3585 replies to this topic

[HighDesertWizard]

Metrodorus... I have very much appreciated your posts. They have helped me to realize where my thoughts about the method of action were wrong...

That said, we disagree about how much we already know... We've disagreed about that for a while... Disagreement is a good thing.

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

Figure 2 shows Fullerene C60s in macrophages in the spleen. There is a voluminous scientific literature about macrophages in mammals, including humans. What we know, from Figure 2 of the Baati study, is that any Complete Explanation will involve some kind of Explanation of those Fullerenes shown in the macrophages. This is not so simple a thing...

And it's a big data point. Don't you think? If you don't agree that's a big data point, then, make the argument that we should ignore it...

You've insisted, at least a couple times now, that the science of Fullerenes is incompletely understood, And I agree that it is. But I have not understood that you were arguing that Fullerene C60s magically changed all the known and published science about macrophages, I mean, specifically, their essential functions and detailed activity...

I don't believe in that kind of magic. And it turned out Version 1 of my JAC Explanation couldn't survive serious reflection about the meaning of that Figure 2 data point... So... my Round 1 Version got knocked out...

We'll soon see if the other two Round 1 Contending Explanations can survive the Figure 2 Evidence Test as is. I don't think they can. And I'm going to try to make the case that they can't survive it as is. Sure, they can be adapted, get broader, and grow, just as I intend to grow the JAC Version 1 Explanation... I hope they can survive it. I want them to survive it. I'm going to steal components of the other 2 contending Explanations and integrate them into the JAC Round 2 Explanation.

I think this game is fun to play...

Edited by wccaguy, 24 June 2012 - 04:22 AM.

[niner]

Figure 2 shows Fullerene C60s in macrophages in the spleen. There is a voluminous scientific literature about macrophages in mammals, including humans. What we know, from Figure 2 of the Baati study, is that any Complete Explanation will involve some kind of Explanation of those Fullerenes shown in the macrophages. This is not so simple a thing...

And it's a big data point. Don't you think? If you don't agree that's a big data point, then, make the argument that we should ignore it...

I don't think so. Fig 2 shows macrophages that contain visible particles ("crystals" or aggregates of some kind) of what is thought to be a C60 compound. This was in animals that were given an extra high dose of C60/OO by intraperitoneal injection. The mice getting the same high dose orally had little or no particles in the spleen. Essentially what has happened here is the C60 compound precipitated out in the blood, which was filtered by the spleen. The macrophages did their normal job of phagocytosing particulate junk in the blood, just like they would do if you were standing near a bus breathing diesel smoke. There's no reason to believe that this has anything to do with the remarkable results of the long term arm of the study, which used only oral dosing with a lower dose of C60. When dosed orally, with a lower mg/kg dose, there won't be the sort of precipitation in the blood that was seen with high i.p. dosing.

[Metrodorus]

I'm with niner on this one....in fact, Baati , if I recall, points out that the precipitated fullerene is biologically a non-participant, and its presence in the macrophages was not significant.

It is only while it is in dissolved state that the fullerene has its affect, according to Baati's understanding of the data, as stated explicitly in the study.

[HighDesertWizard]

Figure 2 shows Fullerene C60s in macrophages in the spleen. There is a voluminous scientific literature about macrophages in mammals, including humans. What we know, from Figure 2 of the Baati study, is that any Complete Explanation will involve some kind of Explanation of those Fullerenes shown in the macrophages. This is not so simple a thing...

And it's a big data point. Don't you think? If you don't agree that's a big data point, then, make the argument that we should ignore it...

I don't think so. Fig 2 shows macrophages that contain visible particles ("crystals" or aggregates of some kind) of what is thought to be a C60 compound. This was in animals that were given an extra high dose of C60/OO by intraperitoneal injection. The mice getting the same high dose orally had little or no particles in the spleen. Essentially what has happened here is the C60 compound precipitated out in the blood, which was filtered by the spleen. The macrophages did their normal job of phagocytosing particulate junk in the blood, just like they would do if you were standing near a bus breathing diesel smoke. There's no reason to believe that this has anything to do with the remarkable results of the long term arm of the study, which used only oral dosing with a lower dose of C60. When dosed orally, with a lower mg/kg dose, there won't be the sort of precipitation in the blood that was seen with high i.p. dosing.

