is inhibited
  • Tracey is referenced 2 or 3 times in the study.
AFAIK, this is the most significant evidence to date that Astragalus related herbs May trigger The Inflammatory Reflex (aka, the Cholinergic Anti-Inflammatory Pathway).
 
IMO, what needs doing with an Astragalus-related herb is what Tracey and teams have done multiple times... Do the supplementation with and without the Vagus Nerve to the Spleen being cut before administration of lethal endotoxemia to determine if the beneficial effect is entirely due to The Inflammatory Reflex or not...
 
My bet continues to be that TIR is the mechanism of action...
 
A key hint this may be true... The small dosing required for TA-65 like substances to have a beneficial effect.
 
:)

 

 
 
BINGO !
 
More evidence, this time profound, that my conjecture from July 2018 MIGHT be true...
 
My hunch ... can be formulated as a falsifiable hypothesis.
 
Vagus Nerve signaling, via the Cholinergic Anti-Inflammatory Pathway, is the larger biological context Mechanism of Action underlying the experiment observation that TA-65 can increase Telomere Length without causing cancer.
 
------------------------

 

No time at the moment for much more than a study link a few words sketch...
 

2017, Astragalus polysaccharides combined with ibuprofen exhibit a therapeutic effect on septic rats via an anti‑inflammatory cholinergic pathway
 

Abstract. The aim of the present study was to investigate the effects of Astragalus polysaccharides (APS) in combination with ibuprofen (IBU) in the treatment of sepsis and the underlying mechanism. The combined drug treatment was evaluated in a rat model of cecal ligation and puncture (CLP). The serum concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and acetylcholine (ACh) were determined. Nicotinic acetylcholine (nAChR) α7 receptor expression and histopathological changes in the lung tissue were also observed. When compared with untreated rats and rats treated with either component alone, the combined treatment significantly decreased the production of TNF-α and IL-6 (P<0.05), and increased nAChR α7 receptor mRNA expression and the release of ACh in the serum (P<0.05). These results demonstrated that APS combined with IBU can effectively reduce the generation of inflammatory mediators in the serum of CLP-induced septic rats. These effects may be mediated via a cholinergic anti‑inflammatory pathway involving nAChR α7.

 

  • TA-65 has profound telomerase increasing impact in the entire organism at an extremely small dose
  • How does it do that?
    • Conjecture: it must trigger a significant, effect magnifying innate biological process, like TIR
  • See figures 3 and 4 of the study above
     
  • Astragalus and Ibuprofen increases BOTH
    • acetylcholine expression
    • a7nAchR RNA expression
  • that is to say... Astragalus and Ibuprofen increase the Expression of BOTH the a7 SubUnit of the Nicotinic-Acetylcholine Receptor and its agonist (Acetylcholine)  !!!!

Wow! Now that's potency!

Still, the study authors do NOT conclusively demonstrate that my July 2018 is true...

 

They did NOT do the Falsifying Experiment of cutting the Vagus Nerve to see if the Inflammation-Reducing effect of  the TIR Motor Arm (aka, the Cholinergic Anti-Inflammatory Pathway) was responsible for the effect they found. And they're clear about this....

Notice that they use the word "may" in the last sentence of the abstract...

 

:)  :cool:  :)


Edited by HighDesertWizard, 24 July 2020 - 03:38 PM.

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#224 Nate-2004

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Posted 24 July 2020 - 06:44 PM

I just finished my prototype design of an ear piece in an incredibly polished iPad cad app called Shapr3D. It's designed to stimulate the vagus nerve at the proper point on the choncha (not the tragus) and hook around your ear to stay in place. I've been using a kludgy mockup of it till I can get my STL file to a manufacturer tomorrow (hopefully doesn't cost too much). Might have a friend 3d print a model of it to be sure the measurements are right. It's pretty sleek though. Right now it's designed to connect to a normal tens unit but I'm going to ultimately have it powered by a small rechargeable lithium ion battery. Shouldn't need more than 2.5v of current at a 20hz 100 microsecond pulse rate.  Does that sound right? I'm going by other studies on external vagus stimulation. My device is designed to fit on either ear.

 

Anyway apparently the choncha is where you get the most stimulation of the nerve.


Edited by Nate-2004, 24 July 2020 - 06:51 PM.

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#225 HighDesertWizard

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Posted 14 November 2021 - 09:13 AM

I post this meetup announcement here because Vince and I will be talking about The Inflammatory Reflex...

