25 replies to this topic

[curious_sle]

hat-tip to rs1000 over at sci.life-extension
-
Neurobiol Aging. 2006 Oct 30; [Epub ahead of print]

A carboxyfullerene SOD mimetic improves cognition and extends the
lifespan of mice.

Quick KL, Ali SS, Arch R, Xiong C, Wozniak D, Dugan LL.

Department of Neurology, Washington University School of Medicine, St.
Louis, MO 63110, United States.

In lower organisms, such as Caenorhabditis elegans and Drosophila,
many genes identified as key regulators of aging are involved in
either detoxification of reactive oxygen species or the cellular
response to oxidatively-damaged macromolecules. Transgenic mice have
been generated to study these genes in mammalian aging, but have not
in general exhibited the expected lifespan extension or beneficial
behavioral effects, possibly reflecting compensatory changes during
development. We administered a small-molecule synthetic enzyme
superoxide dismutase (SOD) mimetic to wild-type (i.e. non-transgenic,
non-senescence accelerated) mice starting at middle age. Chronic
treatment not only reduced age-associated oxidative stress and
mitochondrial radical production, but significantly extended lifespan.
Treated mice also exhibited improved performance on the Morris water
maze learning and memory task. This is to our knowledge the first
demonstration that an administered antioxidant with mitochondrial
activity and nervous system penetration not only increases lifespan,
but rescues age-related cognitive impairment in mammals. SOD mimetics
with such characteristics may provide unique complements to genetic
strategies to study the contribution of oxidative processes to nervous
system aging.

PMID: 17079053

From full text:

"Here we show that an orally-administered SOD mimetic can
significantly increase lifespan and reduce mitochondrial free radical
production. [...] Non-transgenic C57BL6 mice which received C3 from
12 months of age had an increase in mean (11%) and median (15%)
lifespan (Fig. 2a). Calorie restriction (CR) initiated at 12 months
age extends mean lifespan by 14% (median lifespan by 16%) [36], a
shift in survival that is similar to ours. Since CR has also been
reported to improve free radical handling, this may indicate that
there are overlapping mechanisms between these two interventions. If
this is true, then one would predict that initiating treatment with C3
at 2-3 months of age would result in an even greater increase in
lifespan, since CR started at 2 months of age increases lifespan by
more than 25% [43]."

[olaf.larsson]

Fascinating article, thank you.

[pone11]

Wow, this post from 2007 predates Baati's C60 study by many years, and no one picked up on it.   Let me highlight it.   The full text of the study is here:

http://www.sciencedi...197458006003423

 

This study extends lifespan in *wild* mice by about 11%, but also had pretty remarkable affects on sparing neurological impairment during the aging.   Like C60, C3 was thought to have its effects as an SOD mimetic.

 

In looking through the footnotes, this one that explains the C60 derivative C3 was interesting:

http://www.ncbi.nlm....pubmed/15451059

 

The second study on C3 explains: "Here we show that a tris-malonic acid derivative of the fullerene C60 molecule (C3) is capable of removing the biologically important superoxide radical with a rate constant (k(C3)) of 2 x 10(6) mol(-1) s(-1), approximately 100-fold slower than the superoxide dismutases (SOD), a family of enzymes responsible for endogenous dismutation of superoxide. This rate constant is within the range of values reported for several manganese-containing SOD mimetic compounds. The reaction between C3 and superoxide was not via stoichiometric "scavenging," as expected, but through catalytic dismutation of superoxide, indicated by lack of structural modifications to C3, regeneration of oxygen, production of hydrogen peroxide, and absence of EPR-active (paramagnetic) products, all consistent with a catalytic mechanism."

 

Here are the questions I have on the above:

 

* Can any of the chemists among us explain what is the difference between C3 and C60 as Baati used it, in terms of either structure or action?

 

* As I understand it, C60 acts like an SOD2 mimetic that has primary action within mitochondrial membranes.   SOD3 is typically found in extracellular spaces and on the surface of cell membranes, protecting the extracellular area.    Are there any known good SOD3 mimetics that do not decrease endogenous SOD3?   Given that all the C60 studies mention SOD2 and say nothing on SOD3, I assume that C60 is not an SOD3 mimetic?

 

* Was Baati's better result than the above study due to a liposomal formulation, thus increasing bioavailability of the C60?    Or are the differences in the two studies attributable primarily to dosing?   And at some dose of C3 - administered in the same form as the study linked above - might we have seen a similar life extension effect as Baati?

 

At the risk of sounding like a broken record from my other posts, no one has ever done dosing studies on C60.   Recently, a structurally similar antioxidant IAC was studied by an Italian group:

http://biomedgeronto...na.glu160.short

 

See Table 1 in the study.   The dose response of IAC is remarkable!  At specific doses they get 170% lifespan extension, and at slight higher doses more than 50% lifespan REDUCTION.   It may be that these SOD mimetics have very specific ranges of biological usefulness, and lower-than-expected doses of toxicity.    And looking at Table 1, the toxicity is not subtle.   These are remarkable reductions in life expectancy.  The antioxidant had a narrow range of benefit.   It's fantastic that the researcher was thoughtful enough to test at so many concentrations.   

