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Longevity, Morbidity, and Mortality: The TNF Dimension

longevity morbidity mortality tnf tumor necrosis factor

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#1 wccaguy

  • Location:Chicago, IL

Posted 13 June 2012 - 12:30 AM


I've become convinced that TNF is a critical piece of the puzzle for understanding Human Longevity, Morbidity, and Mortality.

I began more seriously considering the role of Tumor Necrosis Factor (TNF) in Longevity, Morbidity, and Mortality as a result of participating in the Buckyballs in Olive Oil double lifespan of Wistar Rats thread. I had earlier become familiar with TNF as a result of a long time spent doing research on the 5-Lipoxygenase (aka, 5-LO or 5-LOX) Inflammatory Pathway, but I hadn’t looked at it specifically with Longevity in mind.

I hadn’t realized how much evidence, explicit and implicit (through multiple study comparison), exists about the importance of TNF. I’ll bet you haven’t either. If more people knew about this evidence, someone would have established a Longecity thread about it long ago. But they haven't and, in fact, they couldn't, because the evidence has only recently become clear enough to see...

The objective here, then, is to establish a Forum Thread to post about, discuss, and debate research related to Tumor Necrosis Factor. Let me be clear. I’m just learning about it myself, but I've learned enough to want to become an expert about it. Maybe you will too.

I’m kicking this thread off by providing multiple layers of evidence showing how critical TNF is to Longevity, Morbidity, and Mortality, including, relatively soon, at least...
  • gene related evidence
  • Extreme Longevity study evidence
  • evidence related to the 5-LO Inflammatory Cascade literature
  • Cholinergic Anti-Inflammatory Pathway evidence
  • insulin resistance study evidence
  • tumor study evidence
  • and others TBD
If you want to review this evidence about TNF's importance quickly, go ahead and skip to post #2 now. You can always come back to review the background material below about TNF later.

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

TNF Background Information

Wikipedia Links

http://en.wikipedia....necrosis_factor (notice a change of name)
http://en.wikipedia....is_factor-alpha

The Paradoxical Role of TNF for Health

A fundamental point about TNF is that it plays a positive role in health through its activation by the Immune System. But it is an Inflammatory Cytokine also so that, once its role in attacking invaders has been accomplished, it becomes a negative factor in health because it attacks tissue. TNF activation is among the most important elements driving the diseases that kill most of us off these days, what are now called Auto-Immune Diseases.

Here’s a study abstract about this paradoxical role...

'>http://www.ncbi.nlm.nih.gov/pubmed/20712570']The dual role of tumor necrosis factor (TNF) in cancer biology

Tumor necrosis factor (TNF) is a cytokine with well known anticancer properties and is being utilized as anticancer agent for the treatment of patients with locally advanced solid tumors. However, TNF role in cancer biology is debated. In fact, in spite of the wealth of evidence supporting its antitumor activity, the cascade of molecular events underlying TNF-mediated tumor regression observed in vivo is still incompletely elucidated. Furthermore, some preclinical findings suggest that TNF may even promote cancer development and progression. With this work we intend to summarize the molecular biology of TNF (with particular regard to its tumor-related activities) and review the experimental and clinical evidence currently available describing the complex and sometime apparently conflicting relationship between this cytokine, cancer biology and antitumor therapy. We also propose a model to explain the dual effect of TNF based on the exposure time and cytokine levels reached within the tumor microenvironment. Finally, we overview recent research findings that might lead to new ways for exploiting the anticancer potential of TNF in the clinical setting.

→ source (external link)

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#2 wccaguy Re: Longevity, Morbidity, and Mortality: The TNF Dimension

  • Location:Chicago, IL

Posted 13 June 2012 - 01:46 AM

I did not complete that post above before I ran out of time to edit it. Here is a more complete version. I hope a moderator can delete that post above, the 2nd post in the thread. thx.

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

The objective of this post is to provide Gene-level evidence that TNF has associations, in multiple and different ways, to Genes that are thought to play a role vis-a-vis Longevity.

It contains a draft list of Longevity-related genes, one study link showing that the gene is thought to be important for aging, and one study link showing that TNF has some association with the gene. I haven't attempted to provide a link to the study which is the most important to either association... The only point here is to say that, in some way, through multiple associations with Genes, TNF appears to be important.

In this thread, I hope we can figure out more about how it is important...

