635 replies to this topic

[niner]

I'm probably going to make a complete ass of myself, (again! ) but ...:

Mammalian Mitochondria Possess Homologous DNA Recombination Activity
http://www.jbc.org/c...1/44/27536.full
It may be possible to improve mitochondrial function (and thereby enhance levels of mitochondrial homologous DNA recombination activity) by supplementing the culture media with high levels of the ketone body 3-hydroxybutyrate.

3-hydroxybutyrate derivatives can be used as nutritional supplements to increase physical performance and as therapeutics to ameliorate symptoms of medical conditions, particularly neurological conditions, such as Alzheimer's and similar conditions:
http://www.google.co...s/US20060280721

3-hydroxybutyrate production seems to be improved by Oleic Acid:
http://www.springerl...7g24232121n272/

Oleic Acid is most prevalent in Olive Oil:
http://www.wisegeek....-oleic-acid.htm

so... ???

Ok so everyone knew that mitochondrial DNA could be repaired and that the process is probably helped by 3-hydroxybutyrate?
No one thinks its possible that the production of 3-hydroxybutyrate or similar could have something to do with C60 in Olive Oil?

I didn't know about the DNA repair. That paper was from 1996, so you'd think everyone would know about it. Did it wind up being a minor player of low significance, or is it inadequate for the needs of mitochondrial DNA? People are talking about schemes to get nuclear DNA to express mitochondrial proteins, so someone sees a need for better technology.

The production of 3-OH-butyrate from oleic acid was in bacteria; I wouldn't expect it to work the same way in humans. We know that olive oil is good for humans. In the C60 rat paper, they saw a substantial improvement in life expectancy from olive oil alone. Jeanne Calment ascribed her longevity to olive oil, which she used a lot of.

[Junk Master]

Jeanne Calment used copious amounts of olive oil as a skin rub. I wonder if she ever included camphor/eucalyptus, as was common in muscle rubs. Camphor is a natural source of fullerenes.

[JohnD60]

Jeanne Calment used copious amounts of olive oil as a skin rub. I wonder if she ever included camphor/eucalyptus, as was common in muscle rubs. Camphor is a natural source of fullerenes.

It is my understanding that Fullernes do not exist naturally in Camphor, only that Camphor can be used as a feedstock for fullerenes. The camphor would still have to be exposed to a high energy point source such as a plasma arc or a hot filament.

[gamesguru]

Jeanne Calment used copious amounts of olive oil as a skin rub. I wonder if she ever included camphor/eucalyptus, as was common in muscle rubs. Camphor is a natural source of fullerenes.

It is my understanding that Fullernes do not exist naturally in Camphor, only that Camphor can be used as a feedstock for fullerenes. The camphor would still have to be exposed to a high energy point source such as a plasma arc or a hot filament.

Yes. It's unlikely that fullerenes would appear naturally in camphor, even though we can use camphor to synthesize fullerenes (http://prl.aps.org/a...v72/i20/p3182_1). Besides, trying to explain Calment's longevity through the action of a single drug is probably naive. A nice hypothesis though. Kudos for that.

[Junk Master]

Not buying it, huh.

Let's try again. Lavender is ubiquitous near Arles where Jeanne Calment lived. Lavender contains camphor. Lavender is often burned as a component of incense. Lavender essential oil is often used in candles. Camphor soot does contain fullerenes.

http://prl.aps.org/a...v72/i20/p3182_1

Still a stretch, but fun to think about.

I know she smoked two cigarettes a day until she was over 100. What if she smoked a mentholated brand that contained camphor at one time? Then cigarettes actually could be the cause of her longevity!

[JohnD60]

The campor soot in the linked publication was produced by a hot filament (probably thousands of degrees, I am not going to pay to read the pub). Burning Campor in an open flame at hundreds of degrees is not going to produce fullernes. It is my understanding that the only way Fullerenes are produced in nature are via lightening. So maybe if you can show that JC had a habit of burning Lavander during thunder storms in close proximity to lightening rods.

[gamesguru]

From http://laserspark.an...lau_07_high.pdf:

Molecular dynamics simulations show that an optimal annealing temperature of 4000 K is required to form well-ordered onions concentric fullerene-like spheres, in agreement with experiment.

[Junk Master]

Too bad she wasn't hit by lightning while running naked through a lavender field after oiling herself up with a generous coating of olive oil.

I know fullerenes are sexy, but what about olive oil/activated charcoal as is used in home hemorrhoid remedies?

[Metrodorus]

Junk Master - you are throwing curve balls here.

There are a handful of studies that show some life extension with conjugated fullerenes; one with mice that showed a reasonable degree of life extension, and the notorious rat study that showed a doubling of life span.

Unconjugated fullerenes, however, are not particularly beneficial - they may be non-toxic, They may not be. Early toxicology studies used toxic solvents, and the results have been (perhaps) discounted.

I think that the conjugation of fullerene with molecules present in olive oil is crucial - and it makes no sense whatsoever to tinker with the basic formula when the knowledge of what is going on is basically non-existent. If you are going down this route, stick to olive oil.

