226 replies to this topic

[RobbieG]

HighDesertWizard, you appear to be the thought leader on the Vagus Nerve/HRV/CAIP nexus, so is there a way to stimulate the nerve by electrical means or through supplementation?  If so, what do you suggest or recommend?  Thanks, - Rob 

[stefan_001]

I am wondering whether there is something to learn from the upstream mechanisms that Honokiol uses suppresblock NF-kb.

Our results indicate that honokiol suppresses NF-κB activated by a variety of agents. This is the first report to examine the effect of honokiol on NF-κB activated by various stimuli. These results suggest that honokiol must act at a step common to all these agents. We found that honokiol blocked the activation of NF-κB without directly interfering with the DNA binding of NF-κB. Further analysis of the pathway indicated that honokiol targets at the level of IKK. However, our in vitro kinase assay results showed that honokiol is not a direct inhibitor of IKK. Thus, it seems that honokiol blocks the activation of IKK by interfering with some upstream regulatory kinases. Akt, NIK, mitogen-activated protein kinase kinase kinase 1, and atypical protein kinase C are candidates because they are upstream kinases that regulate IKK (11). Indeed, our results show that honokiol suppresses TNF-induced activation of Akt.

We found that honokiol inhibited not only inducible NF-κB activation but also constitutively activated NF-κB in multiple myeloma and head and neck squamous cell carcinoma cells. Constitutive active NF-κB activation has been found to be critical for the survival and proliferation of various tumor cell types (11); however, the mechanism of constitutive NF-κB activation is not well understood. Some of the potential mechanisms are overexpression of IκBα without inhibition of NF-κB activity, mutations in the IκBα gene, enhanced IκBα degradation, and constitutive expression of TNF and interleukin-1 (11).

We found that honokiol suppresses NF-κB-dependent reporter gene expression. Honokiol also inhibited the TNF-induced COX-2 promoter activity, which is regulated by NF-κB (30). These results agree with a recent report (5) showing that honokiol inhibits NF-κB luciferase reporter activity. We also found that honokiol suppressed NF-κB activation induced by overexpression of TNFR1, TRADD, TRAF2, NIK, and IKK plasmids but had no effect on activation induced by p65 plasmid. These results suggest that honokiol acts at a step between IKK and p65.

The genes that are involved in the proliferation and metastasis of cancer have been shown to be regulated by NF-κB (11). We showed in this report that honokiol inhibits the expression of cyclin D1 and c-myc, both regulated by NF-κB. Our results also showed that the expressions of COX-2, MMP-9, ICAM-1, and VEGF, which are also regulated by NF-κB, are down-regulated by honokiol. Indeed, honokiol has been shown to down-regulate COX-2 gene expression in the human monocytic THP1 cell line (31). The suppression of invasion (32) and angiogenesis (33) reported previously agrees with the results reported here. The inflammatory cytokines TNF and interleukin-8, both known to promote angiogenesis, have also been shown to be down-regulated by honokiol (4, 5). The down-regulation of nitric oxide synthesis by honokiol reported previously (4) also likely occurs through the suppression of NF-κB activation as reported here.

We also found for the first time that honokiol suppressed RANKL-induced osteoclastogenesis. RANKL mediates osteoclastogenesis in part through activation of NF-κB (34). Thus, it is very likely that suppression of NF-κB by honokiol leads to suppression of osteoclastogenesis.

NF-κB is known to regulate the expression of IAP1, IAP2, Bcl-xL, Bcl-2, TRAF1, and cFLIP, and their overexpression in numerous tumors has been linked to survival, chemoresistance, and radioresistance. Our results indicated that honokiol treatment down-regulates the TNF-induced expression of these gene products. Earlier studies have shown that honokiol down-regulates the expression of the antiapoptotic proteins Bcl-xL (7) and Mcl-1 (35). Our studies also showed that honokiol potentiated the apoptotic effects of TNF, paclitaxel, and doxorubicin. These effects are similar to that reported with a specific inhibitor of NF-κB (36). Two recent reports (10, 35) that honokiol induces apoptosis of human B-cell chronic lymphocytic leukemia and human multiple myeloma through the activation of caspases also agree with the results shown here. Overall, our results indicate that the antiproliferative, proapoptotic, anti-invasive, antiosteoclastogenic, antiangiogenic, and antimetastatic effects of honokiol may be mediated through suppression of NF-κB-regulated gene products.

Edited by stefan_001, 02 January 2016 - 07:25 PM.

[Logic]

I am wondering whether there is something to learn from the upstream mechanisms that Honokiol uses suppresblock NF-kb.

Our results indicate that honokiol suppresses NF-κB activated by a variety of agents. This is the first report to examine the effect of honokiol on NF-κB activated by various stimuli. These results suggest that honokiol must act at a step common to all these agents. We found that honokiol blocked the activation of NF-κB without directly interfering with the DNA binding of NF-κB. Further analysis of the pathway indicated that honokiol targets at the level of IKK. However, our in vitro kinase assay results showed that honokiol is not a direct inhibitor of IKK. Thus, it seems that honokiol blocks the activation of IKK by interfering with some upstream regulatory kinases. Akt, NIK, mitogen-activated protein kinase kinase kinase 1, and atypical protein kinase C are candidates because they are upstream kinases that regulate IKK (11). Indeed, our results show that honokiol suppresses TNF-induced activation of Akt.

We found that honokiol inhibited not only inducible NF-κB activation but also constitutively activated NF-κB in multiple myeloma and head and neck squamous cell carcinoma cells. Constitutive active NF-κB activation has been found to be critical for the survival and proliferation of various tumor cell types (11); however, the mechanism of constitutive NF-κB activation is not well understood. Some of the potential mechanisms are overexpression of IκBα without inhibition of NF-κB activity, mutations in the IκBα gene, enhanced IκBα degradation, and constitutive expression of TNF and interleukin-1 (11).

We found that honokiol suppresses NF-κB-dependent reporter gene expression. Honokiol also inhibited the TNF-induced COX-2 promoter activity, which is regulated by NF-κB (30). These results agree with a recent report (5) showing that honokiol inhibits NF-κB luciferase reporter activity. We also found that honokiol suppressed NF-κB activation induced by overexpression of TNFR1, TRADD, TRAF2, NIK, and IKK plasmids but had no effect on activation induced by p65 plasmid. These results suggest that honokiol acts at a step between IKK and p65.

The genes that are involved in the proliferation and metastasis of cancer have been shown to be regulated by NF-κB (11). We showed in this report that honokiol inhibits the expression of cyclin D1 and c-myc, both regulated by NF-κB. Our results also showed that the expressions of COX-2, MMP-9, ICAM-1, and VEGF, which are also regulated by NF-κB, are down-regulated by honokiol. Indeed, honokiol has been shown to down-regulate COX-2 gene expression in the human monocytic THP1 cell line (31). The suppression of invasion (32) and angiogenesis (33) reported previously agrees with the results reported here. The inflammatory cytokines TNF and interleukin-8, both known to promote angiogenesis, have also been shown to be down-regulated by honokiol (4, 5). The down-regulation of nitric oxide synthesis by honokiol reported previously (4) also likely occurs through the suppression of NF-κB activation as reported here.

We also found for the first time that honokiol suppressed RANKL-induced osteoclastogenesis. RANKL mediates osteoclastogenesis in part through activation of NF-κB (34). Thus, it is very likely that suppression of NF-κB by honokiol leads to suppression of osteoclastogenesis.