 

It is a very fair question to ask will C60 have a similar limited range of benefit, and will C60 lower lifespan at high doses.    This study result on IAC is cautionary.   Those of you who are megadosing C60 really need to read the above study on IAC, study Table 1, and think about the risks you are taking.

 

The world badly needs some dose response studies on C60 in mice or mammals.

 

Edited by pone11, 21 March 2015 - 08:23 PM.

[Kalliste]

Quite possibly it will have deleterious side-effects. Mitohormesis is a corner-stone of health. I don't have a hard time seeing that effect disturbed by an effective antioxidant. IIRC some researchers have achieved significant LE in animals by stopping the endogenous production of some antioxidants via gene-knockout partially. Think it was posted on Fightaging.

 

 

 

 

[niner]

Wow, this post from 2007 predates Baati's C60 study by many years, and no one picked up on it.   Let me highlight it.   The full text of the study is here:

http://www.sciencedi...197458006003423

 

This study extends lifespan in *wild* mice by about 11%, but also had pretty remarkable affects on sparing neurological impairment during the aging.   Like C60, C3 was thought to have its effects as an SOD mimetic.

 

In looking through the footnotes, this one that explains the C60 derivative C3 was interesting:

http://www.ncbi.nlm....pubmed/15451059

 

The second study on C3 explains: "Here we show that a tris-malonic acid derivative of the fullerene C60 molecule (C3) is capable of removing the biologically important superoxide radical with a rate constant (k(C3)) of 2 x 10(6) mol(-1) s(-1), approximately 100-fold slower than the superoxide dismutases (SOD), a family of enzymes responsible for endogenous dismutation of superoxide. This rate constant is within the range of values reported for several manganese-containing SOD mimetic compounds. The reaction between C3 and superoxide was not via stoichiometric "scavenging," as expected, but through catalytic dismutation of superoxide, indicated by lack of structural modifications to C3, regeneration of oxygen, production of hydrogen peroxide, and absence of EPR-active (paramagnetic) products, all consistent with a catalytic mechanism."

 

Here are the questions I have on the above:

 

* Can any of the chemists among us explain what is the difference between C3 and C60 as Baati used it, in terms of either structure or action?

 

* As I understand it, C60 acts like an SOD2 mimetic that has primary action within mitochondrial membranes.   SOD3 is typically found in extracellular spaces and on the surface of cell membranes, protecting the extracellular area.    Are there any known good SOD3 mimetics that do not decrease endogenous SOD3?   Given that all the C60 studies mention SOD2 and say nothing on SOD3, I assume that C60 is not an SOD3 mimetic?

 

* Was Baati's better result than the above study due to a liposomal formulation, thus increasing bioavailability of the C60?    Or are the differences in the two studies attributable primarily to dosing?   And at some dose of C3 - administered in the same form as the study linked above - might we have seen a similar life extension effect as Baati?

 

At the risk of sounding like a broken record from my other posts, no one has ever done dosing studies on C60.   Recently, a structurally similar antioxidant IAC was studied by an Italian group:

http://biomedgeronto...na.glu160.short

 

See Table 1 in the study.   The dose response of IAC is remarkable!  At specific doses they get 170% lifespan extension, and at slight higher doses more than 50% lifespan REDUCTION.   It may be that these SOD mimetics have very specific ranges of biological usefulness, and lower-than-expected doses of toxicity.    And looking at Table 1, the toxicity is not subtle.   These are remarkable reductions in life expectancy.  The antioxidant had a narrow range of benefit.   It's fantastic that the researcher was thoughtful enough to test at so many concentrations.   

 

It is a very fair question to ask will C60 have a similar limited range of benefit, and will C60 lower lifespan at high doses.    This study result on IAC is cautionary.   Those of you who are megadosing C60 really need to read the above study on IAC, study Table 1, and think about the risks you are taking.

 

The world badly needs some dose response studies on C60 in mice or mammals.

 

C3 is c60 with three malonic acid substituents bonded to it in a particular pattern.  Malonic acid is a diacid, so there are a total of six carboxylates on this compound, giving it a net charge of -6 if it's fully deprotonated.  The main thing about it is that it's sufficiently hydrophilic to dissolve in water.

 

C60oo starts out life as a triglyceride with c60 covalently bound to some of the fatty acids.  When it's digested in the body, it becomes a c60 with one or possibly more fatty acid(s), now freed from the triglyceride molecule.  It is very hydrophobic, with a polar head group.  As such, it is likely to be incorporated into membranes.

