635 replies to this topic

[HighDesertWizard]

With P < 0.05, there is only a barely significant correlation between HRV and surviving past 100. That says nothing about causality. The fact that HRV does an about face in late life doesn't mean it's causal of long life; it could just as easily mean that aging causes HRV. There is a lot of evidence that olive oil is good for you, and that the polyphenolic content is mainly responsible. (I'm personally a big fan, and have five liters of a great Piqual in the closet.) Still, I don't know of any evidence that olive oil alone can cause the sort of life extension reported by Baati. Given that, I'd rank the likelihood of explanation as Error > polyphenols > HRV. This could still mean that the combination of polyphenols and lipid-induced CAIP effects are at least parts of the explanation, assuming error is ruled out. To test if CAIP is possible as the primary explanation, rats could be dosed with olive oil that had been stripped of polyphenols.

I can tell from your reply that you aren't acquainted with the Vagus-CAIP-HRV literature. You wouldn't have written what you did if you were.

That literature shows that the efferent Vagus Nerve causally triggers both Higher HRV and the anti-inflammatory acetylcholine release that modulates an overexpressed cytokine Auto-Immune Reponse. You suggest it's only an association. That's not what the literature shows.

Moreover, low HRV is profoundly associated with most of the most serious disease incidence. And with Kevin Tracey's work, we now know why: Low HRV is correlated with no or little Innate Anti-Inflammatory CAIP activity vis-a-vis overly expressed Immune System Cytokines.

I think Tracey is going to win the Nobel Prize in Medicine partly because his work is so "left field" that the evidence takes a lot of people by surprise. After reviewing and digesting it, the first response is: How did I not know this? How could we not have known?

The way to test to see if the Vagus is important is to dose two groups of rats with C60/Olive Oil, with one group having a vagotomy before the dosing begins.

Edited by wccaguy, 01 June 2012 - 01:34 PM.

[Turnbuckle]

et tu, Turnbuckle?

Does it feel "out of left field" because you've never heard of it? I completely understand that feeling. I felt the same way late last year. But then I actually looked at the studies. I recommend starting with the 2007 Review of the Literature... If you have looked at the studies, do you dispute their validity? If so, which one and how? Details...

We live in an age when more and more serious diseases that kill us off before 100 are understood, at least in part, to be Auto-Immune diseases. And the CAIP appears to be the key mechanism modulating the cytokine immune response... The Vagus-HRV-aging studies I've posted are consistent with the argument that individuals with modulated immune responses would experience, in general, more extreme longevity. How, specifically, is that argument coming out of left field?

I'm merely suggesting that Auto-Immune processes of the Vagus-CAIP might be important and that these processes might be important in explaining the Baati study result. I'm not saying I know. I'm merely saying it could be important. Experiments could determine if it is.

Final question... Is this "vagus stuff" more or less left field than niner's suggestion, playful? or serious?, just yesterday that Baati et al might have screwed up the Olive Oil data and other study data in some serious way?



8-)

The effect is small, barely significant, and most likely due to exercise. Those that live past a certain point aren't those just sitting on the sofa.

We conclude that physical exercise is an important tool to prevent and reduce cardiovascular autonomic changes associated with age. Studies have shown that regular exercise improves baroreflex sensitivity and heart rate variability, increases parasympathetic outflow, and decreases sympathetic outflow, thereby reducing cardiopathies related to age.

http://www.ncbi.nlm....49/?tool=pubmed

Not exactly earthshaking, but it should be clear that exercise is the cause, longevity is the effect, and heart rate variability merely a marker. If you could increase HRV by some other means, treating the symptom rather than the disease in other words, the effect on longevity would likely not be there.

[HighDesertWizard]

The effect is small, barely significant, and most likely due to exercise. Those that live past a certain point aren't those just sitting on the sofa.

Not exactly earthshaking, but it should be clear that exercise is the cause, longevity is the effect, and heart rate variability merely a marker. If you could increase HRV by some other means, treating the symptom rather than the disease in other words, the effect on longevity would likely not be there.

Well, sure, except...

• The Mediterranean diet is significantly associated with longer life, apart from exercise... And, coincidently, Olive Oil is important to it and Olive Oil triggers the Vagus...

• Hot off the press just this week, Positive Emotions are significantly associated with centenarians... And, coincidently, Positive Emotions trigger the Vagus...

• Why is stress such a problem for health? It increases the Immune Response and reduces parasympthetic nervous system actiivity (aka reduces vagal tone). Hence, the cytokines generated by the Immune System are not countered by the anti-inflammatory CAIP.

You and niner are both smart. Smarter than I am. But neither of you is familar with the literature about the Vagus-CAIP-HRV. It's NOT just exercise...

The CAIP triggers, through the efferent Vagus Nerve, an anti-inflammatory response to overly expressed immune system generated cytokines. It's THAT cytokine response that triggers "auto-immune diseases." That same efferent Vagus Nerve signal drives higher HRV.

Edited by wccaguy, 01 June 2012 - 02:08 PM.

[Turnbuckle]

"Olive Oil triggers the Vagus..."

Even if it does, what is the mechanism by which a few doses of olive oil and/or C60 could permanently stimulate it?

[maxwatt]

I agree. This Vagus stuff is very left field. In the meantime, we can rejoice that the two oldest people in the world until recently (both over 120) credited their longevity in part to olive oil.

I agree. Not that HRV isn't correlated to longevity, but correlation does not imply causation.

[HighDesertWizard]

Didn’t get much sleep last night and I’m home and back out the door for the evening... I haven’t read the posts since this morning and won’t again until tomorrow.