NF-κB is known to regulate the expression of IAP1, IAP2, Bcl-xL, Bcl-2, TRAF1, and cFLIP, and their overexpression in numerous tumors has been linked to survival, chemoresistance, and radioresistance. Our results indicated that honokiol treatment down-regulates the TNF-induced expression of these gene products. Earlier studies have shown that honokiol down-regulates the expression of the antiapoptotic proteins Bcl-xL (7) and Mcl-1 (35). Our studies also showed that honokiol potentiated the apoptotic effects of TNF, paclitaxel, and doxorubicin. These effects are similar to that reported with a specific inhibitor of NF-κB (36). Two recent reports (10, 35) that honokiol induces apoptosis of human B-cell chronic lymphocytic leukemia and human multiple myeloma through the activation of caspases also agree with the results shown here. Overall, our results indicate that the antiproliferative, proapoptotic, anti-invasive, antiosteoclastogenic, antiangiogenic, and antimetastatic effects of honokiol may be mediated through suppression of NF-κB-regulated gene products.

 

Interesting! Especially the info in genes upregulated by NF-kB
A link to the above study:
http://mcr.aacrjourn...nt/4/9/621.full

Edited by Logic, 03 January 2016 - 01:08 PM.

[stefan_001]

After reading this thread I am left puzzled with the fact that the substances mentioned also in the first post and expected to delay aging:

 

4 – Misc gene and supplement evidence about NF-kB Inhibition importance…
— Rapamycin has been shown to extend lifespan. Turns out, it inhibits NF-kB (http://tinyurl.com/no3ovd8 and http://tinyurl.com/py75ey9)
— Metformin inhibits NF-kB (http://tinyurl.com/nkyxxhy)

 

are also known to inhibit Telemerase in cancer cells lines. In fact it seems many NF-kB blockers inhibit Telemerase. So does that mean:

- they dont inhibit Telemerase in non cancer cell lines?

- that this inhibition of Telemerase will only become visible as a problem in humans at a much later age?

- something else?

 

Update: just found a thread discussing this very topic...will read it tonight

http://www.longecity...-targets/page-3

Edited by stefan_001, 05 January 2016 - 11:14 AM.

[Logic]

After reading this thread I am left puzzled with the fact that the substances mentioned also in the first post and expected to delay aging:

 

4 – Misc gene and supplement evidence about NF-kB Inhibition importance…
— Rapamycin has been shown to extend lifespan. Turns out, it inhibits NF-kB (http://tinyurl.com/no3ovd8 and http://tinyurl.com/py75ey9)
— Metformin inhibits NF-kB (http://tinyurl.com/nkyxxhy)

 

are also known to inhibit Telemerase in cancer cells lines. In fact it seems many NF-kB blockers inhibit Telemerase. So does that mean:

- they dont inhibit Telemerase in non cancer cell lines?

- that this inhibition of Telemerase will only become visible as a problem in humans at a much later age?

- something else?

 

Update: just found a thread discussing this very topic...will read it tonight

http://www.longecity...-targets/page-3

 

Many natural substances that inhibit telomerase in cancerous cells do seem to have the opposite effect in healthy cells Stefan.
Remember that we evolved over billions of years while eating plants...
This co-evolution seems to have given us the same advantages plants get from their natural, protective molecules...

ie: nature/evolution has done WAY more in-vivo 'studies'/adaptations than modern humans can ever hope to achieve in a lab.

Another confounding factor is that we metabolise everything we get into our bodies by whatever means.
This means that the molecules that eventually get into our cells are WAY different to what we eat/snarf/inject. (in descending order) 

Here is a good example:
http://www.longecity...nd-metabolites/

In-vitro Resveratrol = In-vivo Pterostilbene (more or less)  IMHO.

[HighDesertWizard]

After reading this thread I am left puzzled with the fact that the substances mentioned also in the first post and expected to delay aging:

 

4 – Misc gene and supplement evidence about NF-kB Inhibition importance…
— Rapamycin has been shown to extend lifespan. Turns out, it inhibits NF-kB (http://tinyurl.com/no3ovd8 and http://tinyurl.com/py75ey9)
— Metformin inhibits NF-kB (http://tinyurl.com/nkyxxhy)

 

are also known to inhibit Telemerase in cancer cells lines. In fact it seems many NF-kB blockers inhibit Telemerase. So does that mean:

- they dont inhibit Telemerase in non cancer cell lines?

- that this inhibition of Telemerase will only become visible as a problem in humans at a much later age?

- something else?

 

Update: just found a thread discussing this very topic...will read it tonight

http://www.longecity...-targets/page-3

 

Hey stefan... Not all puzzle pieces have come together yet, and I've moved away for a bit from that specific set of questions to another set of questions about the larger Explanation... I like Logic's reply a lot too...

 

Look up thread, on this page 3 to the posts I made on November 9th, to the nfkb1 gene deletion studies... The two studies impacted NF-Kb Subunit p50 expression. There is a study link somewhere close or even in that post that shows that p50 becomes a key component of the telomerase holoenzyme... For December 3rd, you'll see a table in which I wondered out loud about the significance of NF-kB Nuclear Translocation, pCREB and c-fos expression, and the Kinds of NF-kB Inhibiting substances that might also trigger telomerase expression.

 

 

 

I do have a diagram that speaks to the question that I hadn't seen back in November. I found it a week ago in a 2012 study for which there wasn't a full text PDF, but there is now. The knowledge it implicates fills me with awe and wonder... Of course, it's a Kevin Tracey study diagram. I've been saving it for a post that constitutes what is, for me, the next leap up in knowledge of the larger Mechanism of Action.

 

I've given that MoA Explanation a name... More about the name later, hopefully soon... Here's an early peek at the diagram worthy, all by itself along with the knowledge it implicates, of a Nobel Prize... Notice that the acetylcholine expression of the Cholinergic Anti-Inflammatory Pathway can inhibit NF-kB Cytokine Transcription, both, inside and outside the nucleus... I take it Tracey's scope of research isn't intended to address the relationship to Telomerase...

 

And for those following the discussion of F-C60-OO... Do you see the significance of this diagram? 

 

<< SNIP >>
 
Evolution, herself, god bless her, has established this fundamental mechanism for aging and rejuvenation within us, for NF-kB Activation Inhibition [edit 2016-01-05... I should have written NF-kB Cytokine Transcription Inhibition], and no amount of amorphous thinking about death rates of previous centuries demonstrates that we cannot hijack thIs NF-kB-Telomerase mechanism even further for longer and healthier lives.

 

Mastering all the details of this mechanism, established by Evolution herself, is not a dry, academic exercise. The purpose of mastery is to discover how to Hijack it. It's hot to the touch with capacity to increase health and longevity...

 

 

 

Edited by HighDesertWizard, 05 January 2016 - 02:49 PM.

[Logic]

I new thought/hypothesis HDW:
 

The gut is an organ with one of the highest cell turnovers in the body.

This isnt surprising when you consider the vast number and array microbes/pathogens/toxins etc it has to keep isolated from the rest of the organism/body and the fact that one dies of septicemia within hours when it fails to do so.

Now as the gut has a high cell turnover it's likely that telomere length is shorter and stem cell turnover is high etc.
Perhaps what the vagus nerve is doing is signalling the rest of he system that the gut is getting older and less efficient at keeping pathogens and  Indoxyl Sulfate and P-Cresyl Sulfate etc out of the rest of the organism and that it's a good idea to increase TNF, NF-kB etc as a counter measure.

ie:  One big negative feedback loop that results in less telomerase, less stem cell activity etc and thus a more permeable gut and thus more need for NF-lb etc and thus less telomerase etc-etc...?