Longevity-Related Gene - TNF Association Study Evidence

FOXO - Longevity
FOXO - TNF

CETP - Longevity
CETP - TNF

SIRT1 - Longevity
SIRT1 - TNF

Adiponectin - Longevity
Adiponectin - TNF

Klotho - Longevity
Klotho - TNF

C1Q - Longevity
C1Q - TNF

P53 - Longevity
P53 - TNF

IL-6 - Longevity
IL-6 - TNF

IGF1 – Longevity
IGF1 - TNF

AKT1 - Longevity
AKT1 - TNF

I hope I got all those links right. Again, the point here is to demonstrate the association of TNF to some genes that are thought to have an effect on Longevity.

More posts soon about other "layers of evidence" related to the importance of TNF.

Edited by wccaguy, 13 June 2012 - 01:59 AM.

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#3 wccaguy Re: Longevity, Morbidity, and Mortality: The TNF Dimension

  • Location:Chicago, IL

Posted 13 June 2012 - 11:16 AM

A break from presenting those layers of evidence to show a subtlety of the TNF relationship to different mTOR receptor studies that are hot off the press.

First, take a look at this from 2012-03-12...

'>http://www.sciencedaily.com/releases/2012/03/120329141529.htm']Duality of Longevity Drug Explained

The study suggests that molecules that specifically inhibit mTORC1 may combat age-related diseases without the insulin-resistance side effect, which can predispose people to diabetes. Senior author Joseph A. Baur, PhD, assistant professor of Physiology, Perelman School of Medicine, University of Pennsylvania, and colleagues at the Whitehead Institute for Biomedical Research and Broad Institute, Massachusetts Institute of Technology, in Cambridge, MA, describe their work in this week's issue of Science. Baur is also a member of Penn's Institute for Diabetes, Obesity, and Metabolism.

"The hope is that in the future, we will be able to develop molecules that target mTORC1 specifically, separating out the beneficial effects of rapamycin on aging and disease, and leaving behind the insulin-resistance side effect," says Baur. "Our results demonstrate that reduced mTORC1 signaling is sufficient to extend lifespan and mTORC2 signaling has profound effects on metabolism," says co-first author Lan Ye, PhD, postdoctoral fellow in the Baur lab.

"Our findings indicate that mTORC2 may be an important player in the pathogenesis of type 2 diabetes and metabolic syndrome."

→ source (external link)

Second, notice that TNF activity is related to mTORC1 but not mTORC2 from 2012-05-16...

Tumor necrosis factor-alpha (TNF-α)-mediated in vitro human retinal pigment epithelial (RPE) cell migration mainly requires Akt/mTOR complex 1 (mTORC1), but not mTOR complex 2 (mTORC2) signaling

What does it mean in detail? Dunno. But I want to find out.

Edited by wccaguy, 13 June 2012 - 11:39 AM.

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#4 wccaguy Re: Longevity, Morbidity, and Mortality: The TNF Dimension

  • Location:Chicago, IL

Posted 14 June 2012 - 05:32 AM

The importance of TNF struck me recently after I followed up on a hunch that Extreme Longevity Population Studies might indicate it's important. I think the Population Studies show that a statistic computed about the Human Heartbeat is the most important one for thinking about Extreme Longevity. That statistic is called Heart Rate Variability. Here's a Review from 2003 that describes what HRV is and how it might be related to TNF.

What Is “Heart Rate Variability” and Is It Blunted by Tumor Necrosis Factor?

I'll be getting around to making a single post in this thread about the work of Kevin Tracey and others about the CAIP (Cholinergic Anti-Inflammatory Pathway) sometime soon. And then the mechanism underlying the relationship of HRV to TNF will be clearer. In the meantime, I earlier established a thread about the CAIP here if you'd like to explore that now in more detail.

I wanted to post that particular review above as a reminder of how primitive the science around HRV looked before the science of the CAIP appeared on the scene just about the time of that Review. The work of Kevin Tracey transformed our view of the HRV/TNF subject matter and that's why, IMHO, he deserves and will eventually be awarded a Nobel Prize in Medicine.

I've provided links to different kinds of studies below to highlight the importance of the role of TNF even at this high level Population Study Level. I expect the associations shown below to evolve over time like the Gene/TNF associations posted above. I will update the data over time in this thread.

Note... There are multiple studies per association below. I'm not certain that I have chosen the best study documenting each association. I'll be pleased if anyone finds fault with any particular study choice. It will merely cause me to work to find a better one.

