226 replies to this topic

[HighDesertWizard]

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

Edited by HighDesertWizard, 04 July 2017 - 02:28 PM.

[HighDesertWizard]

From a thread about In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming...

 

 

2007

 

Motif module map reveals enforcement of aging by continual NF-κB activity

 

Aging is characterized by specific alterations in gene expression, but their underlying mechanisms and functional consequences are not well understood. Here we develop a systematic approach to identify combinatorial cis-regulatory motifs that drive age-dependent gene expression across different tissues and organisms. Integrated analysis of 365 microarrays spanning nine tissue types predicted fourteen motifs as major regulators of age-dependent gene expression in human and mouse. The motif most strongly associated with aging was that of the transcription factor NF-κB. Inducible genetic blockade of NF-κB for 2 wk in the epidermis of chronologically aged mice reverted the tissue characteristics and global gene expression programs to those of young mice. Age-specific NF-κB blockade and orthogonal cell cycle interventions revealed that NF-κB controls cell cycle exit and gene expression signature of aging in parallel but not sequential pathways. These results identify a conserved network of regulatory pathways underlying mammalian aging and show that NF-κB is continually required to enforce many features of aging in a tissue-specific manner.

 

 

2015

 

NF-κB activation impairs somatic cell reprogramming in ageing - full text at sci-hub
 

ABSTRACT

 

Ageing constitutes a critical impediment to somatic cell reprogramming. We have explored the regulatory mechanisms that constitute age-associated barriers, through derivation of induced pluripotent stem cells (iPSCs) from individuals with premature or physiological ageing. We demonstrate that NF-κB activation blocks the generation of iPSCs in ageing. We also show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs the generation of iPSCs by eliciting the reprogramming repressor DOT1L, which reinforces senescence signals and downregulates pluripotency genes. Genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor–Guillermo progeria syndrome and Hutchinson–Gilford progeria syndrome patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo extends lifespan and ameliorates the accelerated ageing phenotype of progeroid mice, supporting the interest of studying age-associated molecular impairments to identify targets of rejuvenation strategies.

 

<< Fascinating discussion of results on in-vitro human cells and in-vivo rodents. >>

 

DISCUSSION

 

Somatic cell reprogramming constitutes a paradigm of rejuvenation as it involves the complete erasure of aged marks and the restoration of homeostatic balance. The assumption that the aged state, like the differentiated state, requires active maintenance has attracted special attention towards the identification of signals and regulatory mechanisms that sustain ageing, as they may represent prominent targets of rejuvenation strategies14,45. In this regard, although the causal involvement of NF-κB in ageing has been well documented40,42–44,46, our results notably extend this view, establishing a mechanistic link between ageing and cell differentiation through NF-κB signalling. Accordingly, we demonstrate here that NF-κB hyperactivation constitutes a critical impediment to somatic cell reprogramming into iPSCs in both normal and accelerated ageing. This work has also led us to identify the upstream regulators and the main effectors involved in this process. Additionally, our data demonstrate that NF-κB regulation of chromatin-modifying factors has a remarkable impact on the establishment of this reprogramming barrier. In this regard, DOT1Lmediated methylation of Lys 79 in histone H3 represents a molecular crosstalk between ageing and differentiation control36. DOT1L then emerges as a prominent effector of NF-κB activity in ageing.

 

Furthermore, the identification of this molecular mechanism has allowed us to translate this information into a therapeutic approach, which we have successfully evaluated in progeroid animals. Thus, DOT1L inhibition extended longevity and prevented ageing-associated alterations in progeroid mice. Although we have previously demonstrated that NF-κB blockade extends longevity40 , chronic treatment with anti-inflammatory compounds in humans has some side effects that made their administration not generally assumable. However, the possibility of targeting critical effectors of NF-κB response could suppress the observed side effects. Besides, DOT1L inhibitors have been recently tested for the treatment of haematological malignancies, which opens the possibility of using these compounds to treat age-associated alterations. Globally, our results further demonstrate the utility of cell-based models of progeroid syndromes to study ageing mechanisms in general and the pathogenesis of progeria in particular. Moreover, we also provide an experimental proof-of-concept about the relevance of studying the molecular mechanisms underlying reduced reprogramming competence of aged cells to develop rejuvenationbased therapies.

 

 

 

 

 

 

I included the 2nd set of study result pics to highlight the goings on of IκBα during aging. You'll recall that, just recently, a study showed that adding IκBα stem cells to the hypothalamus increased lifespan.