 

When you combine this with TNF/NF-kB etc upregulation from AGEs, the fact that we all live on bacteria 'shit' and don't seem to care what bacteria are taking said shit, perhaps one is close to 'why we age'.

???

 

It seems to me that aging is more a case of 'wiser' cells epigenetically compromising/adapted to prevent immediate demise, than older cells?

Edited by Logic, 05 January 2016 - 03:12 PM.

[HighDesertWizard]

I new thought/hypothesis HDW:
 
The gut is an organ with one of the highest cell turnovers in the body.
This isnt surprising when you consider the vast number and array microbes/pathogens/toxins etc it has to keep isolated from the rest of the organism/body and the fact that one dies of septicemia within hours when it fails to do so.

Now as the gut has a high cell turnover it's likely that telomere length is shorter and stem cell turnover is high etc.
Perhaps what the vagus nerve is doing is signalling the rest of he system that the gut is getting older and less efficient at keeping pathogens and  Indoxyl Sulfate and P-Cresyl Sulfate etc out of the rest of the organism and that it's a good idea to increase TNF, NF-kB etc as a counter measure.

ie:  One big negative feedback loop that results in less telomerase, less stem cell activity etc and thus a more permeable gut and thus more need for NF-lb etc and thus less telomerase etc-etc...?
 
When you combine this with TNF/NF-kB etc upregulation from AGEs, the fact that we all live on bacteria 'shit' and don't seem to care what bacteria are taking said shit, perhaps one is close to 'why we age'.

???
 
It seems to me that aging is more a case of 'wiser' cells epigenetically compromising/adapted to prevent immediate demise, than older cells?

 
Hey Logic... Good points... Here's a Tracey study from 2005 about the Vagal processes in the gut: Fat meets the cholinergic antiinflammatory pathway

 

Edited by HighDesertWizard, 06 January 2016 - 04:53 AM.

[Logic]

Hey Logic... Good points... Here's a Tracey study from 2005 about the Vagal processes in the gut: Fat meets the cholinergic antiinflammatory pathway

 

"...Luyer et al. (15) present compelling evidence that consumption of fat in the diet can activate the cholinergic antiinflammatory pathway (15). They found that administration of high fat nutrition reduced circulating levels of TNF and IL-6 in rats subjected to hemorrhagic shock, a manipulation known to activate high blood cytokine levels. When these experiments were repeated in animals subjected to vagotomy, the administration of the high fat diet no longer prevented the increase..."

 

Thx.  So dietary fat decreases TNF NF-kB. 
I'll stick with my VCO (Coconut OIl = Lauric etc acids) dosing as that also kills Candida, (a NAD+ auxotroph) a whole slew of other nasty bacteria and exposes virii (HIV, HSV, EB, CMV, etc) disguised as nutrients by a lipid layer, to the immune system.  

(Pathogens are the other big increaser of NF-kB)

 

BHT has a similar effect and also greatly reduces lipid peroxidation IMHO.

[HighDesertWizard]

<< SNIP >>

 

"...Luyer et al. (15) present compelling evidence that consumption of fat in the diet can activate the cholinergic antiinflammatory pathway (15). They found that administration of high fat nutrition reduced circulating levels of TNF and IL-6 in rats subjected to hemorrhagic shock, a manipulation known to activate high blood cytokine levels. When these experiments were repeated in animals subjected to vagotomy, the administration of the high fat diet no longer prevented the increase..."

 

Thx.  So dietary fat decreases TNF NF-kB. 
I'll stick with my VCO (Coconut OIl = Lauric etc acids) dosing as that also kills Candida, (a NAD+ auxotroph) a whole slew of other nasty bacteria and exposes virii (HIV, HSV, EB, CMV, etc) disguised as nutrients by a lipid layer, to the immune system.  

(Pathogens are the other big increaser of NF-kB)

 

BHT has a similar effect and also greatly reduces lipid peroxidation IMHO.

 

 

Cytokine Storms, Cytokine Strong Winds, Cytokine Light Breezes ("normal" aging)...

 

Candida... a type of pathogen that can trigger a Cytokine Storm. Evidently, Mother Nature has repeatedly used Cytokine Storms in Homo Sapien history to take out huge numbers all at once to reduce their capacity to reproduce...

 

Question: Over time, who is increasing left to reproduce?

Answer: Those with greater Homeostatic Capacity (aka, Higher Vagal Tone as measured by Heart Rate Variability) to inhibit NF-kB Cytokine Transcription...

 

 

Complement, Candida, and cytokines: The role of C5a in host response to fungi

 

Complement is the central host defense system that clears invading microbes and balances homeostasis. Pathogenic microbes such as Candida albicans have to breach this efficient and important immune defense layer in order to propagate within the host and to establish an infection... The authors show that the complement activation fragment C5a, which is formed in response to Candida infection, induces the cellular release of the inflammatory cytokines IL-6 and IL-1β.

 

C5a anaphylatoxin inhibitor suppresses a lethal cytokine storm in monkeys injected with LPS

 

The complement component C5a induces the expression of plasminogen activator inhibitor-1 in human macrophages via NF-kappaB activation

 

 

Apparently, the Cytokine Storms used by Mother Nature to make Selection Choices take huge numbers of homo sapiens out of the procreating pool all at once and we do not reproduce. But also, apparently, Mother Nature was making Vagal Tone (Heart Rate Variability) differentiating Selection Choices that are Cytokine Light Breezes as recently as the late 1990s. Look again up thread at the Survival Curve graphic figure in the opening post.

 

Here’s the study context... Take a known, Human, Surrogate Marker for Health, it’s a Computed Statistic... Measure this marker for 24 hours in old, wild-type Humans, 65 years old and up with a mean of 73 years… Wait 10 years… 53% of the 347 study animals are now dead... Do some statistical analysis of that surrogate marker data and plot the two survival curves below… That marker, Heart Rate Variability (HRV), has profound implications for human health and longevity... Here’s a link to this study from 1998...

Edited by HighDesertWizard, 06 January 2016 - 01:12 PM.

[HighDesertWizard]

This LongeCity forum is great. The title and URL of this thread have changed but the old URL still works. Here's the reason for the change...

 

I'm a software engineer and Longevity Science Enthusiast. When I do a software project, I log what I learn in an online notebook. It helps enormously.
 
About 4 years ago, I searched for an explanation of an experience I had while attempting to cultivate higher Heart Rate Variability (HRV). I had no idea where that search would lead me and how important the subject might be.
 
Over time. I began to Log my Learning in three forum threads about a mechanism for longevity that is, still, not well known or understood. I understand my views are not common within the Longevity Science Community. There's a focus in these three Learning Log threads but I haven't worked at message coherence. My aim is to document the content that strikes me as important and interesting in the moment.

 

I've given this content a name: the SMILE of Longevity. It's not an Aging Theory. It's an Explanation of Longevity. I've got a lot more to say about the meaning of the SMILE soon enough...

 

Over time, the content of the three Learning Logs has become disorganized so I'm restructuring it. LongeCity Leaders, Mind and caliban, have kindly helped me to rename the three threads so that their titles reflect the content I've imagined should exist in them. This thread is one of them.