 

I don't see any reason why fullerenes couldn't act as general SOD mimetics, regardless of the specific subtype.  They all dismutate superoxide.

 

Baati didn't use a liposomal formulation-- it was just olive oil.  However, when triglycerides are digested, they do exist for a time in a micellar structure known as a chylomicron.  Because we're taking advantage of an existing digestion system, we get great bioavailability despite very low water solubility.  I don't know if Baati's superior LE results were due entirely to dosing.  I suspect not, because c60oo is very likely membrane bound, including the mitochondrial Inner Membrane.  This places it right at the site of most ROS production.  Hydrophilic antioxidants would be further away, so they wouldn't work as good. 

 

The spiky dose- LE response curve, including the dip into negative territory at high doses with not one but two very different antioxidants is striking.  I hope these worm results don't apply to high dose-c60 users.  One thing to consider is that Baati was a tox test, and they used a large dose.   However, that dose was given relatively infrequently, except for the first week.  Most of us are way under the dose used in Baati, though not as much if you consider HED.  Baati's rat's were only dosed for about 6 months, so most of us are way ahead of that.  No one's dead yet, that I know of, but it could take a while for a 50% reduction in lifespan to show up.  I doubt we would see that big of a difference, because we aren't likely to see anything close to the life extension seen in Baati, much less the results from the worm paper.  The world of c60 users is running a gigantic experiment...

[pone11]

 

C3 is c60 with three malonic acid substituents bonded to it in a particular pattern.  Malonic acid is a diacid, so there are a total of six carboxylates on this compound, giving it a net charge of -6 if it's fully deprotonated.  The main thing about it is that it's sufficiently hydrophilic to dissolve in water.

 

C60oo starts out life as a triglyceride with c60 covalently bound to some of the fatty acids.  When it's digested in the body, it becomes a c60 with one or possibly more fatty acid(s), now freed from the triglyceride molecule.  It is very hydrophobic, with a polar head group.  As such, it is likely to be incorporated into membranes.

 

I don't see any reason why fullerenes couldn't act as general SOD mimetics, regardless of the specific subtype.  They all dismutate superoxide.

 

Baati didn't use a liposomal formulation-- it was just olive oil.  However, when triglycerides are digested, they do exist for a time in a micellar structure known as a chylomicron.  Because we're taking advantage of an existing digestion system, we get great bioavailability despite very low water solubility.  I don't know if Baati's superior LE results were due entirely to dosing.  I suspect not, because c60oo is very likely membrane bound, including the mitochondrial Inner Membrane.  This places it right at the site of most ROS production.  Hydrophilic antioxidants would be further away, so they wouldn't work as good. 

 

The spiky dose- LE response curve, including the dip into negative territory at high doses with not one but two very different antioxidants is striking.  I hope these worm results don't apply to high dose-c60 users.  One thing to consider is that Baati was a tox test, and they used a large dose.   However, that dose was given relatively infrequently, except for the first week.  Most of us are way under the dose used in Baati, though not as much if you consider HED.  Baati's rat's were only dosed for about 6 months, so most of us are way ahead of that.  No one's dead yet, that I know of, but it could take a while for a 50% reduction in lifespan to show up.  I doubt we would see that big of a difference, because we aren't likely to see anything close to the life extension seen in Baati, much less the results from the worm paper.  The world of c60 users is running a gigantic experiment...

 

 

Given your descriptions of their structures, could we think about C60+OO as an SOD2-mimetic for the cell membrane and C3 as an SOD3-mimetic for the extracellular environment?  If yes, then you might expect the two to have synergistic effects.

 

What is the approximate human equivalent dose of Baati's study in mg of C60 per week?  

 

Baati's dosing was: "Three groups of 6 rats (10 months old, weighing 465 31 g) were administered daily for one week, then weekly until the end of the second month and then every two weeks until the end of the 7th month, by gavages with 1 ml of water or olive oil or C60 dissolved in olive oil (0.8 mg/ml), respectively."   Has anyone read his rational for:

 

1) Once a week and then once every-two-week dosing?

 

2) Stopping all doses after six months?

 

These hardly seem like random actions and they must have had some intuition about why this was a better approach than some constant dosing until end of life.

Edited by pone11, 22 March 2015 - 09:27 PM.

[pone11]

Given your descriptions of their structures, could we think about C60+OO as an SOD2-mimetic for the cell membrane and C3 as an SOD3-mimetic for the extracellular environment?  If yes, then you might expect the two to have synergistic effects.

 

 

A strange fact to juxtapose here is that the soluble form of fullerenes is reported in this study to increase endogenous levels of catalase and SOD2:

http://www.ncbi.nlm....les/PMC3731423/

 

And just when you think you are starting to understand things, you realize you know very little. :/

[tunt01]

Given your descriptions of their structures, could we think about C60+OO as an SOD2-mimetic for the cell membrane and C3 as an SOD3-mimetic for the extracellular environment? If yes, then you might expect the two to have synergistic effects.