MaxWatt... It’s been buggin’ me all day. You may or may not have called me on my “enigma” comment. I deserve to be called on it. I was overreaching. I believe the CAIP is important here but that doesn’t diminish the importance of the polyphenols. Sooo.. I feel chastened about my comment and wanted to acknowledge it. That said, I’m not especially sorry because these kinds of discussions can lead to overreaching and overreaching can also be a good thing sometimes. 8)

Before I head out, I do want to stir the pot a bit with another, more nuanced, but I think non-trivial, Hypothetical Explanation puzzle piece...

Background

For several days now, I’ve been thinking that one Hypothetical Explanatory Path has been leading straight to TNF (Tumor Necrosis Factor) as an essential element of the Explanation.

• You’ll recall from one of my posts about the CAIP that the key Immune System Cytokine that the Vagus-triggered CAIP suppresses is TNF. (I believe I posted the study Figure from Kevin Tracey’s Review 2007 in this thread or that CAIP thread I established in Aging Theories.)

• You’ll recall, from Tracey2007, that the key body organ that the systemic release of TNF takes place from is the spleen. The spleen has a connection to the Vagus Nerve, an Afferent connection I’m recalling vaguely...

• You’ll recall from Baati 2012 that the rat spleens had the most, but still trivial amount of, C60 in them of any organ, after 8 days, I believe... (I’m working from memory here.)

• You’ll recall from Baati that most of the control group died of tumors.

• TNF is implicated in tumor growth, and I believe IL-6 is as well, through angiogenesis. (Remember that William Li video I posted a while back?)

• And, thanks to the data points you provided Turnbuckle, I’ve found evidence that TNF is implicated in hair loss, skin aging, and muscle dysfunction (perhaps even in canines).

So all these ideas, along with stronger/weaker study evidence, has been rolling around in my head for a few days and I finally got around to the right Google Scholar query pair... “C60 immune”... And bang... Out it popped... Here’s the puzzle piece... I’m clear there is an unpredicted/unexplained nuance... That C60 served as a TNF agonist and not an antagonist.... Gotta go...

Immunostimulatory properties and enhanced TNF- α mediated cellular immunity for tumor therapy by C60(OH)20 nanoparticles

Publications concerning the mechanism of biological activity, especially the immunological mechanism of C60(OH)20 nanoparticles, are relatively limited. However, the structure and characteristics of this carbon allotrope have been widely investigated. In this paper, we have demonstrated that water-soluble C60(OH)20 nanoparticles have an efficient anti-tumor activity in vivo, and show specific immunomodulatory effects to the immune cells, such as T cells and macrophages, both in vivo and in vitro. For example, C60(OH)20 nanoparticles can increase the production of T-helper cell type 1 (Th1) cytokines (IL-2, IFN- γ and TNF-α), and decrease the production of Th2 cytokines (IL-4, IL-5 and IL-6) in serum samples. On the other hand, C60(OH)20 nanoparticles show almost no adverse effect to the viability of immune cells in vitro but stimulate the immune cells to release more cytokines, in particular TNF- α, which plays a key role in the cellular immune process to help eliminate abnormal cells. TNF- α production increased almost three-fold in treated T lymphocytes and macrophages. Accordingly, we conclude that C60(OH)20 nanoparticles have an efficient anti-tumor activity and this effect is associated with an increased CD4+/CD8+ lymphocyte ratio and the enhancement of TNF- α production. The data suggest that C60(OH)20 nanoparticles can improve the immune response to help to scavenge and kill tumor cells.

Edited by wccaguy, 01 June 2012 - 11:34 PM.

[Metrodorus]

I too have been doing much thinking on mechanisms of action, having read quite a lot of the literature that covers the topic.

We have two theories of ageing here to consider - the mitochondrial theory of ageing, and oxidation.

To some extent they are connected.

I do think the olive oil is important - it provides a vehicle for the fullerene to be be absorbed - either as a solute or as lipo-fullerne molecule. Olive oil alone also has its own mitochodrial protective effects, that may be amplified by the fullerene:
http://www.springerl...154m44j3u51137/
http://www.agamfec.c...nsenso_0559.pdf (albeit a biased source)
http://www.ncbi.nlm....pubmed/17243080

Two mechanisms have been proposed in the literature - one the the fullerene acts as a physical shield to the complexes of the mitochodria. This would then have a knock on effect on all the dependent cellular processes.

The other proposed mechanism is a direct catalytic action on complexes on the electron transport chain....with the same ultimate result - decreased damage to the mitochondria, resulting in overall increased lifespan.

We also know that fullerene alone is protective of cartilage, and one, presumes, of other tissues with which it comes into contact.

It would be the syngergy of these protective factors across multiple organs that would result in the increased lifespan that has been previously observed in the mouse study, and now in this rat study.

Add to the mix the observed anti-viral effects of fullerene and the proposed anti-carcinogenic pathways, we have multiple positive effects from a single intervention.

Edited by Metrodorus, 02 June 2012 - 01:26 AM.

[PWAIN]

In another thread, AgeVivo says:

Following the buckyball study I contacted the authors of that incredible paper (rats lived up to 54 months, with errors in the lifespan curves in the paper, followed by long discussions) to know if I could test it at home on my mice, ratger than letting they die from aging without any scientific impact.

This is really bothering me now as I am starting to suspect outright fraud now. How do you accidently make errors in a graph like that? How do you jump nay LEAP from 54 to 66 months? That is a full year out - if they are making mistakes like that (multiple data points no less) then they don't inspire any confidence. I was really keen to try this stuff out, but now I am going to have to rethink - I worry that this is going to be Resveratrol all over again.

Until this gets replicated by someone else, I am going to not believe it. This really has a cold fusion feel to it.