 

I have Moderator capabilities in these threads and, to sharper the distinction among them, I'll be moving some posts of mine around to their proper thread home. I appreciate posts to these Learning Logs by others. If you've posted to them, I may privately ask for your permission/assistance in moving your post(s) like I'll be moving some of mine. I won't touch your posts without your permission. This process will take some time, probably a few months.

 

 

I've already learned a lot in walking this path. I intend to learn more to Hijack the Biological Mechanism of Action for Longevity in the survival curves shown here.

 

I'm just getting warmed up in learning about and taking action on the SMILE and it's mechanism. I hope you'll join me in learning about it.
 

Edited by HighDesertWizard, 07 January 2016 - 02:59 AM.

[HighDesertWizard]

This LongeCity forum is great. The title and URL of this thread have changed but the old URL still works. Here's the reason for the change...

 

I'm a software engineer and Longevity Science Enthusiast. When I do a software project, I log what I learn in an online notebook. It helps enormously.
 
About 4 years ago, I searched for an explanation of an experience I had while attempting to cultivate higher Heart Rate Variability (HRV). I had no idea where that search would lead me and how important the subject might be.
 
Over time. I began to Log my Learning in three forum threads about a mechanism for longevity that is, still, not well known or understood. I understand my views are not common within the Longevity Science Community. There's a focus in these three Learning Log threads but I haven't worked at message coherence. My aim is to document the content that strikes me as important and interesting in the moment.

 

I've given this content a name: the SMILE of Longevity. It's not an Aging Theory. It's an Explanation of Longevity. I've got a lot more to say about the meaning of the SMILE soon enough...

 

Over time, the content of the three Learning Logs has become disorganized so I'm restructuring it. LongeCity Leaders, Mind and caliban, have kindly helped me to rename the three threads so that their titles reflect the content I've imagined should exist in them. This thread is one of them.

 

I have Moderator capabilities in these threads and, to sharper the distinction among them, I'll be moving some posts of mine around to their proper thread home. I appreciate posts to these Learning Logs by others. If you've posted to them, I may privately ask for your permission/assistance in moving your post(s) like I'll be moving some of mine. I won't touch your posts without your permission. This process will take some time, probably a few months.

 

 

I've already learned a lot in walking this path. I intend to learn more to Hijack the Biological Mechanism of Action for Longevity in the survival curves shown here.

 

I'm just getting warmed up in learning about and taking action on the SMILE and it's mechanism. I hope you'll join me in learning about it.
 

Edited by HighDesertWizard, 07 January 2016 - 02:56 AM.

[HighDesertWizard]

This LongeCity forum is great. The title and URL of this thread have changed but the old URL still works. Here's the reason for the change...

 

I'm a software engineer and Longevity Science Enthusiast. When I do a software project, I log what I learn in an online notebook. It helps enormously.
 
About 4 years ago, I searched for an explanation of an experience I had while attempting to cultivate higher Heart Rate Variability (HRV). I had no idea where that search would lead me and how important the subject might be.
 
Over time. I began to Log my Learning in three forum threads about a mechanism for longevity that is, still, not well known or understood. I understand my views are not common within the Longevity Science Community. There's a focus in these three Learning Log threads but I haven't worked at message coherence. My aim is to document the content that strikes me as important and interesting in the moment.

 

I've given this content a name: the SMILE of Longevity. It's not an Aging Theory. It's an Explanation of Longevity. I've got a lot more to say about the meaning of the SMILE soon enough...

 

Over time, the content of the three Learning Logs has become disorganized so I'm restructuring it. LongeCity Leaders, Mind and caliban, have kindly helped me to rename the three threads so that their titles reflect the content I've imagined should exist in them. This thread is one of them.

 

I have Moderator capabilities in these threads and, to sharper the distinction among them, I'll be moving some posts of mine around to their proper thread home. I appreciate posts to these Learning Logs by others. If you've posted to them, I may privately ask for your permission/assistance in moving your post(s) like I'll be moving some of mine. I won't touch your posts without your permission. This process will take some time, probably a few months.

 

 

I've already learned a lot in walking this path. I intend to learn more to Hijack the Biological Mechanism of Action for Longevity in the survival curves shown here.

 

I'm just getting warmed up in learning about and taking action on the SMILE and it's mechanism. I hope you'll join me in learning about it.
 

[Logic]

You are welcome to move my posts around HDW.
Perhaps links to all 3 threads, in all 3 threads is a good idea.

More on fats and Glycation:

 

"...We have also identified oleuropein, a phenolic compound in
Olea europaea leaf extract, olive oil, and olives, as a
potent stimulator of proteasome activities in vitro. Human
primary fibroblasts treated with oleuropein were also more
resistant to oxidative stress and exhibited extended cellular
life span. We have suggested that oleuropein most
likely alters the conformation of 20S α -gated channels
reminiscent to the SDS action...

...Finally, betulinic acid, a pentacyclic

triterpene, has also been shown to act as a proteasome
activator only enhancing the CT-L proteasome activity
[393], while recently lithocholic acid derivatives 3 α - O -
pimeloyl-lithocholic acid methyl ester and its isosteric
isomer were also identifi ed as activators of the chymotrypsin-like
activity...
...The above-mentioned studies investigated compounds
that are mainly interfering with the structure of the 20S
complex with a consequent induction of its activities. Nevertheless,
several exogenous stimuli have been shown to
modulate the expression of proteasome subunits and the
relative activities in mice through the regulation by nuclear
factor (erythroid-derived 2)-like 2 (Nrf2)..."
http://www.tandfonli...762.2013.792926

 

This whole study is a goldmine of anti AGE information, but takes some digesting!
I will post a summary soon.

 

 

 

 

[stefan_001]

 

After reading this thread I am left puzzled with the fact that the substances mentioned also in the first post and expected to delay aging:

 

4 – Misc gene and supplement evidence about NF-kB Inhibition importance…
— Rapamycin has been shown to extend lifespan. Turns out, it inhibits NF-kB (http://tinyurl.com/no3ovd8 and http://tinyurl.com/py75ey9)
— Metformin inhibits NF-kB (http://tinyurl.com/nkyxxhy)

 

are also known to inhibit Telemerase in cancer cells lines. In fact it seems many NF-kB blockers inhibit Telemerase. So does that mean:

- they dont inhibit Telemerase in non cancer cell lines?

- that this inhibition of Telemerase will only become visible as a problem in humans at a much later age?

- something else?

 

Update: just found a thread discussing this very topic...will read it tonight

http://www.longecity...-targets/page-3

 

Many natural substances that inhibit telomerase in cancerous cells do seem to have the opposite effect in healthy cells Stefan.
Remember that we evolved over billions of years while eating plants...
This co-evolution seems to have given us the same advantages plants get from their natural, protective molecules...

ie: nature/evolution has done WAY more in-vivo 'studies'/adaptations than modern humans can ever hope to achieve in a lab.

Another confounding factor is that we metabolise everything we get into our bodies by whatever means.
This means that the molecules that eventually get into our cells are WAY different to what we eat/snarf/inject. (in descending order) 

Here is a good example:
http://www.longecity...nd-metabolites/

In-vitro Resveratrol = In-vivo Pterostilbene (more or less)  IMHO.

 

 

Hello Logic, you do your name honor as this makes a lot of sense. In the mean time trying to read more....