A strange fact to juxtapose here is that the soluble form of fullerenes is reported in this study to increase endogenous levels of catalase and SOD2:
http://www.ncbi.nlm....les/PMC3731423/

And just when you think you are starting to understand things, you realize you know very little. :/

Interesting study. Maybe C60 would be good for someone with rheumatoid arthritis or another proving mamma to say condition.

[niner]

 

Given your descriptions of their structures, could we think about C60+OO as an SOD2-mimetic for the cell membrane and C3 as an SOD3-mimetic for the extracellular environment?  If yes, then you might expect the two to have synergistic effects.

 

 

A strange fact to juxtapose here is that the soluble form of fullerenes is reported in this study to increase endogenous levels of catalase and SOD2:

http://www.ncbi.nlm....les/PMC3731423/

 

And just when you think you are starting to understand things, you realize you know very little. :/

 

Yeah.. Not the usual anti-hormetic effect.  And then there was this example of spiky dose-response:

 

Cells treated with 1 µM fullerol showed marked effect with few apoptotic cells. There was no clear protective effect in either 0.1 or 10 µM

 

The data was shown in Fig. 3, and it was pretty vague, but maybe it looked better in person than the pics in the journal.  This was in vivo vitro data, and 1uM in vitro is a lot of fullerol if you're going to try to deliver it orally.  It presumably washes out fairly quickly, as well. 

 

Edit:  I meant in vitro, but wrote in vivo.  Now corrected.

Edited by niner, 24 March 2015 - 12:13 AM.

[pone11]

 

What is the approximate human equivalent dose of Baati's study in mg of C60 per week?  

 

Baati's dosing was: "Three groups of 6 rats (10 months old, weighing 465 31 g) were administered daily for one week, then weekly until the end of the second month and then every two weeks until the end of the 7th month, by gavages with 1 ml of water or olive oil or C60 dissolved in olive oil (0.8 mg/ml), respectively."   Has anyone read his rational for:

 

1) Once a week and then once every-two-week dosing?

 

2) Stopping all doses after six months?

 

These hardly seem like random actions and they must have had some intuition about why this was a better approach than some constant dosing until end of life.

 

 

I found a Youtube interview of Fathi Moussa, one of the lead researchers in the Baati study:

 

It's hilarious, but the reason they did not dose the rats C60 all the time is because they felt the *olive oil* would be toxic.  You can't make this stuff up.

 

Dr Moussa is very convinced that C60 has no toxicity in any form, but he never gave evidence for that.

[Kalliste]

If rodents can be made to live twice as long by starving and so on I don't expect that a heavy dose regime of fullerenes will cause a 50 % decrease in human lifespan. Maybe a 5 % decrease. But we live very long, most people who dose a lot of it will probably get tired after a few years and stop it. Maybe move on to the next Big Thing (scaling up endogenous antioxidant production via genetic CRISPR surgery ). So we probably need not worry.

 

 

 

Given your descriptions of their structures, could we think about C60+OO as an SOD2-mimetic for the cell membrane and C3 as an SOD3-mimetic for the extracellular environment?  If yes, then you might expect the two to have synergistic effects.

 

 

A strange fact to juxtapose here is that the soluble form of fullerenes is reported in this study to increase endogenous levels of catalase and SOD2:

http://www.ncbi.nlm....les/PMC3731423/

 

And just when you think you are starting to understand things, you realize you know very little. :/

 

 

Fasting and physical activity also increase ROS load. It's called Mitohormesis.

Maybe the fullerenes belong to a class of rare substances that can manage the mitochondrial ROS production in a favorable way that promotes health effects (by inducing autophagy or something along those lines)

[Kalliste]

 

Article preview View full access options

Nature Medicine | Between Bedside and Bench

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Unraveling the Truth About Antioxidants: Mitohormesis explains ROS-induced health benefits

• Michael Ristow

Nature Medicine 20, 709–711 (2014) doi:10.1038/nm.3624 Published online 07 July 2014

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Oxidative stress has long been linked to disease development and accelerated aging, prompting professionals in the biomedical field to suggest the use of antioxidants to prevent or even reverse these conditions. But growing clinical evidence is showing that this in fact might not be effective, calling for additional investigation to prove that certain molecular factors involved in oxidation, specifically reactive oxidative species (ROS), are not detrimental. In “Bedside to Bench,” Michael Ristow highlights recent human studies with antioxidant supplementation that have failed to show any improvement in health span. Moreover, other relevant evidence has pointed towards a beneficial role for ROS in lifespan under stress conditions, although how this is mediated and regulated inside the cell is not fully understood. In “Bench to Bedside,” Hiroyuki Kawagishi and Toren Finkel peruse the biological and signaling underpinnings of ROS in living organisms, which suggest different amounts of ROS may explain their dual role in lifespan and disease and the lack of effect of antioxidants in the body. The authors propose targeting pathways and molecules involved in removing cellular damage rather than ROS, which could make therapies to increase lifespan more effective and preclude diseases caused by oxidation and aging.

http://www.nature.co...ll/nm.3624.html

[pone11]

If rodents can be made to live twice as long by starving and so on I don't expect that a heavy dose regime of fullerenes will cause a 50 % decrease in human lifespan. Maybe a 5 % decrease. But we live very long, most people who dose a lot of it will probably get tired after a few years and stop it. Maybe move on to the next Big Thing (scaling up endogenous antioxidant production via genetic CRISPR surgery ). So we probably need not worry.