 

I posted info about that study, including a survival curve here at Longecity.

 

FWIW, as you may (not) know, I've been focused on NF-kB inhibition via a specific innate mechanism for 5 to 10 years now, depending on how the years are counted. In 2017, I got blood testing done and was more than pleasantly surprised.

N = 1. Anecdotal? Yes.

 

Remember? April 2012... One, out of the blue, oddball study, about C60-OO, triggered a tsunami of discussion and experimentation at Longecity. There was no data about Humans.

 

 

 

 

Edited by HighDesertWizard, 15 August 2017 - 05:06 AM.

[HighDesertWizard]

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.

 

Edited by HighDesertWizard, 22 May 2018 - 05:27 AM.

[Leon93]

HighDesertWizard, how much Astragalus would you recommend taking. I guess the regular clinical proven dose of 30g a day? Personally I don't have that financial option, would you say 1-5g a day would do anything or would just be a waste of money?

[Nate-2004]

HighDesertWizard, how much Astragalus would you recommend taking. I guess the regular clinical proven dose of 30g a day? Personally I don't have that financial option, would you say 1-5g a day would do anything or would just be a waste of money?

 

That or try the liposomal astragalus, which may or may not be significantly more effective.

[Leon93]

Thank you Nate-2004! So even 1 gram would give some benefits right? Also, is there a link where I can view the supplement stack you´re taking? You seem to be one of the more regular, knowledgeable Longecity users.

[HighDesertWizard]

 

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.

 

 

I haven't posted in a while...

• I'm working on a Kindle book for a couple of different target audiences about "The Inflammatory Reflex".
• Writing a book means, of course, that I'll be giving my identity away sooner or later, so I decided a few months ago to out my identity here at Longecity.

---------

 

Regarding the hypothesis I sketched above 13 months ago... I just this week found evidence from 2017 that profoundly supports my hunch. But I didn't formulate that hunch very well. Let me explain.

 

1 - Using the proper name for the Mechanism.

 

Over a period of 10 years, the mechanism first called The Inflammatory Reflex was also called the Cholinergic Anti-Inflammatory Pathway. I've used the latter name often in my posts at Longecity. But what's clear now is that the proper scientific name of the mechanism that Dr Kevin J Tracey discovered and published about in 2002 is The Inflammatory Reflex.

 

2 - Distinguishing means by which The Inflammatory Reflex (TIR) can be triggered

 

Conceptually, there are three ways to trigger TIR...

1. Stimulate Efferent Vagus Nerve Fibers that constitute a portion of the signaling biological infrastructure between Muscarinic Acetylcholine Receptors in the Brain and the Spleen.
   1. They can be stimulated by attaching an electrode to them.
   2. They can also be stimulated by Acetylcholine Expression and that can take place in two other ways
   3. See the diagram below that I've posted many times, more discussion of it here.
2. Increasing Acetylcholine Expression in a way that triggers Muscarinic Acetylcholine Receptors in the brain.
   1. There are a good many different ways to do this (and I've done a lot of them).
   2. See the diagram below, discussion here.
3. At specific Afferent Vagus Nerve access site locations, aka, Acupuncture Acupoints, that stimulate what is called Afferent Vagus nerve fibers.
   1. Several ways to do this also, including, Massage, Acupuncture, Acupressure, etc
   2. But note... Caveat Emptor... Different Acupoint locations implicate different potencies with which one activates the specific set of Muscarinic Acetylcholine Receptors in the brain that trigger TIR.
   3. That's the implication of the study I referenced here, right? 
   4. Tracey depicted an instance of this 3rd means to trigger TIR in a larger diagram context that I previous referenced here.

In the hunch / hypothesis formulated above in July of 2017, I was thinking in terms of the #1 means above, and that was good enough at the time, but more clarity is desirable now.

 

 

Edited by HighDesertWizard, 10 August 2018 - 04:42 PM.

[HighDesertWizard]

Distinguishing means by which The Inflammatory Reflex (TIR) can be triggered

 

Conceptually, there are three ways to trigger TIR...