Seriously disappointed. :(

[jg42122]

In another thread, AgeVivo says:

Following the buckyball study I contacted the authors of that incredible paper (rats lived up to 54 months, with errors in the lifespan curves in the paper, followed by long discussions) to know if I could test it at home on my mice, ratger than letting they die from aging without any scientific impact.

This is really bothering me now as I am starting to suspect outright fraud now. How do you accidently make errors in a graph like that? How do you jump nay LEAP from 54 to 66 months? That is a full year out - if they are making mistakes like that (multiple data points no less) then they don't inspire any confidence. I was really keen to try this stuff out, but now I am going to have to rethink - I worry that this is going to be Resveratrol all over again.

Until this gets replicated by someone else, I am going to not believe it. This really has a cold fusion feel to it.

Seriously disappointed. :(

I have not read of any errors in the paper that would lead me to believe any fraud happened. Also their have been reports from members here that have taken the mixture and had positive results, sure a human could have a placebo effect but some of the reports are in pets as well would those posters be part of this out right fraud as well?

[Turnbuckle]

I have not read of any errors in the paper that would lead me to believe any fraud happened. Also their have been reports from members here that have taken the mixture and had positive results, sure a human could have a placebo effect but some of the reports are in pets as well would those posters be part of this out right fraud as well?

There is a whole lot of excitement based on very little experience, and most of those are special cases:

There's me, but my mitochondria were damaged by statins, and the sudden improvement made the effect convincing. If it had happened over months, I couldn't have said it was the C60 and not something else.

I've also reported on two dogs, and one showed impressive improvements within a few days. Years ago that dog had a course of heartworm treatment with an arsenic medication, and arsenic compounds are known to damage mitochondria. So like me, his mitochondria were likely not in good shape.

There's HappyPhysicist, who said, "I have noticed nothing whatsoever." He is another special case in that he is trying to cure or at least stop the progression of ALS.

There's Krell, who said 4 hours after taking 2mg C60 in OO, "I ran my standard 2 mile training run. My time was somewhat slower than normal, probably due to higher than normal temperature and humidity, and I definitely did not feel any increased stamina." But Krell has the opposite situation. With all his running he is no doubt in top mitochondrial form, and I doubt that anyone with mitochondria in top form would notice a positive difference.

And there's one other person here who said they had a positive response but they would report it later.

So that's it so far. There's a lot of excitement, and one person is even selling this stuff over the internet quoting me and others here, but if we look at this honestly, we have as our best evidence that C60 is a good thing:

a few rats that lived dramatically longer,
one human who had a special problem and noticed an immediate improvement,
one dog that had a special problem and was improved in days, and said dog belonged to said human,
and assorted papers saying that C60 does this or that in vitro or in rats

And that's it.

So I encourage whoever else has taken this stuff to let us know how it's working out. Good, bad, or whatever.

[Turnbuckle]

How do you accidently make errors in a graph like that?

What errors?

[PWAIN]

What errors?

The following is taken from AgeVivo's post where he talks about talking to the authors of the paper. These are his words (the author of the paper) - note the highlight:

"...rats lived up to 54 months, with errors in the lifespan curves in the paper"

I didn't make this up, I wish I did, I really do. The rats did not live 66 months after all, the graph was wrong - at least that is what the author is saying.

I remember a lot of positive results with Resveratrol including in animals. Maxwatts toe is literally famous and Missmini's dog is a relative hero as he battled cancer but no indication of life extension. Resveratrol looks great for general health but it won't make you live longer. I am not sure that that is even true of C60 in oo. Lets face it, who would have doubted Sinclair when he pushed Resveratrol and yet....

[Turnbuckle]

The following is taken from AgeVivo's post where he talks about talking to the authors of the paper. These are his words (the author of the paper) - note the highlight:

"...rats lived up to 54 months, with errors in the lifespan curves in the paper"

The way I read that post (below), it's not a quote by the authors. It's AgeVivo saying this and it's not at all clear what he means by it.

Dear All,

Following thoughts on MPrize at home I had 3 mice at home. Following the buckyball study I contacted the authors of that incredible paper (rats lived up to 54 months, with errors in the lifespan curves in the paper, followed by long discussions) to know if I could test it at home on my mice, ratger than letting they die from aging without any scientific impact. They were very sympathetic; they'd like some independent researcher to reproduce their experiment in a robust and standard way but in the meantime... here I am:

TODO: improve text of this post.

[Metrodorus]

The graph, probably put together by an intern, was wrong. The data in the text of the study however, was not wrong, and this has been confirmed by the authors.
Thus, it isn't really important.

[jg42122]

The graph, probably put together by an intern, was wrong. The data in the text of the study however, was not wrong, and this has been confirmed by the authors.
Thus, it isn't really important.

That's what I thought too.

[niner]

In another thread, AgeVivo says:

Following the buckyball study I contacted the authors of that incredible paper (rats lived up to 54 months, with errors in the lifespan curves in the paper, followed by long discussions) to know if I could test it at home on my mice, ratger than letting they die from aging without any scientific impact.

This is really bothering me now as I am starting to suspect outright fraud now. How do you accidently make errors in a graph like that? How do you jump nay LEAP from 54 to 66 months? That is a full year out - if they are making mistakes like that (multiple data points no less) then they don't inspire any confidence. I was really keen to try this stuff out, but now I am going to have to rethink - I worry that this is going to be Resveratrol all over again.

Until this gets replicated by someone else, I am going to not believe it. This really has a cold fusion feel to it.

Seriously disappointed. :(

The rats started out at 10 months old, so if it meant 54 months after that, then it would only be an error of 2 months, still hardly excusable but not so egregious.