...

Fasting and physical activity also increase ROS load. It's called Mitohormesis.

Maybe the fullerenes belong to a class of rare substances that can manage the mitochondrial ROS production in a favorable way that promotes health effects (by inducing autophagy or something along those lines)

 

No one knows, but the IAC antioxidant has some similarities to C60 and it had a very narrow range of benefit, and when the benefit stops it quickly crashes and shortens lifespan by a LOT.   Maybe the antioxidant is so good it blocks all ROS signals and the cell cannot be healthy without some ROS.   The point is C60 has no dosing studies.  Don't assume anything about benefits of megadoses.

 

I had already made the point on hormesis?   Physical activity causing small amounts of ROS is why it is successful as a way to increase mitochondria.  What if an antioxidant blocked all that ROS, and no amount of exercise would signal the cell to get stronger and more energetic?    It might be that you want the antioxidants to block 90% of the ROS but let just enough get through that the signaling functions still work.

[Kalliste]

I was reading two threads at once and got them mixed. Sorry

[YOLF]

 

Wow, this post from 2007 predates Baati's C60 study by many years, and no one picked up on it.   Let me highlight it.   The full text of the study is here:

http://www.sciencedi...197458006003423

 

This study extends lifespan in *wild* mice by about 11%, but also had pretty remarkable affects on sparing neurological impairment during the aging.   Like C60, C3 was thought to have its effects as an SOD mimetic.

 

In looking through the footnotes, this one that explains the C60 derivative C3 was interesting:

http://www.ncbi.nlm....pubmed/15451059

 

The second study on C3 explains: "Here we show that a tris-malonic acid derivative of the fullerene C60 molecule (C3) is capable of removing the biologically important superoxide radical with a rate constant (k(C3)) of 2 x 10(6) mol(-1) s(-1), approximately 100-fold slower than the superoxide dismutases (SOD), a family of enzymes responsible for endogenous dismutation of superoxide. This rate constant is within the range of values reported for several manganese-containing SOD mimetic compounds. The reaction between C3 and superoxide was not via stoichiometric "scavenging," as expected, but through catalytic dismutation of superoxide, indicated by lack of structural modifications to C3, regeneration of oxygen, production of hydrogen peroxide, and absence of EPR-active (paramagnetic) products, all consistent with a catalytic mechanism."

 

Here are the questions I have on the above:

 

* Can any of the chemists among us explain what is the difference between C3 and C60 as Baati used it, in terms of either structure or action?

 

* As I understand it, C60 acts like an SOD2 mimetic that has primary action within mitochondrial membranes.   SOD3 is typically found in extracellular spaces and on the surface of cell membranes, protecting the extracellular area.    Are there any known good SOD3 mimetics that do not decrease endogenous SOD3?   Given that all the C60 studies mention SOD2 and say nothing on SOD3, I assume that C60 is not an SOD3 mimetic?

 

* Was Baati's better result than the above study due to a liposomal formulation, thus increasing bioavailability of the C60?    Or are the differences in the two studies attributable primarily to dosing?   And at some dose of C3 - administered in the same form as the study linked above - might we have seen a similar life extension effect as Baati?

 

At the risk of sounding like a broken record from my other posts, no one has ever done dosing studies on C60.   Recently, a structurally similar antioxidant IAC was studied by an Italian group:

http://biomedgeronto...na.glu160.short

 

See Table 1 in the study.   The dose response of IAC is remarkable!  At specific doses they get 170% lifespan extension, and at slight higher doses more than 50% lifespan REDUCTION.   It may be that these SOD mimetics have very specific ranges of biological usefulness, and lower-than-expected doses of toxicity.    And looking at Table 1, the toxicity is not subtle.   These are remarkable reductions in life expectancy.  The antioxidant had a narrow range of benefit.   It's fantastic that the researcher was thoughtful enough to test at so many concentrations.   

 

It is a very fair question to ask will C60 have a similar limited range of benefit, and will C60 lower lifespan at high doses.    This study result on IAC is cautionary.   Those of you who are megadosing C60 really need to read the above study on IAC, study Table 1, and think about the risks you are taking.

 

The world badly needs some dose response studies on C60 in mice or mammals.