 

[stefan_001]

 

After reading this thread I am left puzzled with the fact that the substances mentioned also in the first post and expected to delay aging:

 

4 – Misc gene and supplement evidence about NF-kB Inhibition importance…
— Rapamycin has been shown to extend lifespan. Turns out, it inhibits NF-kB (http://tinyurl.com/no3ovd8 and http://tinyurl.com/py75ey9)
— Metformin inhibits NF-kB (http://tinyurl.com/nkyxxhy)

 

are also known to inhibit Telemerase in cancer cells lines. In fact it seems many NF-kB blockers inhibit Telemerase. So does that mean:

- they dont inhibit Telemerase in non cancer cell lines?

- that this inhibition of Telemerase will only become visible as a problem in humans at a much later age?

- something else?

 

Update: just found a thread discussing this very topic...will read it tonight

http://www.longecity...-targets/page-3

 

Hey stefan... Not all puzzle pieces have come together yet, and I've moved away for a bit from that specific set of questions to another set of questions about the larger Explanation... I like Logic's reply a lot too...

 

Look up thread, on this page 3 to the posts I made on November 9th, to the nfkb1 gene deletion studies... The two studies impacted NF-Kb Subunit p50 expression. There is a study link somewhere close or even in that post that shows that p50 becomes a key component of the telomerase holoenzyme... For December 3rd, you'll see a table in which I wondered out loud about the significance of NF-kB Nuclear Translocation, pCREB and c-fos expression, and the Kinds of NF-kB Inhibiting substances that might also trigger telomerase expression.

 

 

 

I do have a diagram that speaks to the question that I hadn't seen back in November. I found it a week ago in a 2012 study for which there wasn't a full text PDF, but there is now. The knowledge it implicates fills me with awe and wonder... Of course, it's a Kevin Tracey study diagram. I've been saving it for a post that constitutes what is, for me, the next leap up in knowledge of the larger Mechanism of Action.

 

I've given that MoA Explanation a name... More about the name later, hopefully soon... Here's an early peek at the diagram worthy, all by itself along with the knowledge it implicates, of a Nobel Prize... Notice that the acetylcholine expression of the Cholinergic Anti-Inflammatory Pathway can inhibit NF-kB Cytokine Transcription, both, inside and outside the nucleus... I take it Tracey's scope of research isn't intended to address the relationship to Telomerase...

 

And for those following the discussion of F-C60-OO... Do you see the significance of this diagram? 

 

<< SNIP >>
 
Evolution, herself, god bless her, has established this fundamental mechanism for aging and rejuvenation within us, for NF-kB Activation Inhibition [edit 2016-01-05... I should have written NF-kB Cytokine Transcription Inhibition], and no amount of amorphous thinking about death rates of previous centuries demonstrates that we cannot hijack thIs NF-kB-Telomerase mechanism even further for longer and healthier lives.

 

Mastering all the details of this mechanism, established by Evolution herself, is not a dry, academic exercise. The purpose of mastery is to discover how to Hijack it. It's hot to the touch with capacity to increase health and longevity...

 

 

 

 

 

Hello HDW, appreciate a lot your reaction. And clearly I dont know enough yet about this to really comment. But one thing did come to mind about this. I am assuming the vagus nerve would travel through the spine. So if we look at people with spine injuries there must be cases where the vagus nerve is cut and we see some health challenges confirming the role of the vagus mechanisms?

 

[Logic]

"...Surprisingly, the production of the inflammatory cytokine IL-6 was completely abolished (100% inhibition) by PLE [extract of the fern Polypodium leucotomos, sold as 'sunblock' pills] at all doses tested..."

http://www.ncbi.nlm....pubmed/10928072

Edited by Logic, 08 January 2016 - 07:56 PM.

[HighDesertWizard]

Two general theories about aging exist within the Longevity Science Movement. This LongeCity Forum Thread is not intended to discuss these two schools in detail. In this opening post it’s enough to point out, not their differences, but their similarities.

 

[ Note: In a future version of this post, a paragraph summarizing the focus of the two general Aging Theories will appear here. The two theories are known, of course, by something like the following two: “the Wear and Tear Damage Theory of Aging” and the “Programmed Theory of Aging”. Two key thought leaders for these theories are Dr. Aubrety de Grey and Dr. Joshua Mitteldorf. ]

 

Note that these two schools are both Aging Theories and neither of them has much, if anything, to say that looks like an Explanation of Longevity.

 

The SMILE of Longevity is a different kind of thing. It provides an Explanation of a Mechanism of Action focused on Increasing Longevity. The SMILE mechanism is complex, being comprised of multiple biological objects of various types: organs, interactions between organs, nerves, various cell types, agonist and antagonist substances, etc. Specific biological objects are required for the SMILE Mechanism of Action to function optimally. Kevin Tracey and his teams have found that Intact Vagal and Splenic Signaling is required for optimal SMILE longevity.

 

It’s enough today to state clearly… Despite its overall complexity, the Focus of the SMILE Explanation mechanism is NF-kB Cytokine Transcription Inhibition.

 

[ Note: I’ll provide the rationale for the name, SMILE of Longevity, soon enough, hopefully soon. I’m a professional software engineer and Longevity Science Hobbyist so things take time. I have just a few more tasks before the context structure for moving forward is in place. Setting this thread in motion is one of those tasks. :-) ]

 

 

A Credible Explanation of Longevity should, at least, do two things.

• Provide Survival Curve evidence that, directly or indirectly, establishes the Explanation Mechanism Focus as improving survival odds. I'll continue to provide this required survival odds evidence for the SMILE of Longevity here.

   

• Provide evidence about the ways Evolution Selection Pressure was and is focused on the Explanation of Longevity Mechanism Focus.

 

The purpose of this thread is to discuss the Selection Pressures that establish the SMILE as a credible Explanation of a Mechanism fundamental to Longevity.

 

A few notes about the thread... 

• This thread is a Log of Learning… The purpose is to get distinct evidence and argument on the table and not worry so much about ensuring detailed logical flow across posts. Your patience is appreciated.
   
• I’ve made a number of posts related to this topic in other SMILE of Longevity - Learning Log threads. This is the first and largest of the move of posts from those threads that began with the recent thread rename described here.
   
• Finally, for now, I’d appreciate it if others would hold off on making posts until I get the thread moderating capabilities I need to effectively do it.

I look forward to more focused reflection and discussion about the work of Mother Nature in us...

 

:-)

Edited by HighDesertWizard, 09 January 2016 - 05:13 PM.

[HighDesertWizard]

Despite the scale and complexity of the entire mechanism, the Focus of the SMILE Mechanism is NF-kB Cytokine Transcription Inhibition, especially in the Spleen...

 

Has Mother Nature been Selecting individual Homo Sapiens out of the gene pool with a focus on NF-kB functions?

 

Providing evidence and argument to address that question is the purpose of this thread. Let's organize the evidence using three concepts.

 

Evidence about Selection Pressure establishing the SMILE of Longevity Mechanism in homo sapiens may be organized in terms of 3 concepts.

• Pandemics, including Cytokine Storms, that Select Out huge numbers of us in a relatively short time

And, to continue with the weather metaphor...

• Cytokine Strong Winds that accelerate aging in some individuals
• Cytokine Light Breezes that we feel hardly at all and drive "normal aging"

Notes...

• The latter two labels aren't scientific, but Cytokine Storm appears in the titles and text of many studies, so we're going with the weather theme.
• This is a Log for Learning and I'm working on several dimensions of the SMILE at once, so I won't bother now too much with formatting and flow across posts. The point is to accumulate the Selection Pressure evidence here. I think you'll get the point of the evidence.