1. Stimulate Efferent Vagus Nerve Fibers that constitute a portion of the signaling biological infrastructure between Muscarinic Acetylcholine Receptors in the Brain and the Spleen.
   1. They can be stimulated by attaching an electrode to them.
   2. They can also be stimulated by Acetylcholine Expression and that can take place in two other ways
   3. See the diagram below that I've posted many times, more discussion of it here.
2. Increasing Acetylcholine Expression in a way that triggers Muscarinic Acetylcholine Receptors in the brain.
   1. There are a good many different ways to do this (and I've done a lot of them).
   2. See the diagram below, discussion here.
3. At specific Afferent Vagus Nerve access site locations, aka, Acupuncture Acupoints, that stimulate what is called Afferent Vagus nerve fibers.
   1. Several ways to do this also, including, Massage, Acupuncture, Acupressure, etc
   2. But note... Caveat Emptor... Different Acupoint locations implicate different potencies with which one activates the specific set of Muscarinic Acetylcholine Receptors in the brain that trigger TIR.
   3. That's the implication of the study I referenced here, right? 
   4. Tracey depicted an instance of this 3rd means to trigger TIR in a larger diagram context that I previous referenced here.

In the hunch / hypothesis formulated above in July of 2017, I was thinking in terms of the #1 means above, and that was good enough at the time, but more clarity is desirable now.

 

Just found this study, published after I posted my hunch / hypothesis in 2017, that strongly suggests Astragalus Polysaccharides have profound health effects via triggering TIR... I believe that triggering takes place via the 2nd means I list above.

 

That is... Astragalus-related compounds that trigger Telomerase expression are Muscarinic Acetylcholine agonists... I don't believe they are merely Acetycholine Esterase inhibitors, like Galantamine, for example...

Astragalus Polysaccharides are not the compound that is in TA-65, but close, and the study below is non-trivial confirmation that my hunch is on the right track... No, more than that... It's confirmation that the Content of this entire forum thread, created in 2015, with the belief that the science of the healthful effects of Telomeres and Telomerase Expression cannot be understood without understanding The Inflammatory Reflex has been on the right track...

 

-------

 

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.

Edited by HighDesertWizard, 10 August 2018 - 05:12 PM.

[QuestforLife]

There is a great deal of discussion here of interfering with inflammation and hence preventing the harm it causes. But there isn't much discussion of what the underlying cause of the inflammation we're trying to stop actually is.

This review article brings home quite how much of us isn't human but microbial.

http://www.discovery...tory-processes/

It seems madness to discuss the aging process and its solutions without taking into account that we are absolutely chock full of potentially harmful pathogens.

It might well be that the great antibiotic and vaccination breakthroughs of the late 19th and early 20th century was just the first part of the battle to defeat disease, with the greatest disease being aging itself.

[HighDesertWizard]

There is a great deal of discussion here of interfering with inflammation and hence preventing the harm it causes. But there isn't much discussion of what the underlying cause of the inflammation we're trying to stop actually is.

This review article brings home quite how much of us isn't human but microbial.

http://www.discovery...tory-processes/

It seems madness to discuss the aging process and its solutions without taking into account that we are absolutely chock full of potentially harmful pathogens.

It might well be that the great antibiotic and vaccination breakthroughs of the late 19th and early 20th century was just the first part of the battle to defeat disease, with the greatest disease being aging itself.

 

I appreciate your reply QuestforLife... Truly...

 

I agree with the sentiment expressed in the last sentence, namely, that, in the last 150 years humans began to understand and address the danger to health and life that external and internal pathogens represent.

 

And I agree that in that time we've only engaged in the first part of what the battle to defeat disease, no, aging requires.

 

And I believe it's become increasingly clear that inflammation is a primary, if not the primary, driver of aging. And your post suggests you believe inflammation is important because your post is about one means of inhibiting it. 

 

But I profoundly disagree with you and, as far as I know, virtually all other Longevity Science Enthusiasts, about what the key is to the second part of the battle...

 

----

 

You haven't seen the gorilla yet. I can tell.

 

For several years, even though I was spending enormous time doing research about The Inflammatory Reflex, and had even begun to understand what it is, in this game of understanding aging and rejuvenation, I was still counting the players in white passing the basketball. I didn't see the gorilla.

 

 

Well, and then, there is The Monkey Business Illusion...

 

I can clearly see the gorilla now, but it took years of squinting this way and that to see it clearly.

 

But I bet I can catch it now in a photo waving its arms. It's huge so, in the first pic, I'll post the arm waving, and, in the second, I'll post a pic of the gorilla's body.

 

The problem is, by themselves, the meaning of the pics is difficult to grasp. I looked at them for years and didn't understand their meaning. So I'll write up a couple pic captions and post them to clarify the meaning as I've come to understand it.