 

C3 is c60 with three malonic acid substituents bonded to it in a particular pattern.  Malonic acid is a diacid, so there are a total of six carboxylates on this compound, giving it a net charge of -6 if it's fully deprotonated.  The main thing about it is that it's sufficiently hydrophilic to dissolve in water.

 

C60oo starts out life as a triglyceride with c60 covalently bound to some of the fatty acids.  When it's digested in the body, it becomes a c60 with one or possibly more fatty acid(s), now freed from the triglyceride molecule.  It is very hydrophobic, with a polar head group.  As such, it is likely to be incorporated into membranes.

 

I don't see any reason why fullerenes couldn't act as general SOD mimetics, regardless of the specific subtype.  They all dismutate superoxide.

 

Baati didn't use a liposomal formulation-- it was just olive oil.  However, when triglycerides are digested, they do exist for a time in a micellar structure known as a chylomicron.  Because we're taking advantage of an existing digestion system, we get great bioavailability despite very low water solubility.  I don't know if Baati's superior LE results were due entirely to dosing.  I suspect not, because c60oo is very likely membrane bound, including the mitochondrial Inner Membrane.  This places it right at the site of most ROS production.  Hydrophilic antioxidants would be further away, so they wouldn't work as good. 

 

The spiky dose- LE response curve, including the dip into negative territory at high doses with not one but two very different antioxidants is striking.  I hope these worm results don't apply to high dose-c60 users.  One thing to consider is that Baati was a tox test, and they used a large dose.   However, that dose was given relatively infrequently, except for the first week.  Most of us are way under the dose used in Baati, though not as much if you consider HED.  Baati's rat's were only dosed for about 6 months, so most of us are way ahead of that.  No one's dead yet, that I know of, but it could take a while for a 50% reduction in lifespan to show up.  I doubt we would see that big of a difference, because we aren't likely to see anything close to the life extension seen in Baati, much less the results from the worm paper.  The world of c60 users is running a gigantic experiment...

 

Would it be hard to put this into a supplement or modify the C60 in C60OO to have these characteristics? I'm a big fan of SOD and SOD boosting supplements. Wild Blue Berry extracts and Goji have similar cognitive improvements. There was an article in the latest LEF magazine that was talking about this.

[pone11]

Would it be hard to put this into a supplement or modify the C60 in C60OO to have these characteristics? I'm a big fan of SOD and SOD boosting supplements. Wild Blue Berry extracts and Goji have similar cognitive improvements. There was an article in the latest LEF magazine that was talking about this.

 

 

Careful: as I have posted elsewhere here, Gliadin-based SOD supplements LOWER overall SOD levels.   They supplement SOD but the body responds by lowering its endogenous levels even more than the increase from supplementation, giving you a net negative benefit:

https://www.jstage.j...5/53_5_608/_pdf

 

What you want is an SOD-mimetic that the body doesn't recognize as SOD.  You want something that does not lower the endogenous levels of SOD.   That's what makes C60 so interesting, because it may serve this function.

 

One way of interpreting those IAC antioxidant study results - where a particular dose of IAC increases worm lifespan 170% but a slightly higher dose lowers lifespan 50% - is that the body needs hormesis by exposure to a certain level of free radicals.  That in turn implies that when we take antioxidants we need to design the overall effect of the cocktail to absorb excess free radicals while NOT silencing the hormetic signals from free radicals.  Without those signals, exercise won't make our mitochondria multiply, and it won't make our endogenous defenses rise or stay strong.   So the range of dose effectiveness may be much more narrow than people appreciate.   This is a Goldilocks and the Three Bears problem:  we don't want the porridge to be too hot or too cold, but "just right".

 

What we need badly here are biomarkers!    In a mouse study, it would be useful to find common metabolites that correlate with each level of antioxidant.  That way we could use the biomarker as a guide for optimal dosing of the antioxidant.    The situation we have today with C60 could be illustrated with an analogy.   Imagine you are flying an airplane with no air speed indicator, and you are told that if you fly less than 120 knots air speed that the plane will stall and fall, but if you exceed 150 knots air speed the plane's structure will be compromised and will be destroyed.   So you must fly between 120 and 150, but without the airspeed indicator this is nearly impossible to do.   That's not a perfect analogy because in the case of C60 or IAC underdosing does not kill you.   But the basic idea is that taking an antioxidant that has a very narrow range of benefit - without any biomarker that you can measure on an ongoing basis to indicate to you the effects any specific dose you take - is a little like flying an airplane with no air speed indicator and a narrow flight range.

Edited by pone11, 28 March 2015 - 06:06 PM.

[Kalliste]

I wonder if fullerenes become more active when levels of ROS increase, maybe that causes an increase of their free radical squenching effect. And that would let them protect you from excess ROS while maintaining what is necessary level for normal mitochondrial homeostasis.