The comparison to resveratrol is interesting. Resveratrol had a big buzz in the media, while this seems to be a lot more confined to the life extension community. Resveratrol had an interesting "story" to it, supposedly CR worked through SIRT1, and then these geniuses found a compound that activates SIRT1 in the same way, and there was the whole French "paradox" that they claimed was due to resveratrol in wine. People love nothing better than a good story, and they really latched on to that one.

Cold fusion turned out to be real after all. It was exceedingly hard to reproduce in the early days. I guess no one's ever been able to scale it up.

54 months is still a substantial extension of lifespan. If in the end, it actually turns out that the rats lived (in total) up to 54 months instead of 66, it would actually be MORE believable, in that it's a less preposterous result, though my confidence would go down yet another notch if they could make an error like that in the publication. Was that thing refereed? By life scientists?

Remember, most preclinical research is wrong, and error is still the most likely explanation here, at least for some of it. There's too much evidence from other labs, species, and fullerene analogs to dismiss it entirely.

[AgeVivo]

Sorry for not having read those posts. Don't hesitate to PM me from time to time. Experiment started at age 10 months and ended at age 54 months for the longest lived rats. The authors told me that at the very moment of submitting the article they decided to make nice graphs and that's where they made errors. In particular for the lifespan curves they did not use their nice graph tool correctly. On their paper, when lines go down, instead of going down straight they went down with a decay of one month (in Excel it is the difference between between x-y plots and y plots). If you take their graph and make the correction (I did it myself using paint) you end up to 54 months max, and are better aligned with the text of the paper. The authors had not noticed those errors until it was reported; now they have submitted corrections that should be published very soon.

Yes such an error is strange, especially with such lifespan results. But graph errors happen in many papers, even in very prestigious journals; nothing is seriously bad neither in the paper, the story is credible (the authors were interested in proving the non long-term toxicity of fullerenes and were finding it nice that the treated animals lived longer than controls, without imaginating during the experiment that the lifespans was so great; I understand that they were more afraid to be criticized about the short lifespan (normal lifespan actually) of the water-feeded control; they are from pharmaceutical/chemistry/maths backgrounds; not gerontology; the animal facility is in a pharmaceutical university where I took courses and that has strict rules) and the authors are otherwise recognised to have published serious work in the past. => Nothing to trust for sure but nothing to reject for sure.

So indeed at this stage *THE* thing to do is to repeat the experiment. What I do in my kitchen (link) is not the best. The best is a lifespan experiment done in an approved rodent facility by some independent researcher (ideally known for its good lifespan studies, but that is perhaps not so important)... Perhaps by trying in addition an improved protocol so that it is more interesting than a simple "repeat" experiment (group A = gavage with water; group B = gavage with oil; group C = gavage with oil+C60; group D(/E/F..) = different oil/dose/derivative/scheduling...) -- any such person reading this post? if so please contact the authors.

Edited by AgeVivo, 02 June 2012 - 02:16 PM.

[Turnbuckle]

Sorry for not having read those posts. Don't hesitate to PM me from time to time. Experiment started at age 10 months and ended at age 54 months for the longest lived rats. The authors told me that at the very moment of submitting the article they decided to make nice graphs and that's where they made errors. In particular for the lifespan curves they did not use their nice graph tool correctly. On their paper, when lines go down, instead of going down straight they went down with a decay of one month (in Excel it is the difference between between x-y plots and y plots). If you take their graph and make the correction (I did it myself using paint) you end up to 54 months max, and are better aligned with the text of the paper. The authors had not noticed those errors until it was reported; now they have submitted corrections that should be published very soon.

This explanation doesn't help much. If you're saying that the oldest C60 rats died at 54 months, then that is an error of ten months, not one month, as in "they went down with a decay of one month." I can believe it was off by one month and no one caught it, but not ten.

Perhaps the explanation is that the 54 months refers to the 54th month of the experiment, which would make the rats 64 months.

Edited by Turnbuckle, 02 June 2012 - 03:00 PM.

[HappyPhysicist]

TNF is implicated in tumor growth, and I believe IL-6 is as well, through angiogenesis. (Remember that William Li video I posted a while back?)

• And, thanks to the data points you provided Turnbuckle, I’ve found evidence that TNF is implicated in hair loss, skin aging, and muscle dysfunction (perhaps even in canines).

So all these ideas, along with stronger/weaker study evidence, has been rolling around in my head for a few days and I finally got around to the right Google Scholar query pair... “C60 immune”... And bang... Out it popped... Here’s the puzzle piece... I’m clear there is an unpredicted/unexplained nuance... That C60 served as a TNF agonist and not an antagonist.... Gotta go...

Immunostimulatory properties and enhanced TNF- α mediated cellular immunity for tumor therapy by C60(OH)20 nanoparticles

Publications concerning the mechanism of biological activity, especially the immunological mechanism of C60(OH)20 nanoparticles, are relatively limited. However, the structure and characteristics of this carbon allotrope have been widely investigated. In this paper, we have demonstrated that water-soluble C60(OH)20 nanoparticles have an efficient anti-tumor activity in vivo, and show specific immunomodulatory effects to the immune cells, such as T cells and macrophages, both in vivo and in vitro. For example, C60(OH)20 nanoparticles can increase the production of T-helper cell type 1 (Th1) cytokines (IL-2, IFN- γ and TNF-α), and decrease the production of Th2 cytokines (IL-4, IL-5 and IL-6) in serum samples. On the other hand, C60(OH)20 nanoparticles show almost no adverse effect to the viability of immune cells in vitro but stimulate the immune cells to release more cytokines, in particular TNF- α, which plays a key role in the cellular immune process to help eliminate abnormal cells. TNF- α production increased almost three-fold in treated T lymphocytes and macrophages. Accordingly, we conclude that C60(OH)20 nanoparticles have an efficient anti-tumor activity and this effect is associated with an increased CD4+/CD8+ lymphocyte ratio and the enhancement of TNF- α production. The data suggest that C60(OH)20 nanoparticles can improve the immune response to help to scavenge and kill tumor cells.