Yes. PRECISELY...

Among other things, the function of macrophages is to recognize threats to the Host and defend against the threat. And when Fullerene C60s were presented to the Host in I.P. extra high doses, the evidence of Figure 2 is that macrophages "understood" the C60s to be threats and "consumed" them, incorporating the C60s into themselves, to extinguish the threat to the Host.

The dilemma of the Figure 2 data is this... HOW does some exogenous to the Host substance (C60s), understood by macrophages to be a threat, result in a non-trivial extension of life span?

I thought this through. I couldn't keep my Round 1 Explanation alive as is because I couldn't answer that question. I'm working on an enhanced Round 2 Version

I can't count how many times now I've embarrassed myself with foolish comments in this thread...

I advise careful reflection about this before answering...

Do we ALL really believe our ROUND ONE EXPLANATIONS are the BEST EXPLANATIONS?

As we all are probably aware, Thomas Edison was proud of the fact that it took him ONLY 1000 mistaken hypotheses to invent a light bulb that worked. Do we REALLY think significant life extension is less difficult a problem?

I think it's more difficult and I think, upon reflection, most of us do...

Edited by wccaguy, 24 June 2012 - 04:46 AM.

[niner]

The dilemma of the data of Figure 2 to be Explained is this... HOW does some exogenous to the host substance (C60s) understood by macrophages to be a threat result in a non-trivial extension of life span?

By being in solution, and getting into the mitochondrial membrane, instead of being in the form of a large particle.

[HighDesertWizard]

Background... Macrophages exist throughout the Host. We have evidence that, at least in the spleen, C60s were understood to be a threat, and yet there was a significant life extension impact...

How did C60s get incorporated into Cell Membranes easily without Macrophages recognizing them as threats?

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

From Inflammation and Cancer: Chemical Approaches to Mechanisms, Imaging, and Treatment, 2012

Inflammation is a systemic response to pathogen challenge and injury. It is characterized by the influx of inflammatory cells (e.g., macrophages and neutrophils), induction of vasoconstriction, edema (swelling), erythema (redness), and sensitivity to pain.(1) The logic of inflammation is to defend against the invading pathogen by conducting chemical warfare while limiting damage to the region of the initial infection. Ultimately, inflammatory lesions resolve, and local wounds heal. Acute inflammation is a critical element of host defense, and individuals with genetic mutations that disable the inflammatory response are at elevated risk of infection.(2) Although acute inflammation is beneficial to the organism (albeit perhaps painful and annoying), chronic inflammation contributes to the etiology of many diseases. The list is too long to tabulate but includes cancer, cardiovascular disease, and diabetes. There are many mediators generated during an inflammatory response. Some contribute to the toxicological events that kill the invading pathogen, whereas others recruit additional inflammatory cells to the site of the lesion, induce vasoconstriction, or promote resolution and wound healing. Oxidized lipids, particularly those derived from polyunsaturated fatty acids, contribute to all of these events.(3) Our group studies the chemical events that contribute to inflammation, especially as they relate to cancer. This perspective will highlight some of the key chemical reactions associated with inflammation and cancer that may be mediated by oxygenated metabolites of polyunsaturated fatty acids.

Reactive Species Generated During Inflammation

During the inflammatory response, professional killer cells such as macrophages generate a panoply of highly reactive oxidants as part of the chemical warfare waged on an invading pathogen (Figure 1).(4, 5) All of these oxidants derive from the production of two free radical species—the superoxide anion radical (O2–) and nitric oxide (•NO). Activation of macrophages or neutrophils by particulate or soluble stimuli triggers a burst of O2 consumption catalyzed by the cell surface protein, NADPH oxidase, which transfers an electron from NADPH to oxygen to form O2–.(6) There are a number of NADPH oxidases in humans, but the enzyme in neutrophils and macrophages catalyzes a particularly robust reduction of O2.(7) Concomitant with O2 reduction, arginine is oxidized to •NO by nitric oxide synthase (NOS).(8) There are three NOS’s in human tissue, but the inducible form in macrophages (NOS-2 or iNOS) is of particular interest with respect to inflammation.(9)

Edited by wccaguy, 24 June 2012 - 05:04 AM.