We have a basic assumption that the lipofullerene complex is acting as a SOD mimetic, or perhaps it is simply physically surrounding and protecting the complexes in the mitochondria, preventing peroxidation.

The end result is similar - prevention of oxidative stress within the mitochondria.

Edited by Metrodorus, 24 May 2012 - 04:32 PM.

[HighDesertWizard]

Given my error in pushing for an alternative to Olive Oil as a solvent, I'm hoping to redeem myself with this find... 8-)

If the Olive Oil solvent turns out to have played an important role in the study result, there is another, potentially significant, characteristic of Olive Oil which might explain it. What follows is an attempt to lay out that explanation and evidence for it in the 3 post sections below...

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First

To understand the potential importance of the argument, it's essential to understand The Vagus Nerve, Heart Rate Variability, Cholinergic Anti-Inflammatory Pathway Nexus. It's a non-trivial topic and I've established that Longecity thread to describe and discuss it.

Suffice it to say here that "the cholinergic anti-inflammatory pathway... is a novel function of the efferent vagus nerve. This pathway plays a critical role in controlling the inflammatory response through interaction with peripheral α7 subunit–containing nicotinic acetylcholine receptors expressed on macrophages.... "the modulation of systemic and local inflammation by the cholinergic anti-inflammatory pathway and its function as an interface between the brain and the immune system." The Cholinergic Anti-inflammatory Pathway: A Missing Link in Neuroimmunomodulation

I believe the VN, HRV, CAIP Nexus is the Best Explanation of the biological mechanism underlying The Placebo Effect. I outline the evidence for that belief at the thread link above.

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Second

It turns out that dietary fat triggers Vagus Nerve fibers in the gut. And recent studies have shown that this may be the reason why inflammatory diseases don't occur with more frequency in the gut and elsewhere. Here's a summary of the flow of the mechanism I'm outlining the evidence for...

Long Fatty Acids in the Gut (Olive Oil) -->> Cholecystokinin Receptors -->>
Vagus Nerve Stimulation -->> Cholinergic Anti-Inflammatory Pathway Activation -->>
Reduced Danger of an Over Expressed Auto-Immune Response

Here are three studies about this at a higher level, one of which contains a useful graphic figure...

Fat meets the cholinergic antiinflammatory pathway

The cholinergic antiinflammatory pathway is a neural mechanism that is controlled by the vagus nerve and inhibits local cytokine release, thereby preventing the damaging effects of cytokine overproduction. A new study now shows that dietary fat can activate this pathway, a finding that may help explain the immune system's failure to react to food antigens and commensal bacteria. Here we discuss this new data and its potential implications for dietary intervention in the treatment of inflammatory diseases.

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Mechanisms of CCK signaling from gut to brain

Following the observation that exogenous peripheral injection of CCK could inhibit food intake, the mechanisms by which CCK influences the gut–brain pathway have been the subject of intense study for nearly 30 years. Recently, it has become evident that the system is more complex and that the consequences of CCK's action on the gut–brain pathway are more far reaching than previously recognized. This review will examine the recent evidence showing the role of CCK and CCK1Rs in modulating expression of other receptors for orexigenic and anorexigenic regulatory peptides at the level of vagal afferent neurons. In addition, new evidence showing the importance of the action of CCK at the level of the vagus nerve in the regulation of food intake, body weight, and in activation of an anti-inflammatory pathway will be reviewed.

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Here is the more detailed study supporting the summary study above... I won't burden the post with pasting in the abstract.

Nutritional stimulation of cholecystokinin receptors inhibits inflammation via the vagus nerve

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Third, and finally...

It appears that Olive Oil is among, or is, the most powerful inducers of CCK through specific CCK receptors. And, hence, it is the among the most powerful triggers for the Cholinergic Anti-Inflammatory Pathway...

The G-protein coupled receptor GPR40 mediates long chain fatty acid induced cholecystokinin secretion

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The G-Protein−Coupled Receptor GPR40 Directly Mediates Long-Chain Fatty Acid−Induced Secretion of Cholecystokinin

Background & Aims
Long-chain fatty acid receptors G-protein−coupled receptor 40 (GPR40) (FFAR1) and GPR120 have been implicated in the chemosensation of dietary fats. I cells in the intestine secrete cholecystokinin (CCK), a peptide hormone that stimulates digestion of fat and protein, but these cells are rare and hard to identify. We sought to determine whether dietary fat-induced secretion of CCK is directly mediated by GPR40 expressed on I cells.
Methods
<<SNIP>>
Results
Cells that expressed eGFP also expressed GPR40; expression of GPR40 was 100-fold greater than that of cells that did not express eGFP. In vitro, linoleic, oleic, and linolenic acids increased [Ca2+]i; linolenic acid increased CCK secretion by 53% in isolated GPR40+/+ cells that expressed eGFP. In contrast, in GPR40−/−that expressed eGFP, [Ca2+]i response to linoleic acid was reduced by 50% and there was no significant CCK secretion in response to linolenic acid. In mice, olive oil gavage significantly increased plasma levels of CCK compared with pregavage levels: 5.7-fold in GPR40+/+ mice and 3.1-fold in GPR40−/− mice.
Conclusions
Long-chain fatty acid receptor GPR40 induces secretion of CCK by I cells in response to dietary fat.