This is a big red flag or my purpose of using C60/OO. ALS is thought to be an autoimmune disease and so any substance that stimulates the immune system would be bad. Moreover, a recent discovery by researchers in Ireland showed that for at least a subset of ALS patients of Irish or Scottish decent, a possible cause of ALS is a lack of angiogenesis (growth of new blood cells). The hypothesized mechanism is that when motor neurons die (they die at a rate of about 1%/year in healthy individuals), they secrete angiongenin, which encourages blood vessels to take their place to nourish the remaining motor neurons. In certain types of ALS, this doesn't happen and the dead motor neurons prevent nutrients from reaching the remaining neurons, leading to a cascade effect, and the rate at which we lose motor neurons grows and increases form 1% to 10 or 30%, causing death in just a few years.

ALS has been called 'anti-cancer' by one astute forum poster. In many cases what is bad for cancer is good for ALS and vice versa.

So if C60 is suppressing angiogenesis, that will suppress cancer by keeping microscopic cancers from every growing beyond a few cells, but may exacerbate ALS.

So, If i suddenly take a turn for the worse, this might be good news for everyone else.

Edited by HappyPhysicist, 02 June 2012 - 03:39 PM.

[Junk Master]

Thanks Turnbuckle.

Coming at this from a more pragmatic angle, Anthony mentioned a 4/5 cup daily dose for a "human rat hybrid"...lol...

4/5 a cup of olive oil has roughly 1, 500 calories

Adding an additional 1,500 calories per day for 50 days to your diet will inevitably result in significant weight gain.

Burning off 1,500 calories through additional exercise, barring injury, will definitely leave you fit-- think 12-15 miles per day of jogging-- but compliance seems unlikely.

Even a strict diet, combined with increased exercise seems unlikely to stop weight gain.

[PWAIN]

Sorry for not having read those posts. Don't hesitate to PM me from time to time. Experiment started at age 10 months and ended at age 54 months for the longest lived rats. The authors told me that at the very moment of submitting the article they decided to make nice graphs and that's where they made errors. In particular for the lifespan curves they did not use their nice graph tool correctly. On their paper, when lines go down, instead of going down straight they went down with a decay of one month (in Excel it is the difference between between x-y plots and y plots). If you take their graph and make the correction (I did it myself using paint) you end up to 54 months max, and are better aligned with the text of the paper. The authors had not noticed those errors until it was reported; now they have submitted corrections that should be published very soon.

Yes such an error is strange, especially with such lifespan results. But graph errors happen in many papers, even in very prestigious journals; nothing is seriously bad neither in the paper, the story is credible (the authors were interested in proving the non long-term toxicity of fullerenes and were finding it nice that the treated animals lived longer than controls, without imaginating during the experiment that the lifespans was so great; I understand that they were more afraid to be criticized about the short lifespan (normal lifespan actually) of the water-feeded control; they are from pharmaceutical/chemistry/maths backgrounds; not gerontology; the animal facility is in a pharmaceutical university where I took courses and that has strict rules) and the authors are otherwise recognised to have published serious work in the past. => Nothing to trust for sure but nothing to reject for sure.

So indeed at this stage *THE* thing to do is to repeat the experiment. What I do in my kitchen (link) is not the best. The best is a lifespan experiment done in an approved rodent facility by some independent researcher (ideally known for its good lifespan studies, but that is perhaps not so important)... Perhaps by trying in addition an improved protocol so that it is more interesting than a simple "repeat" experiment (group A = gavage with water; group B = gavage with oil; group C = gavage with oil+C60; group D(/E/F..) = different oil/dose/derivative/scheduling...) -- any such person reading this post? if so please contact the authors.

Interesting, thanks for clarifying. One thing tho, there is 15 down lines so the error should be 15 months but it isn't. Why is that? I would like to see the modified graph when it is available. For now I will suspend fraud claims and move to wait and see. Fingers crossed that this pans out. Did the authors indicate to you why they believe the olive oil on it's own was so effective?

Niner,
Unfortunately the olive oil result is similar to the Resveratrol from red wine - Med diet ~ Olive oil - Med diet. I think the buzz about Resveratrol took a while to take hold - the take off was fast but the build up was slow. I hope I am wrong, but the similarities are too spookily in my face to ignore without comment.

[HighDesertWizard]

... there is only a barely significant correlation between HRV and surviving past 100.

I agree. This Vagus stuff is very left field. In the meantime, we can rejoice that the two oldest people in the world until recently (both over 120) credited their longevity in part to olive oil.

I agree. Not that HRV isn't correlated to longevity, but correlation does not imply causation.

A few things...

• about niner's point... I provided a link to a study up thread (after niner made that point) that showed findings that contradict his contention. There is a study showing that HRV is higher for centenarians than for those 80 to 100. That study finding is consistent with findings of other studies that looked at old age brackets less than 100. For now, I think we have to take the single study that looked at the question and assume the study authors got it right. Unless niner can Falsify the weight of these studies, I think we have to take them at face value: there is a non-trivial correlation between Longevity, even the Extreme Longevity of centenarians, and high HRV.

• Of course, as David Deutsch would say, knowing just THAT, doesn't explain anything. What's the Explanation for why HRV is correlated with Longevity?

• About that Explanation and the point of the Vagus-CAIP-HRV nexus being about "correlation, not necessarily causation..." It's always a valid question to raise. I addressed it a bit up thread. I have a question in reply...