 

And after that, I'll have a couple questions for readers of this forum thread...

 

----

 

Truth be told, the reason I post less frequently these days is that I'm working on a book about this gorilla in the hope that I can help others to see it and understand its meaning more quickly than I did. I'll publish it this year, hopefully, sooner rather than later.

 

Edited by HighDesertWizard, 18 August 2018 - 11:51 PM.

[QuestforLife]

Alright then HighDesertWizard, I'll wait for you to enlighten me!

 

I still think subclinical microbial infection is contributing to telomere and stem cell exhaustion, because they cause increase proliferation of tissues and this can also cause cancer (https://en.wikipedia...i/Paul_W._Ewald). But I'm open to other ideas.

[QuestforLife]

More evidence linking failing mitophagy, mtDNA leakage and inflammation.

 

https://www.nature.c...1586-018-0448-9

 

Full text at Sci-hub

[Phoebus]

 

 

I can clearly see the gorilla now, but it took years of squinting this way and that to see it clearly.

 

 

and what is the gorilla? or are you not saying until publication? 

 

will you post here when you publish? 

[Nate-2004]

So from what I understand, based on the hallmarks of aging, inflammation plays a key role as an accelerating component in terms of aggravation. It is not one of the primary causes of aging though. However, if there is some means of inhibiting NFkb via stimulation of the vagus nerve, that's great. It's unfortunate the galantamine doesn't play a role as a muscarinic acetylcholine agonist, I take that sometimes. 

 

The one thing that comes to mind here is that muscarinic acetylcholine receptors are g-protein coupled. Well, depression is associated with both inflammation AND a clumping of g-proteins on lipid rafts. Ketamine treatment is known to clear these clumps for up to two months which may be its mechanism of action. 

 

Just wondering if some dots can be connected here.

 

That and another question, I thought "The Inflammatory Reflex" was a bad thing, why would you want to activate it? Am I misunderstanding this?

Edited by Nate-2004, 18 September 2018 - 08:32 PM.

[HighDesertWizard]

For several years, even though I was spending enormous time doing research about The Inflammatory Reflex, and had even begun to understand what it is, in this game of understanding aging and rejuvenation, I was still counting the players in white passing the basketball. I didn't see the gorilla.

 

 

Well, and then, there is The Monkey Business Illusion...

 

I can clearly see the gorilla now, but it took years of squinting this way and that to see it clearly.

 

But I bet I can catch it now in a photo waving its arms. It's huge so, in the first pic, I'll post the arm waving, and, in the second, I'll post a pic of the gorilla's body.

 

The problem is, by themselves, the meaning of the pics is difficult to grasp. I looked at them for years and didn't understand their meaning. So I'll write up a couple pic captions and post them to clarify the meaning as I've come to understand it.

 

And after that, I'll have a couple questions for readers of this forum thread...

 

I apologize for being tardy with posting the gorilla pic. I'm a longevity science hobbyist, I'm working on that book, have a full-time job, and another non-trivial longevity science conjecture grabbed me by the throat and wouldn't let go until I spit it out...

 

A Heat Shock Protein-Related Switch Initiates the Aging Process in Humans

[HighDesertWizard]

The gorilla appears below...

 

It would like you to stop focusing on the players in white and, instead, focus on IT...

 

  -- >> the meaning of the Survival Probability Pics in the graphic figure.

 

The five survival probability curves are from 5 different studies about 5 different intervention techniques.

 

-->> They depict intervention techniques, dosing, dosing frequency, etc.

 

The survival probability magic is not in some new substance or technique

 

Unless you've had a Splenectomy or Vagotomy, the mechanism is within you and has been in you since birth

 

I believe I understand The Inflammatory Reflex, what it is and how to trigger it, better than anyone else at Longecity

 

When I write about it enthusiastically in this thread established about it to try to help you...

 

--> And you don't understand what it is

--> And how it works

--> And how to trigger it

--> And you're not already trying to trigger it

 

--> Why do you waste your time (and mine) talking about anything else?

 

With all due respect... When this kind of gorilla is in the room, why are you fixated on the players in white?

 

 

The book I'm writing explains each of the studies shown above in detail.

 

But I posted all but one of these images and links to the studies they appear in more than a year ago

 

Except for the one at bottom right, the study links can be found in the SMILE of Longevity: Survival Curves thread

 

The Survival Probability image on the bottom right is from a Human Trial of a TIR triggering substance. The trial was stopped after two years for ethical reasons. Statistically more humans were surviving who took the substance than who didn't.
 

https://www.ncbi.nlm...les/PMC3937252/

Edited by HighDesertWizard, 24 October 2018 - 02:51 AM.