Edited by wccaguy, 25 May 2012 - 10:37 AM.

[HighDesertWizard]

I appreciated Junk Master's recent throwing of "curve ball" explanations of the study result. While they might not have been great, they did elicit reasoned and articulate objections which clarified issues. His curve balls provoked some people with significant knowledge to respond who may not have responded had he not thrown the curve balls. So, I say, keep up that great pitching Junk Master... 8-)

Attempts to state explanatory arguments in a provocative way can be a means to clarify what might be going on... So, here's an attempt at a strong version of the argument about the role of Olive Oil (and the CAIP) based on the explanation and evidence in the preceding post.

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• The Mediterranean Diet, The Placebo Effect, and measurable HIGH Heart Rate Variability are three of the most powerful general health promoters known, even if we aren't clear about the mechanism of action.

• Significant evidence exists that the mechanism of action for these three health promoters is the same: The Vagus Nerve, Heart Rate Variability, Cholinergic Anti-Inflammatory Pathway Nexus.

• Olive Oil is a key component of the Mediterranean Diet.

• Olive Oil powerfully triggers the CAIP by means of certain and specific means which are known. .

• It's more than a coincidence that, when they ingest Fullerene C60s dissolved in Olive Oil instead of alternative solvents, rats experience a startling extension of life span, even if we don't know what it is about the combination that is important to the study result.

• That it is the Olive Oil combination with C60s that extended life spans in the surprising way it did suggests that our innate Immune System driven CAIP is implicated in some way in the study result.

Edited by wccaguy, 25 May 2012 - 11:15 AM.

[Metrodorus]

2011 paper on fullerenes, with a focus on the affect of side chains on fullerene activity in biological systems

This 2012 review article is worth reading, as it summarises the current state of knowledge.

The section commencing "Biodistribution and toxicity" would be of most interest to this thread, and the paragraphs under "chemotherapeutics" are also interesting.

Edited by Metrodorus, 25 May 2012 - 01:40 PM.

[niner]

What about concerns with "clumping?"

This 2011 review talks about the low toxicity of fullerene aggregates, also called "nC60", in fish.

Here's a study that also mentions human cells.

Toxicol Lett. 2010 Aug 16;197(2):128-34. Epub 2010 May 21.
Intrinsic biological property of colloidal fullerene nanoparticles (nC60): lack of lethality after high dose exposure to human epidermal and bacterial cells.
Xia XR, Monteiro-Riviere NA, Riviere JE.

Center for Chemical Toxicology Research and Pharmacokinetics, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA. xia@ncsu.edu

Colloidal fullerene nanoparticles (nC60) were reported to be toxic to fish brains, human cells and microorganisms, while new observations suggest that the observed toxicity may be due to tetrahydrofuran (THF) solvent or its oxidative by-products in nC60 preparations. Here, we report a novel method for preparing nC60 nanoparticles that does not use THF solvent, but provides nC60 with an average particle size of 43.8 nm and a yield approximately 100 times higher than the THF method. The prepared nC60 showed a similar antioxidant capacity compared to a water-soluble vitamin E analog. No mortality to human epidermal keratinocytes was observed at a concentration 170 times higher than the reported LC50 values for other human cell lines. No toxicity was observed to E. coli or B. subtilis at up to 342 microg/mL nC60 for 16 h, which was hundred times higher than the reported minimum inhibitory concentrations of nC60 prepared using THF method for these two bacteria. When E. coli was exposed to 85.5 microg/mL nC60 with daily passage for 4 days, the stationary phase populations at different passages were not statistically different (p = 0.05) from the control without nC60 nanoparticles. These results reveal that the intrinsic biological property of nC60 is non-toxic, confirming the prior non-toxic reports when using nC60 prepared with non-THF methods.

An earlier paper does find some problems with both nC60 and fullerols when a human endothelial cell line was soaked in a high concentration for 24 hours. I don't worry very much about such experiments, since the conditions are so unrealistic relative to the in vivo exposure, but it points toward toxicities to look for in an animal model or human. I checked the methods section, and it doesn't look like THF was used to create the nC60. It's certainly no guarantee that you'll find a toxicity, but at any rate, here it is:

Int J Nanomedicine. 2008;3(1):59-68.
Adverse effects of fullerenes on endothelial cells: fullerenol C60(OH)24 induced tissue factor and ICAM-I membrane expression and apoptosis in vitro.
Gelderman MP, Simakova O, Clogston JD, Patri AK, Siddiqui SF, Vostal AC, Simak J.

CBER, FDA, 1401 Rockville Pike, HFM 335, Rockville, MD 20852-1448, USA.