[revenant]

Happy Physicist last post was June 13th. Does anyone know if he is ok?

[taho]

How did C60s get incorporated into Cell Membranes easily without Macrophages recognizing them as threats?

They are probably too small to be recognised as a threat.

It sees a small pack of (more or less) inert atoms or a deformed lipid. Clusters of c60 that could be recognised, break apart when entering lipid membrane, so that "removes" them.

[smithx]

Happy Physicist last post was June 13th. Does anyone know if he is ok?

I was also worrying about him. Does anyone have contact info?

[Turnbuckle]

Happy Physicist last post was June 13th. Does anyone know if he is ok?

I was also worrying about him. Does anyone have contact info?

Contacting a member through this site should get to them.

[arska]

Another study on fullerene toxicity with

Wistar rats

:
http://www.particlea...m/content/7/1/4

--------

Results

In the intratracheal instillation study, both the 0.1 mg and 0.2 mg fullerene groups did not show a significant increase of the total cell and neutrophil count in BALF or in the expression of CINC-1,-2αβ and-3 in the lung, while the high-dose, 1 mg group only showed a transient significant increase of neutrophils and expression of CINC-1,-2αβ and -3. In the inhalation study, there were no increases of total cell and neutrophil count in BALF, CINC-1,-2αβ and-3 in the fullerene group.

-----

[Allen Walters]

I went out riding my bike yesterday and can say c60/oo doesn't stop sunburns. Also went out drinking last night and have a healthy hangover today, so no improvement in alcohol tolerance for me. The only side effect I've noticed is that I sleep longer, and that's it so far.

[Spider_]

Happy Physicist last post was June 13th. Does anyone know if he is ok?

I believe he is on vacation at the moment.

[Metrodorus]

Fullerenes in olive oil are pretty. Here is a shot I snapped from my phone of the City of London viewed through a bottle of fullerene dissolved in olive oil.

Edited by Metrodorus, 24 June 2012 - 05:50 PM.

[Metrodorus]

Just to put the whole macrophage - fullerene pathway to bed, here are some studies that show no significant effect on macrophages.

http://www.sciencedi...008622305006871


Anti-inflammatory action:
http://www.jimmunol....179/1/665.short

No significant difference from the control group in vivo
http://pubs.acs.org/....1021/nl0710710

This study (fullerene dissolved in squalane) is probably as close as we can get at the moment to an olive-oil fullerene model, in the extant literature:
http://www.sciencedi...14296121000548X

[niner]

This study (fullerene dissolved in squalane) is probably as close as we can get at the moment to an olive-oil fullerene model, in the extant literature:
http://www.sciencedi...14296121000548X

Thanks for the refs, Metrodorus. From this abstract:

Our results suggest that Sql-fullerene might be explored as a potential medicine for the treatment of metabolic syndrome or other obesity-related disorders.

This seems to be consistent with what we're seeing.

[zen]

Sub-acute oral toxicity study with fullerene C60 in rats
https://www.jstage.j...ticle/-char/ja/

....(vehicle: corn oil), 1, 10, 100, or 1,000 mg/kg/day for 29 days, followed by a 14-day recovery period. No deaths occurred in any groups, and there were no changes from controls in detailed clinical observations, body weights, and food consumption in any treatment groups. Moreover, no treatment-related histopathological changes were found in any organs examined at the end of the administration period and at the end of the recovery period.....

[Turnbuckle]

Sub-acute oral toxicity study with fullerene C60 in rats
https://www.jstage.j...ticle/-char/ja/

....(vehicle: corn oil), 1, 10, 100, or 1,000 mg/kg/day for 29 days, followed by a 14-day recovery period. No deaths occurred in any groups, and there were no changes from controls in detailed clinical observations, body weights, and food consumption in any treatment groups. Moreover, no treatment-related histopathological changes were found in any organs examined at the end of the administration period and at the end of the recovery period.....