 
We'll start with Pandemics, including Cytokine Storms, with special focus on the most devastating pandemics in human history... A striking graphic figure and a list of the top 10 appear below...

 

We want to know how many of these devastating pandemics implicate NF-kB in one way or another...

 

 

 

Top 10 Deadliest Pandemics

 

Throughout history, disease has afflicted millions of people in many parts of the world causing much pain and suffering in the form of illness, disability, and death. The word pandemic means an epidemic of infectious disease that has spread through human populations across a large geographic region; for instance multiple continents, or even worldwide. Pandemics originate from microscopic enemies, such as parasites, viruses and bacteria, which may be passed to us from infected people,animals, or insects.

• The Black Death
• Influenza
• Plague of Justinian
• Plague of Athens
• Third Pandemic
• Cholera
• SARS
• Antoine Plague
• Malaria
• Smallpox

Edited by HighDesertWizard, 23 January 2016 - 01:03 AM.

[HighDesertWizard]

In this post, I'm logging evidence background key to a larger argument I'm working on...

 

 

The principles Dr. Katcher expresses in this article have had significant impact on my thinking. IMO, it's one of the most significant Longevity Science articles of 2015. It's time now to circle back and begin to log why this article is always on my mind, but with a twist... Dr. Katcher is obviously not yet acquainted with the work of Kevin Tracey...

 

To start, two principles from Dr. Katcher...

 

<< SNIP >>

 

6. Cellular Aging Changes Cause Aging Changes in Organs and Organ Systems, Reciprocally, Changes in Organs and Organ Systems Effect Cellular Aging Changes
7. Cells and Organs Both Signal their Age Status and Receive Age-status Information Via the Bloodstream

 

<< SNIP >>

 

Key points... Biological objects of different type and size are important... They communicate via the bloodstream...

 

Here's a recent post I made in a thread about F-C60-OO and Splenic Macrophages...

 

 

<< SNIP >>

 

The most widely believed explanations of the Baati study longevity benefit have something in common. They ignore key evidence from the study itself. The evidence is ignored because the explanations themselves cannot account for it. By definition, it must be presumed to be irrelevant to the longevity benefit.

 

What is ignored?

• "C60 concentrations reached the limit of solubility in spleens"
• There is a picture showing Splenic Macrophages engulfing F-C60 crystals

Now, it's true that the animals showing spleen accumulation weren't the ones with the longevity benefit. They were killed early in the study. Nevertheless, kmoody has confirmed that F-C60 accumulates in the Spleen and in the Liver.

 

Has a study showed that the Splenic Macrophage data is irrelevant to the longevity and tumor inhibition benefit? No...

 

Are there other studies demonstrating that Splenic Macrophages are important to increased survival odds and might be to cancer prevention? Yes...

 

turnbuckle... You appear to take other studies showing F-C60 accumulating in mitochondria seriously while ignoring where the Baati study actually found F-C60 accumulating. Have I missed something? Does your preferred explanation address F-C60 accumulation in the spleen. If not, why have you presumed to ignore that evidence?

 

A few key findings--of many that exist--are relevant here. Lots of details to explore

• The organ Origins of Tumor Associated Macrophages have been identified and the study "positions the spleen as an important extramedullary site, which can continuously supply growing tumors with these [cancer promoting macrophage and neutraphil] cells."
• Kevin Tracey and his teams have determined that "Intact Splenic Signaling" is required for Lifespan Benefit upon lethal inflammation intervention. The focus of that beneficial Splenic Signaling is NF-kB Cytokine Transcription Inhibition. And it's that Inhibition that underlies the emerging demonstrations of survival benefit when NF-kB is inhibited.
• F-60-OH has been shown to inhibit NF-kB Nuclear Translocation and hence inhibit Cytokine Transcription. BTW, that study finding means that All the survival curves shown in this thread are Within Topic Scope in any discussion of the F-C60-OO lifespan benefit.

In 2012, Tracey and his teams published a diagram showing the key biological objects underlying the survival benefit they've uncovered and, in one way or another, are demonstrated empirically here. All the biological objects shown are relevant to the explanation of the F-C60-OO lifespan benefit. (To keep this short, I won't address the Olive Oil and Intestine evidence.)

 

<< SNIP >>

 

 

Following up on the evidence above that the Spleen is a very significant organ origin of Tumor Associated Macrophages (TAMs), there's this...

 

Protein Sequence Analysis and Classification reveals that...

 

TGF-beta 1 mRNA levels in adult murine tissues indicates that expression is predominant in spleen, lung and placenta [PMID: 2628730].

 

TGF-B1 is a significant signaling pathway by which TAMs promote tumors...

• Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma

   

• Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-β1 signaling pathway

TAMs can be "Re-educated" by NF-kB Inhibition in a way consistent with the Tracey diagram above that highlights the importance of inhibiting NF-kB within Macrophages...

 

... When NF-κB signaling is inhibited specifically in TAMs, they become cytotoxic to tumor cells and switch to a “classically” activated phenotype... Targeting NF-κB signaling in TAMs also promotes regression of advanced tumors in vivo by induction of macrophage tumoricidal activity and activation of antitumor activity through IL-12–dependent NK cell recruitment.

Edited by HighDesertWizard, 16 January 2016 - 07:38 PM.

[HighDesertWizard]

The Tracey team that created the diagram in the last post only depicted what it had studied. But by adding a single graphic element representing the blood circulation system flow through the Spleen and Liver we can easily imagine additional hypotheses. Here's my hand-drawn, quick and dirty version of the Tracey study diagram above depicting the blood circulation flow...

 

 

 

We see above that the Spleen is a major organ origin of TAMs and TGF-B1... We also see that TAMs are a major trigger for tumor growth and spread as well as an increase in TGF-B1 expression.

 

Is there greater significance to these findings?

 

Irina Conboy is a leading Heterochronic Parabiosis scientist... Sew two mouse circulation systems together and the older mouse gets younger. Links...

• Drug perks up old muscles and aging brains
   
• At FightAging; A Look at Some of the Aging Research of Irina Conboy

Question: How does the older animal get younger?
Conboy's Approach and Answer... Search for Factors in the Blood that drive Aging... Her latest and greatest finding is that TGF-B1 is a Blood Factor worth taking a serious look at. And the approach is focused on development of chemicals that reduce aging related blood factors like TGF-B1...

 

A Better Question: What Biological Objects (aka, organs) the circulation flows through are setting the System Blood Factor Contexts impacting Aging?

 

The answer supported by evidence is clear...The Spleen is a highly probable source of the TGF-B1 in the blood circulation that Heterochronic Parabiosis studies have found to be a Aging Promoting Blood Factor in the blood of older study animals.

 

The implication is clear... Interventions that reduce TAM secretion of TGF-B1, namely, NF-kB Cytokine Transcription Inhibition of TAM Expression, reduces TGF-B1...

 

The implication is clear... NF-kB Cytokine Transcription Inhibition in the Spleen, perhaps along with other factors, is a significant in the findings of Heterochronic Parabiosis studies that find rising TGF-B1 levels implicated in Aging...

Edited by HighDesertWizard, 17 January 2016 - 06:04 PM.

[LeeYa]

Great thread, thank you HighDesertWizard!