We studied the effects of a C60 water suspension at 4 microg/mL (nC60) and the water soluble fullerenol C60(OH)24 at final concentrations of 1-100 microg/mL on human umbilical vein endothelial cells (HUVECs) in culture. We found that a 24 hr treatment of HUVECs with C60(OH)24 at 100 microg/mL significantly increased cell surface expression of ICAM-1(CD54) (67 +/- 4% CD54+ cells vs. 19 +/- 2 % CD540 cells in control; p < 0.001). In addition, this treatment induced the expression of tissue factor (CD142) on HUVECs (54 +/- 20% CD142+ cells vs 4 +/- 2% CD142+ cells in control; p = 0.008) and increased exposure of phosphatidylserine (PS) (29 +/- 2% PS+ cells vs. 12 +/- 5% PS+ cells in control; p < 0.001). Analysis of cell cycle and DNA fragmentation (TUNEL) showed that both nC60 and C60(OH)24 caused G1 arrest of HUVECs and C60(OH)24 induced significant apoptosis (21 +/- 2% TUNEL+ cells at 100 microg/mL of C60(OH)24 vs. 4 +/- 2% TUNEL+ cells in control; p < 0.001). We also demonstrated that both nC60 and C60(OH)24 induced a rapid concentration dependent elevation of intracellular calcium [Ca2+]i. This could be inhibited by EGTA, suggesting that the source of [Ca2+]i in fullerene stimulated calcium flux is predominantly from the extracellular environment. In conclusion, fullerenol C60(OH)24 had both pro-inflammatory and pro-apoptotic effects on HUVECs, indicating possible adverse effects of fullerenes on the endothelium.

PMID: 18488416
PMCID: PMC2527653 Free PMC Article

The method of preparation of nC60 in this paper was simply to add ordinary granular C60 to water, stir it for two weeks, and centrifuge at 4000 g's to remove larger particles. Given the amount of time they had in water, it's possible that there was some formation of fullerols, which can occur in water under mild conditions. They used a particle size analyzer to confirm the existence of the aggregates, which might have been hydroxylated on the exterior, but didn't do anything that would exclude any fully dissolved fullerols that may have been present. While I'm not really concerned about the in vitro effects they saw here, their preparation method does point out one thing: If centrifuging at 4000 g's leaves nC60 in water, there's no way that it's going to remove it from olive oil. Thus, if there was any nC60 formed in the preparation given to the rats, nothing they did would have removed it. Therefore, the rat paper constitutes a tox study on nC60, to the extent that it's actually formed in olive oil, which may or may not occur.

Finally, there are a couple of papers (here and here) using water-stirred nC60, exposing fish to fairly high concentrations over long times, that find increased levels of lipid peroxidation and some other markers of oxidative stress. This work, along with the in vitro work above, suggests that water-stirred nC60 at high dose levels would be problematic. Exactly how that relates to C60/olive oil is an open question, but I suspect that at low doses and in combination with an antioxidant fullerene species, it wouldn't be a problem.

[HighDesertWizard]

Turnbuckle.... Did your doctors diagnose you as having Myasthenia gravis based on your statin use?

My reading of the literature says that's what you had that vanished... Right? Wrong?

I'm thinking through explanations based on my last serious post... Have you posted everything you've noticed that has changed? YOUR experience is the exoerience, so far, that any explanation must account for...

Thx

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. I'd like that to happen and I'm willing to put time and energy into putting the puzzle pieces I know something about on the table...

Oops... I misspoke. I ALREADY did put a very significant puzzle piece on the table. It's that Vagus/CAIP/HRV literature plus the Olive Oil triggering the Vagus content I just posted yesterday...

So I'm going to continue to follow the trail of evidence that seems appropriate. I will TRULY APPRECIATE specific and detailed feedback about what I describe here, especially when I get off track... Hit me in the head if I'm going further than the evidence supports...

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

I believe there are insights into an explanation of the study from Turnbuckle's health turn around. I'd like to focus on it a bit assuming he doesn't mind. I don't think he minds. He volunteered his info and his "sonny... snake oil.." joke a few pages back let us all know he has a sense of humor and doesn't take himself or us too seriously. Still, he's doing this batsh*t crazy buckyball experiment on himself... He's a serious guy. 8-)

--------------------------------------------------------------------
Background...

Statins may aggravate myasthenia gravis

From Wikipedia...

Myasthenia gravis (from Greek μύς "muscle", ἀσθένεια "weakness", and Latin: gravis "serious"; abbreviated MG) is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability. It is an autoimmune disorder, in which weakness is caused by circulating antibodies that block acetylcholine receptors at the postsynaptic neuromuscular junction, inhibiting the excitatory effects of the neurotransmitter acetylcholine on nicotinic receptors throughout neuromuscular junctions.

I don't have time to find the best study, but there are quite a few studies showing that some cases of myasthenia gravas involve a "leaky gut."

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

Let's think this out... I'm not going to repeat or summarize the content of my last post here about the Cholinergic Anti-Inflammatory Pathway (CAIP). I'm assuming everyone's up to speed on it. You should be if you're interested in explanations of the study result.

Assuming my hypothesis that C60 acts to strip methyl groups from the mitochondrial DNA is correct...

Hypothesis #1

• The Olive Oil solvent would have triggered CCK receptors stimulating the Vagus Nerve in the gut.

• The C60s have interacted with damaged CCK receptors (or other elements closely related to it) and stripped the methyl groups from it? The important net result: A resetting of the mitochondrial DNA relating to Vagus Nerve sensitivity in the gut.