[YOLF]

 

Would it be hard to put this into a supplement or modify the C60 in C60OO to have these characteristics? I'm a big fan of SOD and SOD boosting supplements. Wild Blue Berry extracts and Goji have similar cognitive improvements. There was an article in the latest LEF magazine that was talking about this.

 

 

Careful: as I have posted elsewhere here, Gliadin-based SOD supplements LOWER overall SOD levels.   They supplement SOD but the body responds by lowering its endogenous levels even more than the increase from supplementation, giving you a net negative benefit:

https://www.jstage.j...5/53_5_608/_pdf

 

What you want is an SOD-mimetic that the body doesn't recognize as SOD.  You want something that does not lower the endogenous levels of SOD.   That's what makes C60 so interesting, because it may serve this function.

 

One way of interpreting those IAC antioxidant study results - where a particular dose of IAC increases worm lifespan 170% but a slightly higher dose lowers lifespan 50% - is that the body needs hormesis by exposure to a certain level of free radicals.  That in turn implies that when we take antioxidants we need to design the overall effect of the cocktail to absorb excess free radicals while NOT silencing the hormetic signals from free radicals.  Without those signals, exercise won't make our mitochondria multiply, and it won't make our endogenous defenses rise or stay strong.   So the range of dose effectiveness may be much more narrow than people appreciate.   This is a Goldilocks and the Three Bears problem:  we don't want the porridge to be too hot or too cold, but "just right".

 

What we need badly here are biomarkers!    In a mouse study, it would be useful to find common metabolites that correlate with each level of antioxidant.  That way we could use the biomarker as a guide for optimal dosing of the antioxidant.    The situation we have today with C60 could be illustrated with an analogy.   Imagine you are flying an airplane with no air speed indicator, and you are told that if you fly less than 120 knots air speed that the plane will stall and fall, but if you exceed 150 knots air speed the plane's structure will be compromised and will be destroyed.   So you must fly between 120 and 150, but without the airspeed indicator this is nearly impossible to do.   That's not a perfect analogy because in the case of C60 or IAC underdosing does not kill you.   But the basic idea is that taking an antioxidant that has a very narrow range of benefit - without any biomarker that you can measure on an ongoing basis to indicate to you the effects any specific dose you take - is a little like flying an airplane with no air speed indicator and a narrow flight range.

 

Ok, so let's design a study to search for or develop useful biomarker testing that can be done at home and do one of LongeCity's matched fundraiser. Is that something you could design? Anyone?

[pone11]

Ok, so let's design a study to search for or develop useful biomarker testing that can be done at home and do one of LongeCity's matched fundraiser. Is that something you could design? Anyone?

 

 

I am not the guy to design the study, but I certainly think it is a worthy undertaking for Longecity to help fund rat studies with C60 that test dosing and look for biomarkers.

 

Possible biomarkers might be various markers for lipid peroxidation.   Wouldn't it be nice if we discovered that the optimal dose corresponds to some fixed percentage reduction of lipid peroxidation before taking the antioxidant?   And the marker for overdosing might be lipid peroxidation going to very low levels.   Since there are many commercial tests for lipid peroxidation, that kind of biomarker directly benefits humans that are experimenting on themselves.

[Kalliste]

 

 

Would it be hard to put this into a supplement or modify the C60 in C60OO to have these characteristics? I'm a big fan of SOD and SOD boosting supplements. Wild Blue Berry extracts and Goji have similar cognitive improvements. There was an article in the latest LEF magazine that was talking about this.

 

 

Careful: as I have posted elsewhere here, Gliadin-based SOD supplements LOWER overall SOD levels.   They supplement SOD but the body responds by lowering its endogenous levels even more than the increase from supplementation, giving you a net negative benefit:

https://www.jstage.j...5/53_5_608/_pdf

 

What you want is an SOD-mimetic that the body doesn't recognize as SOD.  You want something that does not lower the endogenous levels of SOD.   That's what makes C60 so interesting, because it may serve this function.

 

One way of interpreting those IAC antioxidant study results - where a particular dose of IAC increases worm lifespan 170% but a slightly higher dose lowers lifespan 50% - is that the body needs hormesis by exposure to a certain level of free radicals.  That in turn implies that when we take antioxidants we need to design the overall effect of the cocktail to absorb excess free radicals while NOT silencing the hormetic signals from free radicals.  Without those signals, exercise won't make our mitochondria multiply, and it won't make our endogenous defenses rise or stay strong.   So the range of dose effectiveness may be much more narrow than people appreciate.   This is a Goldilocks and the Three Bears problem:  we don't want the porridge to be too hot or too cold, but "just right".