 

This study provides another little piece to the puzzle:

 

 

 

 Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF production during endotoxemia. Peripheral administration of the acetylcholinesterase inhibitor galantamine significantly reduced serum TNF levels through vagus nerve signaling, and protected against lethality during murine endotoxemia. Administration of a centrally-acting muscarinic receptor antagonist abolished the suppression of TNF by galantamine, indicating that suppressing acetylcholinesterase activity, coupled with central muscarinic receptors, controls peripheral cytokine responses. Administration of galantamine to α7nAChR knockout mice failed to suppress TNF levels, indicating that the α7nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of galantamine. These findings show that inhibition of brain acetylcholinesterase suppresses systemic inflammation through a central muscarinic receptor-mediated and vagal- and α7nAChR-dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor can be utilized to suppress abnormal inflammation to therapeutic advantage.

 

Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway

http://www.sciencedi...889159108003000

[Never_Ending]

I new thought/hypothesis HDW:
 

The gut is an organ with one of the highest cell turnovers in the body.

This isnt surprising when you consider the vast number and array microbes/pathogens/toxins etc it has to keep isolated from the rest of the organism/body and the fact that one dies of septicemia within hours when it fails to do so.

Now as the gut has a high cell turnover it's likely that telomere length is shorter and stem cell turnover is high etc.
Perhaps what the vagus nerve is doing is signalling the rest of he system that the gut is getting older and less efficient at keeping pathogens and  Indoxyl Sulfate and P-Cresyl Sulfate etc out of the rest of the organism and that it's a good idea to increase TNF, NF-kB etc as a counter measure.

ie:  One big negative feedback loop that results in less telomerase, less stem cell activity etc and thus a more permeable gut and thus more need for NF-lb etc and thus less telomerase etc-etc...?

 

When you combine this with TNF/NF-kB etc upregulation from AGEs, the fact that we all live on bacteria 'shit' and don't seem to care what bacteria are taking said shit, perhaps one is close to 'why we age'.

???

 

It seems to me that aging is more a case of 'wiser' cells epigenetically compromising/adapted to prevent immediate demise, than older cells?

 

That would make sense yes. In some way I think the signs of aging is a self-protection mechanism, only in some ways though. The lack of mobility, the slowing down of metabolism etc. These can be seen as a way of conserving some biological integrity in the body(telomeres likely is one aspect). When people are young the body goes through accelerated cell turnover just like specific organs like you mentioned the gut has the same aspect. Things like telomerase and protective substances like many natural compounds(or synthetic) are restorative and act to maintain the body's integrity ....the result is the body will take longer to kick into that aging mode. The more of that delay the better.

 

Things like NF-kb is an example of something that originally serves to inflame and defend against foreign substances and pathogens but at the same time affects us badly over the long term.

 

Does this contradict the mouse study of fusing two mice? not really.  It's quite possible that the aged mouse received signals(via blood compounds) making it's body think that it has the "reserves" of a young mouse and starting to expend more, because during the fusion in some ways it DOES have. This is somewhat different from what the instinctive conclusion to seeing the study might be.

 

So the things people consume and environment can be used to help keep or even(possibly) restore the body's integrity , that would

still be a big part of aging prevention

Edited by Never_Ending, 29 January 2016 - 06:25 PM.

[sub7]

HighDesertWizard, you appear to be the thought leader on the Vagus Nerve/HRV/CAIP nexus, so is there a way to stimulate the nerve by electrical means or through supplementation?  If so, what do you suggest or recommend?  Thanks, - Rob 

 

I have the exact same question please

Anything we can do as of today through any sort of means to benefit from this mechanism?
 

[Santi]

I thought this was interesting. Headphones designed to stimulate the vagus nerve and increase your dopamine levels while you listen to music.

http://www.inquisitr...s-get-you-high/

[sub7]

I thought this was interesting. Headphones designed to stimulate the vagus nerve and increase your dopamine levels while you listen to music.

http://www.inquisitr...s-get-you-high/

 

Hmmm

Anything we can do at home with a similar 9 volt battery in a safe manner?

[Logic]

Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis

...The brain-gut axis is a bi-directional system of communication between the brain and the gastrointestinal tract, linking emotional and cognitive centres of the brain with peripheral control and function of the gut (Figure 1). Serotonin is a key element of this axis, acting as a neurotransmitter in the CNS and in the enteric nervous system that is present in the wall of the gut. In addition, serotonin is produced by endocrine cells and acts as a paracrine hormone in the gut and as an endocrine hormone, carried through the blood bound to platelets. Its role as a hormone acts to link the two ends of the brain-gut axis...

http://www.mdpi.com/...6643/8/1/56/htm

 

Tryptophan: ‘essential’ for the pathogenesis of irritable bowel syndrome?

Indolamine dioxygenase (IDO) is the key enzyme involved in the conversion of tryptophan in the intestine. The enzyme catalyses oxidation of tryptophan to kynurenine in a reaction that produces peroxide and gives rise to highly reactive and potentially harmful oxygen and hydroxyl radicals. The IDO reaction may therefore contribute to what is generally called oxidative stress [1,2]. Oxygen and hydroxyl radicals formed as a result of the IDO reaction will accelerate the oxidation of nitrogen monoxide (NO) to nitrite (NO2) and of ferrous iron compounds to ferric iron compounds. The reactive oxygen products have an antimicrobial effect, but may also harm mitochondria and lead to increased production of inflammatory cytokines (TNF-α, IL-6) [3,4] and be causally related to fatigue and pain hypersensitivity [5,6].

http://www.ncbi.nlm....les/PMC4266036/

 

Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function

...The kynurenine pathway also provides the precursors for the dietary supplement niacin, a collective term for nicotinamide and nicotinic acid. Under normal conditions, most of the tryptophan that enters the oxidative pathway is converted to CO2 and water in the glutarate pathway. Only if this branch of the pathway is saturated, NAD becomes a major product of metabolism.3 Although metabolites of the glutarate pathway are present in many tissues, including the intestine, NAD synthesis is only possible in the liver, because this is the only organ that possesses all the necessary enzymes.28...

 

...TDO exclusively accepts tryptophan as substrate, IDO has a broader specificity and can also take 5-HTP, 5-HT and tryptamin.29 The expression of IDO increases in response to infection and inflammation, with interferon-γ being the strongest stimulator. Mononuclear cells that synthesize IDO reduce extracellular tryptophan concentration so that adjacent T-cells, which depend on tryptophan from the extracellular environment, are unable to activate and proliferate upon encountering antigens. Therefore, IDO might play a role in preventing the initiation of autoimmune disease by enforcing T-cell tolerance through suppressing their proliferation.28 Hence, high local expression of IDO by mononuclear cells may represent an anti-inflammatory and immunosuppressive mechanism tempting to counterbalance tissue damage.30 This mechanism could be involved in intestinal pathophysiology, as IDO expression is markedly induced in lesional colonic biopsies of inflammatory bowel disease (IBD) patients30 and increased IDO activity has been observed in patients with celiac disease31 and diverticulitis.32 A similar IDO-based intrinsic immunoescape mechanism is probably employed by colon tumour cells.33

Besides through the regulatory effect of IDO on T-cells and immune function, inflammatory responses in the ENS and the gastrointestinal tract related to the kynurenine pathway can also be based on a sensitive balance between the pro-inflammatory, excitotoxic quinolinic acid and the anti-inflammatory, neuroprotective kynurenic acid...