Has anyone suggesting the Vagus-CAIP-HRV nexus is about correlation, and not necessarily causation, actually read Kevin Tracey's 2007 CAIP Review article? I've posted links to it multiple times and said "this is a big puzzle piece." I've also posted his "CAIP Wiring Diagram."

​-------------------------------------------------------------

The following figure (the "wiring diagram") and caption text followed by article text are from Tracey2007...

"Brain networks regulate the outflow of the cholinergic antiinflammatory pathway. Earlier work indicated that muscarinic brain networks can modulate vagus nerve regulation of other visceral functions. Examples include brain regulation of glycogen synthesis in the liver, of vasovagal syncope mediated by the Bezold-Jarisch cardiovascular reflex, and of exocrine pancreatic secretion (30–33). Recent results showing that intracerebroventricular administration of muscarine receptor agonists significantly decreases serum TNF levels during endotoxemia indicate that muscarinic brain networks also regulate the cytokine-controlling function of the vagus nerve. (34). Intracerebral administration of muscarine agonists also stimulates an increase in vagus nerve signaling to the heart as measured by increasing instantaneous heart rate variability, a result that couples the activation of a muscarinic brain network to two indicators of increased vagus nerve activity in the periphery: (a) increasing instantaneous heart rate variability and (b) decreasing cytokine production (34). It is interesting to consider that centrally activating muscarinic agents might be used as molecular tools to study and dissect the physiology and functional anatomy of the cholinergic antiinflammatory pathway along the path from the brain to the vagus nerve, across the common celiac branch, and into the spleen to prevent or modulate the development of cytokine-mediated disease."

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

If you still want to make the argument that the Vagus-CAIP-HRV nexus is correlation, not causation, let's be clear... Your argument is with Dr. Kevin Tracey and not with me...

Nevertheless, I'm open to hearing specific objections to the correlation/causation point he makes about that nexus. But let's be fair, right? No more off the cuff, uninformed statements about this question. If you're going to argue for mere correlation, you need to provide a detailed argument based on an actual reading, at least, of his 2007 Review article.

• Oh, and about Kevin Tracey and my prediction that he would win the Nobel Prize in Medicine for his work on the CAIP, you know, his work about how Innate Immunity, Auto-Immune Diseases, Inflammatory Conditions and Disease, HRV, TNF, etc. are all related to each other... I didn't know the following before I made the prediction but I thought, "surely, he's being considered." So, I googled around a bit. Here's what I found.

Members of the Faculty at the Karolinska Institutet select who is to win the Nobel Prize in Medicine/Physiology each year. Tracey's work, apparently, caught their attention. The Institute awarded him an Honorary Doctorate in 2009. Gotta' date, I guess, before you make a final selection down the road.

Have we settled this question now?

Edited by wccaguy, 02 June 2012 - 05:13 PM.

[Turnbuckle]

If you still want to make the argument that the Vagus-CAIP-HRV nexus is correlation, not causation, let's be clear... Your argument is with Dr. Kevin Tracey and not with me......Have we settled this question now?

I think the question was, wccaguy, about correlation v causality with longevity, and this Tracey review doesn't do it. (If it does, please point it out.) And the second question was about the mechanism of how a limited interval of supplementation could stimulate the vagus nerve in a sustained way.

Edited by Turnbuckle, 02 June 2012 - 05:21 PM.

[Turnbuckle]

Interesting, thanks for clarifying. One thing tho, there is 15 down lines so the error should be 15 months but it isn't. Why is that? I would like to see the modified graph when it is available. For now I will suspend fraud claims and move to wait and see. Fingers crossed that this pans out. Did the authors indicate to you why they believe the olive oil on it's own was so effective?

According to the text, the first control rat died at M17, and this is shown properly on the chart. Then--

At M38 all water-treated control rats were dead (Fig. 3a). This
agrees with the expected lifespan of this animal species that is
thirty to thirty six months. At this time 67% of olive-oil-treated rats
and 100% of C60-treated rats were still alive.

This also jibes with the chart. So if there was a plotting error, it only happened with the animals past this point.

Edited by Turnbuckle, 02 June 2012 - 05:16 PM.

[HighDesertWizard]

I think the question was, wccaguy, about correlation v causality with longevity, and this doesn't do it. And the second question was about the mechanism of how a limited interval of supplementation could stimulate the vagus nerve in a sustained way.

Turnbuckle... I take your point that, while putting up evidence, I muddied the waters about what the questions are. So, Thank You for objecting and clarifying... Here is a list of 3 questions. I'm rephrasing them a bit so that they are different than I might have phrased them earlier up thread...

• Vagus-CAIP-HRV correlation or causation with regard to Longevity
• Correlation or causation of Vagus Stimulation leading to higher HRV
• How is the CAIP related to an Explanation of the Baati-Fullerene C60-Olive Oil study result

Regarding question 1...

I think correlation is indisputable. I do follow Popper/Deutsch in believing that nothing can ever be proven with certainty. There are only good, better, best Explanations.

I think I've addressed niner's objection. I believe the argument burden is on him now to make the case that there is "barely" any correlation of HRV to Longevity assuming he still wants to make that case. To be fair to him, he did make that point before I posted the study link about HRV in Centenarians. I personally think, based on studies I've posted about and some I haven't, that the Vagus-CAIP-HRV nexus is the Best Explanation for Extreme Longevity in Humans we've witnessed to date (i.e., centenarians).

Up thread, I tried to summarize my feeling about this as follows...