• That would also have released acetylcholine via the CAIP.

Alternatively... Hypothesis #2

• The C60s did a reset of methyl groups but on the Acetylcholine Nicotinic Receptors (subunit 10?) causing the Myasthenia Gravas.

• And increased acetylcholine Nicotinic Subunit 7 release somehow impacted the damaged acetylcholine receptor responsible for Myasthenia Gravas.

• I'm less clear about this one... Does it mean anything that it's the Acetylcholine Nicotinic Alpha 7 subunit that is implicated in the CAIP and that it's Acetylcholine Nicotinic Alpha 10 which is implicated in Myasthenia Gravas. Dunno... Just talking out loud...

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If you're truly familiar with the literature I posted yesterday, you'll immediately notice that Hypothesis #1 is actually quite profound and could be a very important element of a plausible explanation of the doubling of life span study result...

A resetting of the Mitochondrial DNA in the gut related to our Innate Anti-Inflammatory mechanisms resets our ability to manage the auto-immune diseases (like cancer) which, increasingly, knock us off as we age... It seems to me to be a big deal...

And BTW, this idea of a resetting of that mechanism in the gut suggests that Turnbuckle has proposed another great idea, namely, that periodic resets by means of Buckyball/Olive Oil could have profound impacts on life extension...

Thoughts? What did I get right? What did I get wrong?

Oh, I forgot, one last thing...

I seriously wish this forum offered the emoticon which shows the person munching on some popcorn and watching the thread.

This is one of the more interesting threads on this forum, IMHO..........

malbecman... put down the popcorn, wipe the butter off your fingers and get yourself on over to google scholar. we're counting on you for some key piece of evidence related to the explanation... 8-)

Edited by wccaguy, 26 May 2012 - 03:17 PM.

[Metrodorus]

wccaguy
"I believe that at least 80% of the scientific knowledge required to explain this buckyball study result already exists in the literature:"

I think not - really, no-one has a handle on what is going on in this rat study that lead to such dramatic results .... assuming the experiment is repeatable.

We can account for some things more or less by way of analogy, but in terms of the actual metabolism of the particular lipo fullerene molecules formed when fullerene reacts/dissolves in olive oil, it is all pretty much up in the air.

I would say we know approximately 0% in terms of the biochemistry what is actually going on with these particular fullerene based molecules in biological systems.

Knowing what we do not know is important. Let's not kid ourselves.

So far we have a collection of hypotheses, no more, no less. Some are more plausible than others.

We have some observed results, with varying degrees of life extension arising in a number of related studies, all testing different fullerene based molecules.

[niner]

J Nutr Biochem. 2010 Apr;21(4):290-6. Epub 2009 Apr 14.
Dietary extra-virgin olive oil rich in phenolic antioxidants and the aging process: long-term effects in the rat.
Jacomelli M, Pitozzi V, Zaid M, Larrosa M, Tonini G, Martini A, Urbani S, Taticchi A, Servili M, Dolara P, Giovannelli L.

Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy. lisa.giovannelli@unifi.it

The aim of the present work was to verify whether extra-virgin olive oil, a food naturally containing phenolic antioxidants, has the potential to protect from the pro-aging effects of a high-calorie diet. Male rats were fed from age 12 months to senescence a high-calorie diet containing either corn oil (CO), or extra-virgin olive oil with high (H-EVOO) or low (L-EVOO) amounts of phenols. The prolonged high fat intake led to obesity, liver lipid degeneration and insulin resistance, which were not counteracted by high phenol intake. No difference in overall survival was found at the end of the experiment in the animals treated with H-EVOO compared to the other groups. However, we did detect a protective effect of olive oil on some age-related pathologies and on blood pressure, of which the former was associated with the antioxidant content. Concomitantly, a decrease in DNA oxidative damage in blood cells and plasma TBARS and an increase in liver superoxide dismutase were detected following H-EVOO consumption. Thus, although olive oil phenols cannot reverse the detrimental effects of a prolonged intake of high amounts of fat, improving the quality of olive oil in terms of antioxidant content can be beneficial.

PMID: 19369055

Yet Baati et al. found an 18% increase in Estimated Median Lifespan from olive oil alone. How to explain this discrepancy?

[niner]

You know folks, I put a huge piece of the puzzle on the table with those posts about the Vagus--CAIP--HRV--HighFatDiet literature. When I got no response, I made that 80% statement deliberately to provoke a response and I got the kind of responses I expected. Is that the best anyone can do? You've got more time before I reply by Monday evening. I want someone to make this harder for me.

Here's a clue... For you to have a winning argument, you're gonna have to be familiar with that Vagus--CAIP--HRV--HighFatDiet literature I pointed to up thread on this page... 8-)

I don't think any of us have the time and energy to go through a dozen papers on the Vagus--CAIP--HRV nexus on the thin chance that it's relevant to the reported effects of C60. Remember, there is a large difference in lifespan enhancement between the olive oil control and the C60/olive oil mixture. I don't see how the vagal mechanism explains that. If you could present the evidence (as concisely as possible, like one paragraph, not ten pages) that olive oil in the sort of dose used here was able to activate the vagal mechanism, then it would get a little more interesting.