[HighDesertWizard]

 

 

The epigraph page...

 

[HighDesertWizard]

[HighDesertWizard]

Dr Tracey doesn't talk much about TIR Survival Probability findings in public... But he is the lead author of 3 of the 5 survival probability studies shown above.

 

I've posted these videos that explain a bit about TIR before, I'm happy to post them again... There is some overlapping content but some unique content in each. I've watched both at least 5 to 8 times.

 

In the second video look for a technique that might be used to monitor inflammation to automatically maintain homeostasis...

 

Nate: you asked a great question about why it's called The Inflammatory Reflex. The answer is in video #2.

 

I loves me them gorillas!

 

 

 

Edited by HighDesertWizard, 24 October 2018 - 03:52 AM.

[HighDesertWizard]

The fact...

 

The Inflammatory Reflex
exists in humans

 

means

 

it's silly
no, stupid

 

to imagine
we should First
figure out how to
"outsmart evolution"

 

Maybe later we do that

 

How 'bout
First
we focus on how

 

To Hijack It

 

for Increased
Health
Survival Probability

 

-- Steve Buss

Edited by HighDesertWizard, 24 October 2018 - 03:48 AM.

[Nate-2004]

This may be related, I'm only halfway through that second video.

 

https://www.eurekale...c-isf101718.php

[HighDesertWizard]

Recently found more evidence supporting that single-sentence conjecture/explanation that answers a key question about TA-65's Biological Mechanism of Action...
 

<SNIP>
 
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.

 
I hadn't noticed Logic's post below until recently... Back in the day, he had come to the same opinion I had in this forum thread by referencing this forum thread...
 

<SNIP>

The real reason for telomerase shortening and a large part of aging IMHO is here:
http://www.longecity...and-telomerase/

 
Later in 2016 he references a fact about Astragalus I was unaware of until reading his post... He also speculated about what the fact meant... Here's his post...
 

Further proof that Astragalus is probably mainly fixing the gut and that the decrease in NF-kB is what is having system wide pro telomere effects:
 
...Astragalus IV appears to have an apparent oral bioavailability of 2.2% in rats when serum was measured by HPLC with mass spectrometric detection after solid phase extraction[26] and the one human study to attempt to measure Astragalosides in serum could not find any...
 
http://examine.com/s...s membranaceus/
http://www.ncbi.nlm....pubmed/16507649
 
NB:

• ...Angelicae Sinensis increases bioavailability of Astragalus flavonoids...
• ...Astragalus membranaceus and Angelicae Sinensis are highly synergistic, meaning they are more powerful when taken together.
• This combination is traditionally called Dang-gui buxue tang...
• ...Astragalus appears to have the ability to inhibit the CYP3A4 enzyme, and may increase the AUC of some pharmaceuticals when coingested...

http://examine.com/s...s membranaceus/

 

 
Let's unpack the details Logic wrote about...
 
1 - The problem Logic realized that must be explained...
 
"Astragalus IV appears to have an apparent oral bioavailability of 2.2% in rats when serum was measured by HPLC with mass spectrometric detection after solid phase extraction[26] and the one human study to attempt to measure Astragalosides in serum could not find any..."
 
The problem put another way... How can a substance have healthful telomere-lengthening-effects without causing with cancer, when it's bioavailability is poor to non-existent in the blood circulation?
 
2 - Given that problem, Logic understood that something unusual must be going on.

 

He speculated about what the explanation might be and he provided some supporting study links as evidence to support his speculation... "Astragalus is probably mainly fixing the gut and that the decrease in NF-kB is what is having system wide pro telomere effects".

 

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

 

A post soon-to-follow will provide a summary of the evidence so far discovered for the conjecture/explanation stated at the top of this post...

Edited by HighDesertWizard, 04 November 2018 - 11:46 AM.

[HighDesertWizard]

March 2017, Disease-Modifying Effects of M1 Muscarinic Acetylcholine Receptor Activation in an Alzheimer’s Disease Mouse Model

 

Alzheimer’s disease (AD) is the leading cause of dementia worldwide, and currently no disease-modifying therapy is available to slow or prevent AD, underscoring the urgent need for neuroprotective therapies. Selective M1 muscarinic acetylcholine receptor (mAChR) activation is an attractive mechanism for AD therapy since M1 mediates key effects on memory, cognition, and behavior and has potential for disease-modifying effects on Aβ formation and tau phosphorylation....