 

...The wide range of bacterial species capable of producing indole include E. coli, Proteus vulgaris, Paracolobactrum coliforme, Achromobacter liquefaciens and Bacteriodes spp. The formation of indole is catabolyzed by the enzyme tryptophanase, which is inducible by tryptophan and repressible by glucose in most bacteria.39 By-products of this conversion are pyruvate, which can be used in fermentation or respiration reactions, and ammonia, which can have potentially toxic effects on the intestinal epithelium. High protein diets are therefore able to induce bacterial tryptophanase activity, which in turn results in overproduction of indole and other compounds that can thereby reach toxic concentrations in the colon.39...

 

...Some bacterial products are toxic to other microbiota, and this provides competitive advantage for the producers. Some indolic compounds are known to have bacteriostatic effect on Gram negative enterobacteria, especially within the genera Salmonella and Shigella.39 The increased urinary excretion of indolic compounds reflects variations in gut microbiota composition in relation to nutritional competition. For instance, indolyl acetic acid has been reported to inhibit the growth and survival of Lactobacilli, and specifically L. paracasei.44 Also, indolyl propionic acid has been shown to be a powerful antioxidant, and is currently being investigated as a possible treatment for Alzheimer’s disease.40...

 

...Recent studies suggest the involvement of tryptophan metabolic routes in the pathogenesis of several common gastrointestinal disorders, such as IBD, IBS, celiac disease and diverticulitis.

A common mechanism could possibly be the upregulation of IDO. Elevated kynurenine and kynurenine/tryptophan ratios, indicative of increased IDO activity, have been observed under inflammatory conditions, such as IBD, which result in altered T-cell proliferation and survival.30 Such a mechanism could also account for altered tryptophan catabolism in IBS patients, as studies have reported immune activation and pro-inflammatory cytokine production in IBS.48

Moreover, upregulation of IDO induces a metabolic shift, which is presumably also involved in the pathogenesis of IBS. Recent studies have shown that both females49 and males50 with IBS have increased kynurenine concentrations compared to controls. Furthermore, a positive correlation was found between IBS severity and the kynurenine/tryptophan ratio. Those with severe IBS symptoms have increased shunting of tryptophan along the kynurenine pathway which contributes to the abnormal serotonergic function.49 Altered serotonergic conditions have directly been associated with malfunction of the intestine in IBS.

Besides a role in the pathological states of the intestines, serotonin has also been suggested to be involved in the pathogenesis of non-alcoholic steatohepatitis. Degradation of serotonin by MAO also yields ROS as byproducts. Increased uptake and catabolism of serotonin in the liver therefore leads to overproduction of ROS resulting in hepatocellular injury by mitochondrial damage and inflammation.2 In recent years, the understanding of the (patho)physiological role of tryptophan metabolites, mostly serotonin, in the gastrointestinal tract has increased significantly.1,2,31,34,35,49 Nevertheless, further investigation will be needed to assess the biological role of other tryptophan derivates. This will lead to a better comprehension of the pathogenesis of the most common causes of gastrointestinal morbidity...

 

...Probiotic supplementation, for instance, can aim to replace or reduce the number of potentially harmful proteolytic E. coli and Clostridia producing toxic tryptophan breakdown products by enriching populations of gut microbiota that have more advantageous metabolic activity. Future activities will be directed to influence the gut microbiota in a targeted way, ideally by enhancing beneficial effects and minimizing adverse effects...

http://onlinelibrary...09.01370.x/full

.

 

Edited by Logic, 25 February 2016 - 11:11 AM.

[HighDesertWizard]

 

There's a puzzle in the literature evidence reviewed thus far about the relationship of NF-kB Activation/Translocation Inhibition and Telomerase Expression. I won't take the time now to provide a link for the statements below. I believe literature references to each of them exists up thread. Let's recap the puzzle elements...
 
<< SNIP >>

• The post referenced in the quotation above contained a couple graphic figures. To understand what follows below, you'll need to have digested what's going on in those pics. You will also need to have digested those posts about p50 and p65 awhile back. [Logic: Your post immediately above triggered great feeling. I feel often I'm posting into some void. It's a great feeling to know someone is paying attention! :-) ]
• I'm out on the edge of my current knowledge and capability here with this post. In this post, I'm thinking and asking questions I believe are important out loud and online. My questions may be stupid to ask. :-)
• Asking these questions will lead to answers but I have no idea what the answers will look like. That's what makes it fun...
• Some study, perhaps already published, or soon to be published, will speak to the issue highlighted in the table below.

 

 

Regarding the bottom left-most cell in the figure above, I found a diagram from a Kevin Tracey study published in 2009 that was hidden behind a paywall until recently. The full text study is entitled Reflex control of immunity. Notice that Tracey directly addressed the question raised by that figure above posted 19 months ago back in 2009, namely...

 

Question: What's the pathway by which NF-kB Translocates to the nucleus, providing p50 and p65 to the Telomerase holoenzyme, but is inhibited from Transcribing Inflammatory Cytokines...

 

Answer: the a7 nAchR via the JAK2 / STAT3 pathway...

 

 

Edited by HighDesertWizard, 29 June 2017 - 03:29 AM.

[HighDesertWizard]

It's been a while since I posted here... It dawned on me in December 2015, that The Inflammatory Reflex was a bigger deal than I had imagined... Contracted major writer's block...

 

Didn't stop doing research, but couldn't write...

 

Also, about that time, I upped my game of triggering The Inflammatory Reflex (aka, the Cholinergic Anti-Inflammatory Reflex) with a significant dosing regimen. Agonists of the M! Muscarinic Receptor and other substances that enhance it... A few months ago, I got blood testing done...

• ESR = 0
• CRP < 0.2
• Mostly telling... My lifelong high Lp(a), aka, the widowmaker LDL, was in the normal range for the first time ever. Lp(a) is driven by IL-6 and I'm happy about that.

Also, I braced myself and got my Teloyears measured at Teloyears (Elizabeth Blackburn is a partner). Braced myself because I had an MI 20 years ago at 42 yo. And 5 years later, at 47, I had a 3X CABG. As I waited for the test results, I reasoned that if I could just get to an average length for my age, I'd be ok with that, because, at least, I had pulled even. Short Telomere length is associated with cardiac related risk...

• Telomeres and Telomerase in Cardiovascular Diseases
• Telomere Length Predicts the Life Expectancy of Patients with Heart Disease

I cannot prove that my test result below is a result of my deliberate triggering of the CAIP/TIR... I have not done TA-65, and no one among my family and friends thinks of me when they imagine who they know with an incredibly great diet and exercise regimen... So I think I'll continue doing what I've been doing...

 

 

Edited by HighDesertWizard, 29 June 2017 - 04:17 AM.

[HighDesertWizard]

A 2012 study demonstrated that key Cholinergic Anti-Inflammatory Pathway (CAP) elements were required for the protective effect of pretreatment with electroacupuncture at a specific acupoint that affects the efferent neural circuits of the autonomic nervous system. These required elements were the same that a Tracey study had earlier highlighted, namely... Central Muscarinic Receptor, Vagus Nerve, Peripheral Nicotinic Receptor, and Spleen

 

I've posted the Meier-Kaplan Survival Curve figures here.

 

In a 2017 literature review, Kevin Tracey provided a different slant on a wiring diagram of the CAP that includes this new finding that at least one specific electro-acupunture point is wired to Central Muscarinic Receptors posted about above. That diagram appears below...

 

Edited by HighDesertWizard, 02 July 2017 - 01:06 AM.