[AgeVivo]

Yet Baati et al. found an 18% increase in Estimated Median Lifespan from olive oil alone. How to explain this discrepancy?

temporary treatment
p9 of http://extremelongev...0-Fullerene.pdf :

in order to avoid the negative effects of prolonged olive oil administration such as obesity, excessive steatosis, liver lipid degeneration, and insulin resistance [45], we treated the rats daily only during 7 days and weekly during the first two months, then every two weeks until one control rat died

[JohnD60]

I've read and understand the objections to my recent 80% comment. You know folks, I put a huge piece of the puzzle on the table with those posts about the Vagus--CAIP--HRV--HighFatDiet literature. When I got no response, I made that 80% statement deliberately to provoke a response and I got the kind of responses I expected. Is that the best anyone can do? You've got more time before I reply by Monday evening. I want someone to make this harder for me.

I have a strong bias that the effect of the Fullerenes, if any, is systemic at the cellular or mito level. It does not make any sense to me that a change in one specific bio system would have such a great impact on longevity. As i see it, numerous vagus mutations would have arisen over the past 1000 years, and there would be examples of very long lived people. Given this bias, I will not spend the better part of my day reading all your citations.

[Turnbuckle]

I wonder if C60 is acting like MitoQ (mitoquinone)--

MitoQ is an orally active antioxidant that has the ability to target mitochondrial dysfunction. The agent is currently under development by Antipodean Pharmaceuticals Inc in phase II clinical trials for Parkinson's disease and liver damage associated with HCV infection. MitoQ has demonstrated encouraging preclinical results in numerous studies in isolated mitochondria, cells and tissues undergoing oxidative stress and apoptotic death. MitoQ aims to not only mimic the role of the endogenous mitochondrial antioxidant coenzyme Q10 (CoQ10), but also to augment substantially the antioxidant capacity of CoQ to supraphysiological levels in a mitochondrial membrane potential-dependent manner. MitoQ represents the first foray into the clinic in an attempt to deliver an antioxidant to an intracellular region that is responsible for the formation of increased levels of potentially deleterious reactive oxygen species. Results from the clinical trials with MitoQ will have important repercussions on the relevance of a mitochondrial-targeted approach.

--or at least how people hoped mitoquinone would work--a super CoQ10--whereas it might actually be a prooxidant.

A general discussion on mitoquinone and analogous drugs--
http://www.discovery...s-as-therapies/

CoQ10 itself has not been found to extend the lifespan of rats.

Edited by Turnbuckle, 27 May 2012 - 07:06 PM.

[HighDesertWizard]

wccaguy, on 26 May 2012 - 07:26 PM, said:
I've read and understand the objections to my recent 80% comment. You know folks, I put a huge piece of the puzzle on the table with those posts about the Vagus--CAIP--HRV--HighFatDiet literature. When I got no response, I made that 80% statement deliberately to provoke a response and I got the kind of responses I expected. Is that the best anyone can do? You've got more time before I reply by Monday evening. I want someone to make this harder for me.

I have a strong bias that the effect of the Fullerenes, if any, is systemic at the cellular or mito level. It does not make any sense to me that a change in one specific bio system would have such a great impact on longevity. As i see it, numerous vagus mutations would have arisen over the past 1000 years, and there would be examples of very long lived people. Given this bias, I will not spend the better part of my day reading all your citations.

Thank you John...

Heart Rate Variability (HRV) is computed and measures "Vagal Tone," "Parasympathetic Dominance," "Autonomic Balance," etc.

Higher HRV is healthier and indicative of Vagus Activation/Stimulation. Lower HRV is implicated in more serious disease, morbidity, and death. Kevin Tracey's work on the Vagus/CAIP Nexus explains the physiology and biology of HRV.

In fact, the scientific evidence is clear that numerous vagus mutations must have arisen over thousands of years (because they exist in other mammals) and it is recognized as an independent predictor of present day extreme longevity, by means of Heart Rate Variability measurement.

I've posted about 25 study abstract snippets about HRV to drive home the point here. A sample addressing your specific point...

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Relation of high heart rate variability to healthy longevity

The population's aging underscores the need to understand the process and define the physiologic markers predictive of healthy longevity. The findings that aging is associated with a progressive decrease in heart rate variability (HRV), an index of autonomic function, suggests that longevity might depend on preservation of autonomic function. However, little is known about late life changes.... The HRV-sympathetic function continues to decrease throughout life. In contrast, the decrease in HRV-parasympathetic function reaches its nadir in the eighth decade, followed by reversal and a progressive increase to higher levels (p <0.05), more characteristic of a younger population. In conclusion, healthy longevity depends on preservation of autonomic function, in particular, HRV-parasympathetic function, despite the early age-related decrease. The eighth decade reversal of the decrease in HRV-parasympathetic function and its subsequent increase are key determinants of longevity. Persistently high HRV in the elderly represents a marker predictive of longevity.