 

 

VXgiqRJ.jpg 
 
 
In 2019, I began to chat live with Vincent Giuliano, an independent longevity science researcher and writer at his blog, Anti-AgingFireWalls.com. HIs blog is one of the few that is auto-posted to Longecity.org every time he posts there. At almost 92 years old, Vince is almost certainly the oldest-living blogger about longevity science in the world. He's written about 500 articles about Healthy Longevity for 12 years. Vince is the most remarkable person I've ever encountered. It's an honor for me to say that he is my mentor, my longevity science research collaborator/partner, and my friend.
 
Our collaboration to try to understand and configure an explanation of rejuvenation processes has been going on for about 2 years. From the outset, we believed that any credible and complete explanation of rejuvenation must, at a minimum, include the following...

  • reference to The Inflammatory Reflex and it's Motor Arm, the Cholinergic Anti-Inflammatory Pathway
    • How can a rejuvenation explanation be considered credible if it doesn't include reference to the most significant mammalian, physiological adaption that increases survival probability?
  • reference to the healthy longevity promoting Stress (aka, Hormetic) Response
    • rather than understanding healthy stress-related interventions as different in kind than purported "True Longevity Promoting Interventions" we take them to be critical to understanding rejuvenation.
  • reference to the most healthy of emerging, proven-to-be-rejuvenating interventions
    • like Hyperbaric Oxygen Therapy and Near Infrared Light
    • For an explanation to be complete and credible, it needs to explain these proven intervention techniques too

Vince and I will be giving a talk on November 20 at 4pm, GMT, at a meeting of the London Futurists meetup. The talk is entitled, "Younging: Triggering Ancient Mechanisms for Rejuvenation". It will be accessible real time via Zoom and a live YouTube video feed. (See the meetup link for details.) After the talk, I'll provide a link to the YouTube video here.
 
From the meetup announcement...

 

Independent longevity researchers Vince Giuliano and Steve Buss believe that the number and content of scientific-study puzzle pieces have approached a critical threshold. It is now possible, they claim, to assemble a good explanation, in which natural body rejuvenation processes play a vital role. This comprehensive new explanation integrates existing theories and also highlights an age-reversal process they have identified and named Younging.


Vince and Steve believe that this emerging explanation constitutes a paradigm shift for the longevity science movement. Already-proven rejuvenation explanations and interventions can ONLY be properly understood to fit together via understanding recent evidence of ancient, evolutionarily-conserved mechanisms.

 

Vince and Steve will be happy to answer questions during the meetup and participate in the post-meetup, all-attendees-can-participate discussion.


Edited by HighDesertWizard, 14 November 2021 - 09:18 AM.

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#226 HighDesertWizard

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Posted 21 November 2021 - 07:30 PM

The YouTube video of the talk Vincent Giuliano and I gave yesterday at the London Futurists meetup is now online...

 

I spoke about The Inflammatory Reflex in the talk...

I'll be creating a new Longecity Forum thread to discuss these ideas and more soon...



Click HERE to rent this BIOSCIENCE adspot to support LongeCity (this will replace the google ad above).

#227 HighDesertWizard

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Posted 31 March 2023 - 08:06 PM

My name is Steve Buss and I'm the person doing a talk next Tuesday, April 5,2023, at the Zoom link below.

 

https://us02web.zoom...zdmcDZPSUpydz09

  • I am a professional software engineer and independent longevity science researcher.  Longevity science has  been my obsessive hobby for 25 years.
  • I lucked out in late 2011 when I came across the science of The Inflammatory Reflex and its Motor Arm, the Cholinergic Anti-Inflammatory Pathway
  • I collaborate closely with Vincent Giuliano of the Anti-Aging Firewalls blog.

---------

 

I began this Longecity Forum thread close to 11 years ago. At that time, I wrote that the Cholinergic Anti-Inflammatory Pathway is important. When I look back on much of the content of this thread, I'm a bit embarrassed, because its my learning log and there is no systematic description of the CAP in it. My only excuse is that I have a full time job and other things to do...

 

Only recently did I begin to see the science underlying the CAP as having a relationship to the Aging Factors in the Blood Plasma literature.

 

But now I do see the relationship now, and in some detail too, enough to be able to specify a Regimen Sequence of Interventions...

  • summarize a first draft Longevity-Promoting Regimen Sequence using both these intervention approaches

The talk will include

  • a graphical depiction of what I now believe is the optimal sequencing of Plasmapheresis and Cholinergic Anti-Inflammatory Pathway Interventions
  • the reasoning/explanation of that sequencing

:)
 

Here's a link to the Longecity post in the image below...

 

HgA9wsCh.jpg


Edited by HighDesertWizard, 31 March 2023 - 08:08 PM.

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Also tagged with one or more of these keywords: vagus, cholinergic, anti-inflammatory, heart rate variability, spleen, smile

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