The interesting part--Using liquid chromatography-tandem mass spectrometry, fullerene C60 were not detected in the liver, spleen or kidney at the end of the administration period and also at the end of the recovery period--so you wonder if any was actually dissolved in the corn oil.

[niner]

The interesting part--Using liquid chromatography-tandem mass spectrometry, fullerene C60 were not detected in the liver, spleen or kidney at the end of the administration period and also at the end of the recovery period--so you wonder if any was actually dissolved in the corn oil.

Yep. They hardly got anything dissolved, so the rats were dosed with big chunks of C60 floating in corn oil. You can see that from the micrographs. They just didn't give it enough time to dissolve. Later, the feces and stomach contents of the high dose (1000mg/kg!?, are they kidding?) animals they sacrificed were black. So they just pooped out the vast majority of the C60. These guys didn't centrifuge or filter their solutions. They also admitted that the solubility in corn oil, for them, was only 0.1 mg/ml. So this doesn't add much to the Baati study, except for one point that might be quite important to us: If we were to skip filtration and centrifugation, we'd probably just poop out the particles, which has been pointed out by others in this thread already. That's actually a pretty significant result, for our purposes.

@zen, thanks for that paper.

[Turnbuckle]

If we were to skip filtration and centrifugation, we'd probably just poop out the particles, which has been pointed out by others in this thread already. That's actually a pretty significant result, for our purposes.

And we would live at least 2 more weeks, though I'm not so sure that would do me.

[niner]

If we were to skip filtration and centrifugation, we'd probably just poop out the particles, which has been pointed out by others in this thread already. That's actually a pretty significant result, for our purposes.

And we would live at least 2 more weeks, though I'm not so sure that would do me.

Yeah, it's only acute tox. At least we know it won't kill (or obviously harm) us immediately. Do we have any reason to believe it would harm us? (other than "we don't know")

[maxwatt]

Here is a paper Sillewater turned up on olive oil. OO intake was associated with a significant decrease in mortality. Consistent with Baati's study results. I wonder about he interaction between OO and C60. Just what exactly is going on?

Am J Clin Nutr. 2012 Jul;96(1):142-9. Epub 2012 May 30.

Olive oil intake and mortality within the Spanish population (EPIC-Spain).

Buckland G, Mayén AL, Agudo A, Travier N, Navarro C, Huerta JM, Chirlaque MD, Barricarte A, Ardanaz E,Moreno-Iribas C, Marin P, Quirós JR, Redondo ML, Amiano P, Dorronsoro M, Arriola L, Molina E, Sanchez MJ, Gonzalez CA.

Source

Unit of Nutrition, Environment, and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Spain.

Abstract

BACKGROUND:

Olive oil consumption is associated with a decreased risk of several chronic diseases, in particular cardiovascular disease (CVD). However, data on the effects of olive oil on overall mortality are scarce.
OBJECTIVE:

We evaluated the association between olive oil and overall and cause-specificmortality in the Spanish population in the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain).
DESIGN:

A total of 40,622 participants (62% female) aged 29-69 y were recruited from 5 Spanishregions in 1992-1996. The association between olive oil (analyzed as a categorical and continuous variable) and overall and cause-specific mortality (CVD, cancer, and other causes) was analyzed by using Cox proportional hazards regression models adjusted for potential confounders.
RESULTS:

A total of 1915 deaths were reported during 13.4 y of follow-up: 416 CVD deaths, 956 cancer deaths, and 417 deaths from other causes (for 126 deaths the cause was not available). In comparison with nonconsumers, the highest quartile of olive oil consumption was associated with a 26% (95% CI: 13%, 36%) reduction in risk of overall mortality and a 44% (95% CI: 21%, 60%) reduction in CVD mortality. For each increase in olive oil of 10 g · 2000 kcal(-1) · d(-1), there was a 7% (95% CI: 3%, 10%) decreased risk of overall mortality and a 13% (95% CI: 6%, 20%) decreased risk of CVD mortality. No significant association was observed between olive oil and cancer mortality.
CONCLUSIONS:

Olive oil was associated with a decreased risk of overall mortality and an important reduction in CVD mortality in this large Mediterranean cohort. This provides further evidence on the beneficial effects of one of the key Mediterranean dietary components.