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We studied the significance for further survival of heart rate variability and other variables in the very elderly...
Logistic regression analysis using backward elimination detected three factors, dementia, LF/HF , and age, that independently influenced mortality. Mortality risk increased with greater age..., more severe dementia, or lower LF/HF [i.e., HRV].

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Consequently, the low-frequency/high-frequency ratio (0.43±0.07 compared with 0.91±0.05; P < 0.02) was also lower in the healthy centenarians than in the aged subjects. Our study demonstrates that the basal low-frequency/high-frequency ratio, an indirect index of cardiac sympathovagal balance, is lower in healthy centenarians than in aged subjects.

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These data confirm an age-related decline in sympathetic activity. Compared with elderly subjects from 81 to 100 years of age ultra-centenarians have significantly higher spectral parasympathetic indexes. Parasympathetic predominance may be the neuroautonomic feature that helps to protect ultra-centenarians against cardiovascular disease.

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This study demonstrated that age had a greater impact on HRV than sex. The older age group had consistently lower HRV than younger people. The values generated in this study may be useful in health care settings to determine abnormal ranges of HRV under different clinical and experimental conditions.

Edited by wccaguy, 27 May 2012 - 08:42 PM.

[HighDesertWizard]

Consider this...

A good--Hard to Vary and Falsifiable--Explanation* of this life-span-doubling, olive-oil-dissolving-C60s rat study will address issues in "a systemic way at the cellular or mito level" just as John has suggested that it must. It must do so because there is overwhelming evidence that this kind of effect is critical to longevity.

A good explanation must also address (or provide a foundation for addressing) the issue of systemic inflammation because there is overwhelming evidence that inflammation drives aging. A good explanation must also address (or provide a foundation for addressing) the issue of auto-immune action because it's clear that auto-immune diseases kill us off too early. And so on...

When radical life extension is a reality, all the scientifically credible schools of thought about aging will be be able to point to actual evidence and say "see, I told ya so."

I believe this is an extremely useful guide and constraint for us developing explanations in general, and for this rat study in particular.

I'm fleshing out an explanation of this rat study result for myself and, at some point, for presentation here. And I've found it useful to ask myself... "Ok, how is this current explanation formulation valid and useful, not only in terms of one theory of aging, but in several theories of aging." Every time I take that approach, I find some new insight about a known fact that makes the Evolving Explanation Harder to Vary and Falsifiable...


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* I use the phrase "good--Hard to Vary and Falsifiable--Explanation" following the meaning used by David Deutsch. I've posted a youtube video of Deutsch talking about good explanations and a video about Karl Popper's notion of Falsifiability here.

Edited by wccaguy, 27 May 2012 - 09:49 PM.

[Metrodorus]

Oral ingestion of nanotubes as a contaminant : This is the most recent summary of the evidence I could find ( January 2012)

http://www.webmedcen...ticle_view/2932
Single- and multiwalled carbon nanotubes (SW/MWCNTs)
These new nanoproducts are in scope of interest because their size parameters are very close to asbestos. Their primary genotoxicity was rejected evaluating results of in vitro Ames, cytogenetic and in vivo mutagenicity data. Only mitotic inhibition was observed with SW tubes [7]. The investigation on carbon nanotubes has accelerated after Poland and co-workers' scandalous announcement. An unethical media campaign was initiated accusing CNTs of mesothelioma inducing effect based on granuloma formation in a 5-day animal study [8]. Some recent studies delivered further but limited evidences while others rejected the hypothesis. In our rat model only granuloma but no mesothelioma formation was observed after 1-year direct peritoneal exposure to high doses of both SW- and MWCNTs
Footnotes:
7. Szendi K, Varga C. Lack of genotoxicity of carbon nanotubes in a pilot study. Anticancer Res 2008; 28: 349-52.
8. Poland CA, Duffin R, Kinloch I, Maynard A, Wallace WAH, Seaton A, Stone V, Brown S, MacNee W, Donaldson K. Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nature Nanotech 2008; 3: 423-8.
9. Varga C, Szendi K. Carbon nanotubes induce granulomas but not mesotheliomas. In Vivo 2010; 24: 153-6.

My Note: As peritoneal exposure is far more invasive than that which users of fullerene would be exposed to as a result of oral ingestion, I think the risk is small, and even this small risk can be minimised by increasing the purity of the fullerene stock.

Edited by Metrodorus, 27 May 2012 - 09:37 PM.

[Turnbuckle]

I’d previously suggested that C60 reduced methylation of mtDNA and thereby reset the epigenetic age to zero, but here is a new paper that shows that mitochondrial methylation actually decreases with increasing age. (See Fig. 2 where the 5-hydroxymethylcytosine content drops off dramatically between 4 and 24 months.)

http://www.scribd.co...in-Mitochondria

Nuclear DNA seems to go in the opposite direction. The same paper says “In postmortem human brain samples, methylation of nuclear DNA (ncDNA) appears to positively correlate with aging.”

Dang.