Higher HRV -->> Extreme Longevity: http://www.ncbi.nlm....pubmed/20381674
Vagus Activation -->> Higher HRV: http://www.jci.org/articles/view/30555
Positive Emotions -->> Extreme Longevity: http://www.impactagi...bs/100456a.html
Positive Emotions -->> Vagus Activation: http://www.ncbi.nlm....pubmed/20851735
Exercise -->> Extreme Longevity: http://extremelongev...ds/sardinia.pdf
Exercise -->> Vagus Activation: http://www.ncbi.nlm....pubmed/11560079

But let me put the question to you: What Better Explanation of Extreme Longevity in Humans is there, documented with positive correlation study evidence about humans?

Regarding question 2... In my last post, I had it specifically in mind to implicitly object to your post below, keeping in mind the 6 studies above, and Tracey's work on the CAIP...

... it should be clear that exercise is the cause, longevity is the effect, and heart rate variability merely a marker. If you could increase HRV by some other means, treating the symptom rather than the disease in other words, the effect on longevity would likely not be there.

I think my last post successfully rebuts your point. I agree that HRV is a marker, not the cause. I think Tracey's work shows that. But, IMO, physical exercise cannot now, given the evidence, be considered the "cause" because there are other triggers of higher HRV that also are correlated with Longevity. They are correlated, instead, with Vagus Stimulation and the CAIP activated by Vagus Stimulation.

Regarding question 3... The question is an important one. My last post didn't address it. An Explanation has been forming in my mind. The explanation is larger now than just Olive Oil in the gut. When I can articulate in writing in a coherent way, I'll post it.

• I think that C60/TNF study I posted about last night is a significant element/clue for understanding what's going on in Baati. I appreciate you having shared data points about your experience. They implicate TNF as being important. I owe you study links about TNF and symptoms you observed. Thank you!

• And you made another post that got me thinking. That "dang" post you made #557 caught my eye. I think you're right that some kind of "reset" has to have taken place... But what kind of reset? Thanks for that post.

I still believe what I wrote below... If we're persistent, work hard at research and reflection, and we're tough with each other while being appreciative of each other, expecting ourselves to get it wrong as often as others do, we might surprise ourselves at what can be accomplished...

I believe that at least 80% of the scientific knowledge required to explain this buckyball study result already exists in the literature. But the literature is vast and no one person has a handle on all of it. I believe, however, that we, in this forum, have "collective intelligence" about that literature and if we're willing and able to leverage each other's knowledge, I think we can figure out what 2 or 3 of the best possible explanations of the study result are.

Edited by wccaguy, 02 June 2012 - 07:02 PM.

[Turnbuckle]

wccaguy said: I think correlation is indisputable.

That's not being argued.

I think I've addressed niner's objection. I believe the argument burden is on him now to make the case that there is "barely" any correlation of HRV to Longevity assuming he still wants to make that case.

I believe he said that because the significance was given as p<.05, which is a rather loose measure.

Regarding question 3... The question is an important one. My last post didn't address it. An Explanation has been forming in my mind. The explanation is larger now than just Olive Oil in the gut. When I can articulate in writing in a coherent way, I'll post it.

Okay.

[niner]

This is a big red flag or my purpose of using C60/OO. ALS is thought to be an autoimmune disease and so any substance that stimulates the immune system would be bad. Moreover, a recent discovery by researchers in Ireland showed that for at least a subset of ALS patients of Irish or Scottish decent, a possible cause of ALS is a lack of angiogenesis (growth of new blood cells). The hypothesized mechanism is that when motor neurons die (they die at a rate of about 1%/year in healthy individuals), they secrete angiongenin, which encourages blood vessels to take their place to nourish the remaining motor neurons. In certain types of ALS, this doesn't happen and the dead motor neurons prevent nutrients from reaching the remaining neurons, leading to a cascade effect, and the rate at which we lose motor neurons grows and increases form 1% to 10 or 30%, causing death in just a few years.

ALS has been called 'anti-cancer' by one astute forum poster. In many cases what is bad for cancer is good for ALS and vice versa.

So if C60 is suppressing angiogenesis, that will suppress cancer by keeping microscopic cancers from every growing beyond a few cells, but may exacerbate ALS.

So, If i suddenly take a turn for the worse, this might be good news for everyone else.

Well, I don't think anyone is going to be happy if you take a turn for the worse. However, this anti-angiogenesis stuff is pretty soft. That some people develop ALS due to an angiogenesis defect doesn't mean necessarily mean it's the primary mechanism, or yours. I did find some fullerene angiogenesis papers, but the first is Gd@C86(OH)22; comparing it to C60 (as an olive oil adduct, in all probability) is kind of like comparing ethanol to ethane, and that's ignoring the Gd. This paper does make a point of the importance of 'particulates', by which I presume they mean aggregates or microcrystals. If that's a key factor, then filtration/centrifugation might be a good thing for you.

ACS Nano. 2010 May 25;4(5):2773-83.
Potent angiogenesis inhibition by the particulate form of fullerene derivatives.
Meng H, Xing G, Sun B, Zhao F, Lei H, Li W, Song Y, Chen Z, Yuan H, Wang X, Long J, Chen C, Liang X, Zhang N, Chai Z, Zhao Y.

CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China.