 

These findings suggest that chronic M1 [muscarinic acetylcholine receptor (mAChR)] activation has neuroprotective potential for preventing memory impairments and reducing neuropathology in AD. M1 activation therefore represents a promising avenue for preventative treatment, as well as a promising opportunity to combine symptomatic and disease-modifying effects for early AD treatment.

 

Oh, and we know the Mechanism of Action...

 

Edited by HighDesertWizard, 04 November 2018 - 03:55 PM.

[HighDesertWizard]

I've been working on a presentation about what The Inflammatory Reflex (TIR) is and it would be useful to get feedback about some slides. Two studies are especially useful for highlighting the key physiological and survival probability content.

 

Doing this is important also for a couple other reasons

• highlight the impact on survival probability of the net biological effect of TIR, namely, regulating Splenic Macrophage phenotype between M2 vs M1 dominance
   
• make clear what the 1 experiment is that needs doing to determine whether the hypothesis specified stated on July 3, 2017 about the MoA of TA-65 can be falsified.

 

 

Two study graphic figures in the slide pic I've posted upthread and elsewhere with survival curves are taken from the studies that will be reviewed below.

 

2015, Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation

 

Inflammatory conditions characterized by excessive immune cell activation and cytokine release, are associated with bidirectional immune system-brain communication, underlying sickness behavior and other physiological responses. The vagus nerve has an important role in this communication by conveying sensory information to the brain, and brain-derived immunoregulatory signals that suppress peripheral cytokine levels and inflammation. Brain muscarinic acetylcholine receptor (mAChR)-mediated cholinergic signaling has been implicated in this regulation. However, the possibility of controlling inflammation by peripheral administration of centrally-acting mAChR agonists is unexplored. To provide insight we used the centrally-acting M1 mAChR agonist xanomeline, previously developed in the context of Alzheimer’s disease and schizophrenia. Intraperitoneal administration of xanomeline significantly suppressed serum and splenic TNF levels, alleviated sickness behavior, and increased survival during lethal murine endotoxemia. The anti-inflammatory effects of xanomeline were brain mAChR-mediated and required intact vagus nerve and splenic nerve signaling. The anti-inflammatory efficacy of xanomeline was retained for at least 20h, associated with alterations in splenic lymphocyte, and dendritic cell proportions, and decreased splenocyte responsiveness to endotoxin. These results highlight an important role of the M1 mAChR in a neural circuitry to spleen in which brain cholinergic activation lowers peripheral pro-inflammatory cytokines to levels favoring survival. The therapeutic efficacy of xanomeline was also manifested by significantly improved survival in preclinical settings of severe sepsis. These findings are of interest for strategizing novel therapeutic approaches in inflammatory diseases.

 

2012, Electroacupuncture Improves Survival in Rats with Lethal Endotoxemia via the Autonomic Nervous System

 

Background: Recent advances have indicated a complex interplay between the autonomic nervous system and the innate immune system. Targeting neural networks for the treatment of sepsis is being developed as a therapeutic strategy. Because electroacupuncture at select acupoints can modulate activities of the autonomic nervous system, we tested the hypothesis that electroacupuncture at specific acupoints could modulate systemic inflammatory responses and improve survival via its impact on the autonomic nervous system in a rat model of sepsis. Methods: Sprague-Dawley male rats received electroacupuncture for 45 min before and at 1, 2, or 4 h after a lethal dose of intraperitoneal lipopolysaccharide injection (6 mg/ kg). Outcomes included survival and systemic cytokine responses. Also, the possible roles of neural circuitry, including the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, were evaluated. Results: Electroacupuncture pretreatment at the Hegu acupoints significantly attenuate systemic inflammatory responses and improve survival rate from 20% to 80% in rats with lethal endotoxemia. Such a site-specific effect requires the activation of muscarinic receptors in the central nervous system, but not increasing central sympathetic tone. In the periphery synergistic, rather than independent, action of the sympathetic and parasympathetic systems is also necessary. Conclusions: Electroacupuncture pretreatment has a dramatic survival-enhancing effect in rats with lethal endotoxemia, which involves the activation of efferent neural circuits of the autonomic nervous system (e.g., cholinergic antiinflammatory pathway). This approach could be developed as a prophylactic treatment for sepsis or perioperative conditions related to excessive inflammation.