Study Variable Associations

Extreme Longevity (EL) Studies
Higher HRV - Extreme Longevity
Positive Emotions - Extreme Longevity
Exercise - Extreme Longevity
Calorie Restriction - Extreme Longevity

Inverse Relationship - Immune System Cytokine (TNF) with HRV Studies
Higher TNF - Lower HRV
Higher HRV - Reduced TNF
Higher HRV - Reduced Inflammatory Markers - Review

EL Variable - Vagus Activation/HRV Studies
Vagus/CAIP Activation ==>> Triggers Higher HRV
Positive Emotions - Increased “Vagal Tone”
Exercise - Vagus Activation
Calorie Restriction - Higher Parasympathetic Activation/HRV

Edited by wccaguy, 14 June 2012 - 05:52 AM.

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#5 wccaguy Re: Longevity, Morbidity, and Mortality: The TNF Dimension

  • Location:Chicago, IL

Posted 22 June 2012 - 01:09 AM

Here's more information about TNF and its role in various types of amyloidosis. I didn't know, until niner mentioned it below, that amyloidosis becomes more and more of a problem during Extreme Longevity.

And, on this dimension, also, TNF appears to play a critical role...


... Meanwhile, humans that make it to the age of 110 inevitably have a high level of systemic amyloidosis that contributes to a lot of mortality & morbidity, so maybe we should start looking for interventions that prevent it. As fate may have it, resveratrol is reported to be an inhibitor of several important types of amyloidosis. Whether or not it occurs at human-relevant dosage I am not aware.


Just a smattering of Amyloidosis studies...
----------------------------------
vis-a-vis TNF

Long-term TNF-α Blockade in Patients with Amyloid A Amyloidosis Complicating Rheumatic Diseases

Autosomal dominant periodic fever with AA amyloidosis: tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a Turkish family

Anti–Tumor Necrosis Factor Therapy in Fifteen Patients With AA Amyloidosis Secondary to InflammatoryArthritides

Amyloidoses

Anti-TNF treatment in secondary amyloidosis

Effective Anti-TNF-α Therapy Can Induce Rapid Resolution and Sustained Decrease of Gastroduodenal Mucosal Amyloid Deposits in Reactive Amyloidosis Associated with Rheumatoid Arthritis

Ankylosing spondylitis-related secondary amyloidosis responded well to etanercept: a report of three patients

AA Amyloidosis

Tumor Necrosis Factor-α Gene Polymorphisms in FMF and Their Association With Amyloidosis

Anti-TNF agents in familial Mediterranean fever: report of three cases and review of the literature

----------------------------------
vis-a-vis 5-Lipoxygenase

Involvement of 5-lipoxygenase activating protein in the amyloidotic phenotype of an Alzheimer’s disease mouse model

Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice

5-Lipoxygenase gene disruption reduces amyloid-β pathology in a mouse model of Alzheimer’s disease

----------------------------------
Many more products and processes of the 5-LO pathway could also be listed...


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#6 solarfingers Re: Longevity, Morbidity, and Mortality: The TNF Dimension

  • Location:California

Posted 25 September 2013 - 04:19 PM

I did not complete that post above before I ran out of time to edit it. Here is a more complete version. I hope a moderator can delete that post above, the 2nd post in the thread. thx.

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

The objective of this post is to provide Gene-level evidence that TNF has associations, in multiple and different ways, to Genes that are thought to play a role vis-a-vis Longevity.

It contains a draft list of Longevity-related genes, one study link showing that the gene is thought to be important for aging, and one study link showing that TNF has some association with the gene. I haven't attempted to provide a link to the study which is the most important to either association... The only point here is to say that, in some way, through multiple associations with Genes, TNF appears to be important.

In this thread, I hope we can figure out more about how it is important...

Longevity-Related Gene - TNF Association Study Evidence

FOXO - Longevity
FOXO - TNF

CETP - Longevity
CETP - TNF

SIRT1 - Longevity
SIRT1 - TNF

Adiponectin - Longevity
Adiponectin - TNF

Klotho - Longevity
Klotho - TNF

C1Q - Longevity
C1Q - TNF

P53 - Longevity
P53 - TNF

IL-6 - Longevity
IL-6 - TNF

IGF1 – Longevity
IGF1 - TNF

AKT1 - Longevity
AKT1 - TNF

I hope I got all those links right. Again, the point here is to demonstrate the association of TNF to some genes that are thought to have an effect on Longevity.

More posts soon about other "layers of evidence" related to the importance of TNF.