PMID: 22648725

from the paper:

In our study we observed a 26% reduction in mortality in healthy adults in the upper quartile of olive oil consumption, which corresponded to an intake of >29.4 g · 2000 kcal⁻¹ · d⁻¹. These findings contrast with those reported in the EPIC-Greek cohort, which found that olive oil was not associated with overall mortality (13). However, because of its longer follow-up period, our study included more deaths and so may have had a greater statistical power to detect an association. In addition, differences in culture, lifestyle, and background diet may influence results.

29 g = about 2 T of olive oil. Not a lot.

Edited by maxwatt, 26 June 2012 - 03:08 PM.

[HappyPhysicist]

Hey all, thanks for asking about me. I'm doing well. Not much to report. I am still taking the C60/OO. I haven't noticed anything good or bad and I can't tell if my rate of progression has changed.

I am considering upping my dose but to do this I would have to mix the C60/OO with Ensure. I can't imagine doing so would separate the C60 from the Olive Oil.

Any opinions?

[Junk Master]

What is the downside? I can't think of any. From what I've read I'm not convinced filtration or centrifuging is necessary at all. In your case, why not push the envelope?

Keep in mind, I wish you the best, you are in my prayers, and am not trying to influence your personal decisions in any way.

[Rob Wegner]

The movie "Lorenzo's Oil," which is a true story, is based on parents persisting to find a cure for their son until they finally hit upon a therapy involving adding a certain kind of oil containing two specific long chain fatty acids, isolated from rapeseed [canola] oil and olive oil to their son's diet.

[Turnbuckle]

If we were to skip filtration and centrifugation, we'd probably just poop out the particles, which has been pointed out by others in this thread already. That's actually a pretty significant result, for our purposes.

And we would live at least 2 more weeks, though I'm not so sure that would do me.

Yeah, it's only acute tox. At least we know it won't kill (or obviously harm) us immediately. Do we have any reason to believe it would harm us? (other than "we don't know")

One example not directly relevant to the filtration issue: It's possible that fullenenes that accumulate in mitochondrial membranes would interfere with Cytochrome P450 enzymes that also accumulate there. As such they would potentiate the effects of drugs normally degraded by P450--about 75% of all drugs--and could lead to toxic effects of drug doses that were previously nontoxic.

Suppression of P450 has been reported for fullerenols, and I'd expect even more activity for the more hydrophobic fullerenes.

For myself, I'm now wondering if the weird feeling I've been experiencing in the past week is actually due to the 10-20 cups of coffee I drink every day. This would probably be toxic for most people, but as a long term caffeine junkie, it's been okay for me...until now.

Edited by Turnbuckle, 25 June 2012 - 12:42 PM.

[daouda]

One example not directly relevant to the filtration issue: It's possible that fullenenes that accumulate in mitochondrial membranes would interfere with Cytochrome P450 enzymes that also accumulate there. As such they would potentiate the effects of drugs normally degraded by P450--about 75% of all drugs--and could lead to toxic effects of drug doses that were previously nontoxic.

Suppression of P450 has been reported for fullerenols, and I'd expect even more activity for the more hydrophobic fullerenes.

For myself, I'm now wondering if the weird feeling I've been experiencing in the past week is actually due to the 10-20 cups of coffee I drink every day. This would probably be toxic for most people, but as a long term caffeine junkie, it's been okay for me...until now.

This is consistent with JG's anecdotal report there http://www.longecity...post__p__520543
This is a very important thing to establish ASAP (for those already experimenting with C60) so that ppl will adjust dosing of meds and certain supplements (plus certain "dietary drugs" like coffea) accordingly... Not only to we want to avoid injurious toxic effects, but noone wants to have a car accident because of extraordinary drowsiness from a usually mildly anxiolitic dose of some drug or supplement, or insomnia/anxiety from a reasonable dose of stimulant taken in the morning.