Antiangiogenesis is an effective strategy for cancer treatment because uncontrolled tumor growth depends on tumor angiogenesis and sufficient blood supply. Great progress has been made in developing a "molecular" form of angiogenesis inhibitors; however, the narrow inhibition spectrum limits anticancer efficacy as those inhibitors that usually target a few or even a single angiogenic factor among many angiogenic factors might initially be effective but ultimately lead to the failure of the treatment due to the induction of expression of other angiogenic factors. In this work, we report that with a multiple hydroxyl groups functionalized surface, the Gd@C(82)(OH)(22) fullerenic nanoparticles (f-NPs) are capable of simultaneously downregulating more than 10 angiogenic factors in the mRNA level that is further confirmed at the protein level. After studying this antiangiogenesis activity of the f-NPs by cellular experiment, we further investigated its anticancer efficacy in vivo. A two-week treatment with the f-NPs decreased >40% tumor microvessels density and efficiently lowered the speed of blood supply to tumor tissues by approximately 40%. Efficacy of the treatment using f-NPs in nude mice was comparable to the clinic anticancer drug paclitaxel, while no pronounced side effects were found. These findings indicate that the f-NPs with multiple hydroxyl groups serve as a potent antiangiogenesis inhibitor that can simultaneously target multiple angiogenic factors. We propose that using nanoscale "particulate" itself as a new form of medicine (particulate medicine) may be superior to the traditional "molecular" form of medicine (molecular medicine) in cancer treatment.

PMID: 20429577

In this next paper, they did use pristine fullerene, and literally dumped it on the membrane model they were looking at. It had no effect on basal angiogenesis, which strikes me as a good thing. It did show some suppression of VEGF/FGF2 induced angiogenesis, but only 50% with VEGF and 20% with FGF2. Considering the large in vitro dose used, this doesn't strike me as something to worry too much about, particularly since the fullerene clears so rapidly from the tissues. I hypothesize that a small amount of fullerene-fatty acid adduct remains as a component of mitochondrial and other membranes, but as such would not be available to be involved in angiogenesis. Any fullerene that doesn't become incorporated in a membrane or cell would be rapidly cleared, so any effect that it did have on angiogenesis would be transient at best.

FEBS Lett. 2007 Mar 20;581(6):1157-60. Epub 2007 Feb 20.
Carbon inhibits vascular endothelial growth factor- and fibroblast growth factor-promoted angiogenesis.
Murugesan S, Mousa SA, O'connor LJ, Lincoln DW 2nd, Linhardt RJ.

Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA.

Angiogenesis is important for normal growth and wound healing processes. An imbalance of the growth factors involved in this process, however, causes the acceleration of several diseases including malignant, ocular, and inflammatory diseases. Inhibiting angiogenesis through interfering with its pathway is a promising methodology to hinder the progression of these diseases. Herein, we studied the anti-angiogenic effects of various carbon materials such as graphite, multiwalled carbon nanotubes and fullerenes in vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2)-induced angiogenesis evaluated in the chick chorioallantoic membrane (CAM) model. All the carbon materials tested showed substantial anti-angiogenic activity against either FGF2- or VEGF-induced angiogenesis in the CAM model. Those carbon materials did not have any significant effects on basal angiogenesis in the absence of the added growth factors.

PMID: 17331505
PMCID: PMC1994254 Free PMC Article

Edited by niner, 03 June 2012 - 03:38 AM.

[niner]

Once the TNF Explosion is over, the C60 is cleared from your system (according to Baati, but a point which niner disputes and I respect niner a great deal).

Nevertheless, Turnbuckle's experience implies a profound reduction in TNF...

Thanks for the kind words. Amidst the flood of posts in this thread, you might have missed my explanation for the cleared/not cleared discrepancy:

I hypothesize that a small amount of fullerene-fatty acid adduct remains as a component of mitochondrial and other membranes, but as such would not be available to be involved in angiogenesis. Any fullerene that doesn't become incorporated in a membrane or cell would be rapidly cleared, so any effect that it did have on angiogenesis would be transient at best.

Essentially, a relatively small amount of C60-fatty acid adduct is incorporated in the membranes, most of which is entirely intracellular. Not only does it remain there, but it's not available to affect angiogenesis, TNF, or anything else. Baati also looked at individual organs, and found that the C60 cleared from them rapidly. In order for my hypothesis to work, they would have had to miss the C60 in the membranes, either because they didn't look at that fraction, or because the amount that was there was below their limit of detection. Both are possible, but I don't know how they did the measurement.

Now, on TNF:

What TNF explosion? We don't have any evidence that there's a TNF explosion, or even any TNF at all, from C60/olive oil. What about Turnbuckle's experience implies a profound reduction in TNF?

[niner]

The whole TNF hypothesis rests on the following statement in the abstract of Ying Liu's paper that wccaguy posted:

"On the other hand, C₆₀(OH)₂₀ nanoparticles show almost no adverse effect to the viability of immune cells in vitro but stimulate the immune cells to release more cytokines, in particular TNF- α, which plays a key role in the cellular immune process to help eliminate abnormal cells. TNF- α production increased almost three-fold in treated T lymphocytes and macrophages."

C60(OH)20 is a radically different molecule than either pristine C60 or a C60 fatty acid adduct. We can't claim that what happens with one will happen with the other. That phrase "treated T lymphocytes and macrophages" means that this was an in vitro experiment. The concentration and length of exposure in a test tube typically bear no relationship whatsoever to what is seen in the body. Thus, the TNF hypothesis is very tenuous.

It's now legitimate to play "TNF study cards" in this game... Wow! That amounts to thousands more cards that can be played...

I don't think it's legitimate until we at least see some evidence that TNF production is upregulated in vivo from either pristine C60 or the adduct. It would be good to create a thread specifically for the TNF/C60 hypothesis.

[Metrodorus]

Interesting phd thesis on carbon-70 and inflammation reduction. (Published online May 2012)
Author Sarah Brooke Norton

Dampening of inflammation may be one of the contributory mechanisms of our olive oil lipofullerene complex.

https://dizzyg.uls.v...ndle/10156/3832

https://dizzyg.uls.v....pdf?sequence=3

Edited by Metrodorus, 03 June 2012 - 08:14 PM.