I think it is interesting that these can be dealt with by supplementation:

FOXO - EVOO
CETP - Bilberry Extract
SIRT1 - Resveratrol
Adiponectin - Raspberry Ketones
Klotho - Phosphate and vitamine D reduction. (There seems to be doubt that Klotho is involved in longevity)
C1Q - C60-OO
P53 - Resveratrol
IL6 - Omega-3
IGF1 - EVOO
AKT1- Resveratrol
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#7 wccaguy Re: Longevity, Morbidity, and Mortality: The TNF Dimension

  • Location:Chicago, IL

Posted 25 September 2013 - 04:51 PM

I think it is interesting that these can be dealt with by supplementation:

FOXO - EVOO
CETP - Bilberry Extract
SIRT1 - Resveratrol
Adiponectin - Raspberry Ketones
Klotho - Phosphate and vitamine D reduction. (There seems to be doubt that Klotho is involved in longevity)
C1Q - C60-OO
P53 - Resveratrol
IL6 - Omega-3
IGF1 - EVOO
AKT1- Resveratrol


solarfingers... I agree with you about this...

I haven't gotten around to it yet but, BTW, TNF and the other Cytokines play a key role in Negative (for Health) Epigenetic Change...
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#8 nowayout Re: Longevity, Morbidity, and Mortality: The TNF Dimension

  • Location:Earth

Posted 25 September 2013 - 05:21 PM

Well, if TNF is involved in longevity, then we are essentially already running a large longevity experiment considering the hundreds of thousands of people (including me) who are on cytokine inhibitors for inflammatory conditions, including TNF blockers such as Enbrel and Humira, but also blockers of other cytokines.

Of course, these patients have underlying conditions that are significant confounders, but some anti-aging benefits have already been observed, such as a large reduction in Alzheimer's risk for patients on TNF blockers.

Edited by nowayout, 25 September 2013 - 05:25 PM.

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#9 solarfingers Re: Longevity, Morbidity, and Mortality: The TNF Dimension

  • Location:California

Posted 25 September 2013 - 05:45 PM

I guess the question is can we block all TNF? Will the right combination of supplements effectively prevent it from occurring in the body? So many questions...
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#10 nowayout Re: Longevity, Morbidity, and Mortality: The TNF Dimension

  • Location:Earth

Posted 25 September 2013 - 05:52 PM

No, TNF is essential for healthy functioning of the human body. You don't want to block it all.

Edited by nowayout, 25 September 2013 - 05:53 PM.

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#11 niner Re: Longevity, Morbidity, and Mortality: The TNF Dimension

  • Location:Philadelphia

Posted 25 September 2013 - 05:56 PM

I guess the question is can we block all TNF? Will the right combination of supplements effectively prevent it from occurring in the body? So many questions...


Yes, you can block it- that's what nowayout was talking about in the previous post. However, there are consequences. TNF is part of your immune system, and blocking it will make you more susceptible to infection. That is usually a good tradeoff when you have a disease that is characterized by excess TNF, but otherwise may not be. These are very expensive therapies involving monoclonal antibodies. I don't think there's anything in the supplement world that will move the needle very much on TNF. I've not heard any reports of significant life extension from TNF blockade.
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#12 solarfingers Re: Longevity, Morbidity, and Mortality: The TNF Dimension

  • Location:California

Posted 25 September 2013 - 06:10 PM

It would seem that nature would have provided some way to deal with excessive TNF...
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#13 wccaguy Re: Longevity, Morbidity, and Mortality: The TNF Dimension

  • Location:Chicago, IL

Posted 25 September 2013 - 06:37 PM

nowayout is right... We don't want to block it. It's essential for proper Immune Function...

We want to Optimize its Expression...

The body has an Innate Anti-Inflammatory process recently discovered and named by Dr. Kevin Tracey. I've summarized a good deal of his work here.

The Vagus Nerve, Heart Rate Variability, Cholinergic Anti-Inflammatory Pathway Nexus

IMHO, Kevin Tracey's work is among the most important new discoveries of the last 15 years.

For example, here's a link to one of this papers that I hadn't seen at the time I established the thread at the link above.

Understanding Immunity Requires More than Immunology

A couple of things, Niner...

Tracey discusses the relationship of Heart Rate Variability and TNF suppression a great deal in his work. HRV, of course, is subject to manipulation. In this thread, and in that other referenced thread, I provide some of the evidence about HRV and longevity.

In that last link, Tracey discusses the role of the Spleen in TNF generation a great deal. You'll recall that we've had this discussion before vis-a-vis that Olive Oil/C60-Fullerene study a while back... As I recall it, among the pics in that study were macrophages in the Spleen that had captured Fullerenes... Important to the study outcome? Dunno...

Edited by wccaguy, 25 September 2013 - 06:58 PM.

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