[niner]

Yet Baati et al. found an 18% increase in Estimated Median Lifespan from olive oil alone. How to explain this discrepancy?

temporary treatment
p9 of http://extremelongev...0-Fullerene.pdf :

in order to avoid the negative effects of prolonged olive oil administration such as obesity, excessive steatosis, liver lipid degeneration, and insulin resistance [45], we treated the rats daily only during 7 days and weekly during the first two months, then every two weeks until one control rat died

Could be. Has no one ever tested animals with a periodic (and relatively short term) dose of good olive oil without seriously perturbing their diet? If we're to take this Baati paper at face value, then I think we ought to all be hitting the olive oil. A third of the olive oil-only cohort lived 58 months, which must be unheard of in Wistar rats. The rats got about 2ml oil per kg body weight. 140ml for a 70kg human? (without allometric scaling, otherwise less) Is there something special about these large boluses of oil? A lot of people use a couple tablespoons of oil a day; I always have a bottle on the table and put it on a lot of things. Should I occasionally be drinking a half cup of it? Umm, yuck, but I guess we'd only have to do it 24 times in our life. Or should that be scaled to our longer lifespan?

I'm saying all of this as though it were reasonable to take Baati at face value, but that olive oil result is just crazy! How can that possibly be right? Was someone playing a huge practical joke on these guys, periodically replacing their rats with younger ones? This study really, REALLY needs replication. And yet the wheels of commerce are spinning already... Gotta strike while the iron is hot, I guess.

[niner]

I wonder if C60 is acting like MitoQ (mitoquinone)--

That's what I proposed in post 313 of this thread, except that the example I used was a related compound, SkQ1. I still think this is a plausible explanation, mainly hinging on the ability of C60 to react with unsaturated fatty acids under mild conditions, which it appears to do. SkQ1 is reported to be good at squaring the lifespan curve in rodents, which C60/olive oil is extremely good at, if we believe what we read in the paper...

[JohnD60]

Was someone playing a huge practical joke on these guys, periodically replacing their rats with younger ones?

Or one of the student lab assistants accidently killed some rats while placing the olive oil in their stomachs, and replaced them with younger rats. A more optiimistic senario would be that the 'olive oil only' rats were accidently given 'olive oil w/C60" once or twice.

[Junk Master]

Sure seems there's something to high dose olive oil for inflammation. Dang, my Italian Dad has been touting the stuff for years!

[HighDesertWizard]

Could be. Has no one ever tested animals with a periodic (and relatively short term) dose of good olive oil without seriously perturbing their diet? If we're to take this Baati paper at face value, then I think we ought to all be hitting the olive oil. A third of the olive oil-only cohort lived 58 months, which must be unheard of in Wistar rats. The rats got about 2ml oil per kg body weight. 140ml for a 70kg human? (without allometric scaling, otherwise less) Is there something special about these large boluses of oil? A lot of people use a couple tablespoons of oil a day; I always have a bottle on the table and put it on a lot of things. Should I occasionally be drinking a half cup of it? Umm, yuck, but I guess we'd only have to do it 24 times in our life. Or should that be scaled to our longer lifespan?

I'm saying all of this as though it were reasonable to take Baati at face value, but that olive oil result is just crazy! How can that possibly be right? Was someone playing a huge practical joke on these guys, periodically replacing their rats with younger ones? This study really, REALLY needs replication. And yet the wheels of commerce are spinning already... Gotta strike while the iron is hot, I guess.

The explanation for that Olive Oil only study result has already been figured out. I posted about it in post #501. Start reading that post beginning at Second... The essential explanatory flow goes like this...

Long Fatty Acids in the Gut (Olive Oil) -->> Cholecystokinin (CCK) Receptors (GPR40) -->>
Vagus Nerve Stimulation/Activation -->> Greater Parasympathetic ANS Dominance >>
M1 Control in the brain >> Systemic or Localized (Monocyte/Macrophage) Acetylcholine Release >>
Acetylcholine Nicotinic Alpha 7 Receptor >> NF-Kb Suppression >> TNF-a inhibition >>
Reduced Danger of an Over Expressed Auto-Immune Response

And if that weren't enough... This can be monitored real time...

>> Close to real time "Vagal Tone State" data is available via Heart Rate Variability (HRV) measurement.

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More good news? This isn't a rat-only phenomenon... That same CAIP result--very long lifespans--has been shown to exist in humans... See the amazing first study posted finding, highlighted in red, in my post #551 here.

More good news? Vagus Nerve Activation, measured real time via biofeedback by higher HRV, can be trained...

This is NOT to say that the Fullerenes aren't important...

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I think Kevin Tracey is going to win the Nobel Prize for Medicine for his work on this: The Cholinergic Anti-Inflammatory Pathway (CAIP)...

I introduced the literature of the CAIP in this longecity forum thread 2 days ago...

8-)

Edited by wccaguy, 28 May 2012 - 05:12 AM.

[geo]

I wonder. According to the theories (on how C60 might work) mentioned in this forum, what would an old person (say, over 80) expect by taking C60 with olive oil? I mean, whould this person expect improvement of just a delay of what is next to come? In other words, is it logical to assume that by taking C60 with olive oil (assuming of course that the rat study is correct and that it can be applied in humans exactly as it is), the old person will experience a "becoming younger" effect?