 

Edited by HighDesertWizard, 03 December 2018 - 02:32 AM.

[HighDesertWizard]

See previous post... Feedback on slide desired...

 

 

 

Edited by HighDesertWizard, 03 December 2018 - 04:22 AM.

[HighDesertWizard]

Slide 2... Would appreciate feedback...

 

The Fact of the existence, of the preservation, of The Inflammatory Reflex in mammals, including in humans has been demonstrated by a set of remarkable experiments.

 

Maximum survival probability benefit of triggering The Inflammatory Reflex requires 5 things...

1. Intact Vagus Nerve Signaling
2. Intact Splenic Nerve Signaling
3. Intact Spleen
4. Functional and not Antagonized Muscarinic Receptors in Brain
5. a7 Nicotinic-Acetylcholine Receptor Functionality

These 5 physiological/biological requirements for a viable Inflammatory Reflex are highlighted in the pics below highlighted in green.

 

 

 

1. Intact Vagus Nerve Signaling

 

 

Notice that Serum TNF is reduced proportionately greater than Splenic TNF in the Electro-Acupuncture Experiment. A comparable experiment comparing the two was also performed in the Xanomeline study. Here's the pic...

 

Edited by HighDesertWizard, 11 December 2018 - 01:43 PM.

[QuestforLife]

What is the link between accupuncture and anti-inflammatory vagus nerve signalling?

[HighDesertWizard]

In the next few weeks, I'll provide 4 to 7 more slides like the two above...

 

Meanwhile....

 

What is the link between accupuncture and anti-inflammatory vagus nerve signalling?

 

That's a great question, QuestforLife... It's a question I've been asking myself for a while now. I don't have a precise answer and I'm unaware of any writing about it that does speak to the question with precision.

 

I take your question to be a trigger for me to reflect on what we do know, look into what's been published since I last spent time on this, and prepare a summary answer to your question, along with reference links to evidence.

 

Meanwhile, we do know this...

• Hegu acupoint triggering can trigger the Efferent (aks, "Motor") Arm of The Inflammatory Reflex.
• Triggering TIR can profoundly increase survival probability, (aka, "squaring the look of survival curves").
• The diagram below strongly suggests that it's neither an Efferent (aka, "Motor") Arm nor an Afferent (aka, "Sensory") Arm of the Vagus Nerve.
• The route of the link appears to run up the spine which suggests it's a kind of Central Nervous System link.
• In the article below, Tracey and Pavlov don't specify what kind of link it is.

 

 

About The Inflammatory Reflex...

• Want to look closely at a single study that summarizes the evidence about TIR, what it is and how we know what it is?

I suggest this 2015 Review of the Literature, by Tracey and one of the scientists he works with closely.

 

2015, Neural circuitry and immunity

 

• A way to get a sense of the origins of the science of TIR and how it has evolved in the last two decades is to watch these two 40 minute lectures by Kevin Tracey. Some content is common to both. But each also contains unique and important content.

 

 

 

Neural regulation of immunity: molecular mechanisms and clinical translation

 

 

 

 

Edited by HighDesertWizard, 11 December 2018 - 01:49 PM.

[Nate-2004]

Interesting re: the highlighted portion because I'm taking acetylcholinesterase inhibitors (galantamine) on the regular, either before sleep for dreaming or during the day on some days. I've only been doing this for the last month or two though and I'm seeing some interesting positive results memory and cognition wise but I'm wondering how this might be affecting inflammation. 

Edited by Nate-2004, 10 December 2018 - 09:05 PM.

[HighDesertWizard]

A break from the slides to add to the evidence about TIR and Survival Probability in a way I hadn't earlier known...
 
 
A recent thread at Longecity highlighted the benefit of Royal Jelly...

Posted 05 December 2018 - 09:30 AM

https://www.theguard...laim-scientists
 

Researchers at Stanford University found that the main active component in royal jelly, a protein called royalactin, activates a network of genes that bolsters the ability of stem cells to renew themselves. It means that, with royalactin, an organism can produce more stem cells to build and repair itself with.
 