[niner]

One example not directly relevant to the filtration issue: It's possible that fullenenes that accumulate in mitochondrial membranes would interfere with Cytochrome P450 enzymes that also accumulate there. As such they would potentiate the effects of drugs normally degraded by P450--about 75% of all drugs--and could lead to toxic effects of drug doses that were previously nontoxic.

Suppression of P450 has been reported for fullerenols, and I'd expect even more activity for the more hydrophobic fullerenes.

For myself, I'm now wondering if the weird feeling I've been experiencing in the past week is actually due to the 10-20 cups of coffee I drink every day. This would probably be toxic for most people, but as a long term caffeine junkie, it's been okay for me...until now.

This is consistent with JG's anecdotal report there http://www.longecity...post__p__520543
This is a very important thing to establish ASAP (for those already experimenting with C60) so that ppl will adjust dosing of meds and certain supplements (plus certain "dietary drugs" like coffea) accordingly... Not only to we want to avoid injurious toxic effects, but noone wants to have a car accident because of extraordinary drowsiness from a usually mildly anxiolitic dose of some drug or supplement, or insomnia/anxiety from a reasonable dose of stimulant taken in the morning.

I agree that P450 inhibition, particularly of 3A4, is a possible outcome of fullerene use. For the sake of a little perspective, though, we should consider the following: "P450" isn't an enzyme, it's a huge class of enzymes with very different active site geometries, thus very different substrate specificities. Most of them will not be inhibited by fullerenes, because they won't fit in the active site. 3A4 is a particular exception, since it likes large hydrophobes. The percentage of drugs that are metabolized by 3A4 and its close relatives is significant, but it's not 75%. The P450 enzymes that are involved in drug metabolism are widely disseminated throughout the body, with the gut and liver being particularly high in them. The enzymes of the P450 class that are associated with mitochondria are not the ones that metabolize drugs and other xenobiotics. P450 levels are quite fluid. When you take a drug or a supplement for a while, it will actually upregulate the expression of the P450 that metabolizes it. That's one of the many reasons that some drugs seem to lose effectiveness after a while. Thus, a little bit of inhibition might actually make a drug "work better". Obviously, a LOT of inhibition, particularly for a drug that has only one metabolic pathway, is a potential problem. However the majority of drugs have a pretty large window of blood levels that are at least non-lethal. Most drugs have multiple metabolic pathways as well. Finally, we should bear in mind that there are a LOT of P450 inhibitors. Many drugs and even foods are P450 inhibitors. Grapefruit interfering with statin metabolism is a famous example, but there are many more. The odds of a bad outcome because of possible P450 inhibition by C60 are very low. It's something to be aware of, just like one should be aware of the possibility of interaction between any compounds that we mix. It's not something that you need to lose any sleep over; just be observant.

[Allen Walters]

I took my temp before my 15ml of c60/oo, it was 98.5. I took it again 1hr later and it's 98.8. yesterday I took it 4hrs after, and it was 99.2. I will check it again before I leave for work at 3:30.

[Turnbuckle]

The enzymes of the P450 class that are associated with mitochondria are not the ones that metabolize drugs and other xenobiotics.

C60 and P450 enzymes responsible for metabolizing many drugs localize in the same places, including the mitochondria.

Constitutively expressed human cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of approximately 25% of drugs in common clinical use. It is widely accepted that CYP2D6 is localized in the endoplasmic reticulum of cells; however, we have identified this enzyme in the mitochondria of human liver samples and found that extensive inter-individual variability exists in the level of the mitochondrial enzyme.

http://www.ncbi.nlm....les/PMC2789264/

and

We show C70-TR [C70 conjugated with Texas Red for visualization] are non-specifically endocytosed into MC [mast cells] where they are shuttled throughout the cytoplasm, lysosomes, mitochondria, and into endoplasmic reticulum at different times.

http://www.ncbi.nlm....?tool=pmcentrez

CYP1A2, the P450 enzyme that metabolizes caffeine, is localized to the endoplasmic reticulum where it no doubt meets up with C60. Does anything happen? I don't know. I don't even know if I even have a problem with caffeine or with one of the many other supplements I take. But at the moment it is suspicious, so I will go cold turkey on the brew and see what happens.

Edited by Turnbuckle, 25 June 2012 - 04:16 PM.