Royal jelly has intrigued scientists since its dramatic impact on honeybee development first became clear. But its effects on other animals have sparked even more interest. Previous studies have shown that royal jelly can improve the lifespan of a range of animals from nematode worms to mice.“We have a very identifiable avenue through which royal jelly’s effects are carried out,” said Kevin Wang, who led the Stanford team. “It has this activity of keeping stem cells in a self-renewing state.”
Writing in the journal Nature Communications, the Stanford team shows that royalactin increased the ability of mouse stem cells to renew themselves, suggesting the protein can have biological effects across species.
The scientists wondered whether a protein similar to the honeybees’ royalactin may be active in humans. After searching scientific databases, they found one that bore a similar structure. The protein is active in the earliest stages of human embryo development, when it is thought to build up the embryo’s supply of stem cells. When it came to naming the protein, Wang suggested Beyoncé – “a nice name for human queen bee” – but settled for regina, the Latin for queen.
“Everything points to this being a super important molecule,” said Wang. “We have identified an early self-renewal molecule that we think helps to establish the source cells for all of the embryo’s stem cells.”

  
 
It turns out that Royal Jelly is a Muscarinic Acetylcholine agonist...

 

2018, Royal jelly increases peripheral circulation by inducing vasorelaxation through nitric oxide production under healthy conditions
 

<SNIP>

SIGNIFICANCE:

The present study demonstrated that RJ is composed of muscarinic receptor agonist(s), likely ACh, and induces vasorelaxation through nitric oxide (NO) production from the vascular endothelium of healthy rats, leading to increased tail blood circulation. Thus, fresh RJ may improve peripheral circulation in healthy individuals.

 
 
 
We know, from diagrams and studies I've posted upthread, that Muscarinic-Acetylcholine Agonists trigger The Inflammatory Reflex. Are there studies demonstrating that Royal Jelly extends average lifespan?
 
2009, Honeybee royal jelly inhibits autoimmunity in SLE-prone NZB × NZW F1 mice
 
 

Royal jelly (RJ) is a gelatinous secretion from young nurse worker bees (Apis mellifera), which serves as the sole food for the queen bee. Because of its pleiotropic functions for queen bees, RJ has also been used as a dietary supplement with various health benefits for humans. Because RJ is being indicated to have immunomodulatory potential for humans, we undertook the study to determine whether the oral administration of RJ could alter the development of systemic autoimmunity in New Zealand Black (NZB) × New Zealand White (NZW) F1 mice that genetically exhibit many manifestations similar to human systemic lupus erythematosus (SLE). We herein reported that mice administered with RJ showed a significant delay in the onset of the disease, as manifested by decreased proteinuria and a prolongation of lifespan. In addition, RJ administration after the onset of the disease significantly improved the renal symptoms, leading to an extended lifespan. RJ administration to mice caused a significant decrease in the serum level of IL-10, and in the autoantibodies against ssDNA, dsDNA and erythrocytes, as well as a reduction in the number of splenic autoreactive B cells. In conclusion, our data suggest that the use of RJ may be beneficial in the prevention of the early onset of SLE and in the control of the active progression of the manifestations of SLE.

 
 
 

 
 
 

 
 
2003, Royal Jelly prolongs the life span of C3H/HeJ mice: correlation with reduced DNA damage
 

In this study, we investigate the effect of dietary Royal Jelly (RJ) on tissue DNA oxidative damage and on the life span of C3H/HeJ mice. In C3H/HeJ mice that were fed a dietary supplement of RJ for 16 weeks, the levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative stress, were significantly reduced in kidney DNA and serum. Secondly, we determined the effect of dietary RJ on the life span in C3H/HeJ mice. The 50% mice survivals of intermediate- (about 6 mg/kg weight) and high-dose groups (about 60 mg/kg weight) were reached at significantly longer times than that of the control group according to the generalized Wilcoxon test (p<0.05). The average survival times were 88 weeks for the control group vs. 79 weeks for the low-dose group (about 0.6 mg/kg weight), 112 weeks for the intermediate-dose group and 110 weeks for the high-dose group, respectively, showing that RJ extended the average survival time by about 25% compared to the control group. However, RJ did not extend the total life span. These results indicated that dietary RJ increased the average life span of C3H/HeJ mice, possibly through the mechanism of reduced oxidative damage.

 
 
 

 
Notice...

• Royal Jelly did what we desire to do as a first step... Square the Survival Curve
   
• The mice were only fed Royal Jelly for 16 weeks. So this is not a true test of Royal Jelly's impact on Survival Probabiity under continuous dosing conditions.
   
• That said, the effect of beginning to dose Royal Jelly only later in life is not addressed in this study.

Edited by HighDesertWizard, 14 December 2018 - 10:49 AM.