 

What we need badly here are biomarkers!    In a mouse study, it would be useful to find common metabolites that correlate with each level of antioxidant.  That way we could use the biomarker as a guide for optimal dosing of the antioxidant.    The situation we have today with C60 could be illustrated with an analogy.   Imagine you are flying an airplane with no air speed indicator, and you are told that if you fly less than 120 knots air speed that the plane will stall and fall, but if you exceed 150 knots air speed the plane's structure will be compromised and will be destroyed.   So you must fly between 120 and 150, but without the airspeed indicator this is nearly impossible to do.   That's not a perfect analogy because in the case of C60 or IAC underdosing does not kill you.   But the basic idea is that taking an antioxidant that has a very narrow range of benefit - without any biomarker that you can measure on an ongoing basis to indicate to you the effects any specific dose you take - is a little like flying an airplane with no air speed indicator and a narrow flight range.

 

Ok, so let's design a study to search for or develop useful biomarker testing that can be done at home and do one of LongeCity's matched fundraiser. Is that something you could design? Anyone?

 

 

This design should be doable:
 

 

The effect of consumption of Brussels sprouts on levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in human urine was investigated in 10 healthy, male, non-smoking volunteers. Following a 3 week run-in period, five volunteers continued on a diet free of cruciferous vegetables for a subsequent 3 week intervention period (control group), while the other five (sprouts group) consumed 300 g of cooked Brussels sprouts per day, at the expense of 300 g of a glucosinolate-free vegetable. Levels of 8-oxodG in 24 h urine samples were measured by HPLC. In the control group there was no difference between the two periods in levels of 8-oxodG (P = 0.72). In contrast, in the sprouts group the levels of 8-oxodG were decreased by 28% during the intervention period (P = 0.039). The present findings support the results of epidemiologic studies that consumption of cruciferous vegetables may result in a decreased cancer risk.

 

http://carcin.oxford.../16/4/969.short

 

Test kits for 8-oxo-dG are available online

http://www.trevigen....xodG_ELISA_Kit/

http://www.rndsystem...elisa_kits.aspx

 

Another one would be to look at blood pressure like they did with MitoQ in mice.

 

 

An antioxidant that targets specific cell structures—mitochondria—may be able to reverse some of the negative effects of aging on arteries, reducing the risk of heart disease, according to a new study by the University of Colorado Boulder.

When the research team gave old mice—the equivalent of 70- to 80-year-old humans—water containing an antioxidant known as MitoQ for four weeks, their arteries functioned as well as the arteries of mice with an equivalent human age of just 25 to 35 years.

The researchers believe that MitoQ affects the endothelium, a thin layer of cells that lines our blood vessels. One of the many functions of the endothelium is to help arteries dilate when necessary. As people age, the endothelium is less able to trigger dilation and this leads to a greater susceptibility to cardiovascular disease.

“One of the hallmarks of primary aging is endothelial dysfunction,” said Rachel Gioscia-Ryan, a doctoral student in CU-Boulder’s Department of Integrative Physiology and lead author of the new study. “MitoQ completely restored endothelial function in the old mice. They looked like young mice.”

The study, published in the Journal of Physiology, was funded by the National Institute on Aging, one of the 27 institutes and centers of the National Institutes of Health and a leader in the scientific effort to understand the nature of aging.

To trigger blood vessel dilation, the endothelium makes nitric oxide. As we age, the nitric oxide meant to cause dilation is increasingly destroyed by reactive oxygen species such as superoxide, which are produced by many components of our body’s own cells, including organelles called mitochondria.

In a double-whammy, superoxide also reacts directly with the enzyme that makes nitric oxide, reducing the amount of nitric oxide being produced to begin with. All of this means less blood vessel dilation.

Even in the young and healthy, mitochondria produce superoxide, which is necessary in low levels to maintain important cellular functions. Superoxide is kept in check by the body’s own antioxidants, which combine with superoxide to make it less reactive and prevent oxidative damage to cells.

“You have this kind of balance, but with aging there is this shift,” said Gioscia-Ryan, who works in Professor Douglas Seals’ Integrative Physiology of Aging Laboratory at CU-Boulder. “There become way more reactive oxygen species than your antioxidant defenses can handle.”

That phenomenon, known as oxidative stress, occurs when the cells of older adults begin to produce too much superoxide and other reactive oxygen species. Mitochondria are a major source of superoxide in aging cells. The increased superoxide not only interacts with nitric oxide and the endothelium, but can also attack the mitochondria themselves. The damaged mitochondria become increasingly dysfunctional, producing even more reactive oxygen species and creating an undesirable cycle.

Past studies have looked at whether taking antioxidant supplements long term could improve vascular function in patients with cardiovascular disease by restoring balance to the levels of superoxide, but they’ve largely shown that the strategy isn’t effective.

This new study differs because it uses an antioxidant that specifically targets mitochondria. Biochemists manufactured MitoQ by adding a molecule to ubiquinone (also known as coenzyme Q₁₀), a naturally occurring antioxidant. The additional molecule makes the ubiquinone become concentrated in mitochondria.

“The question is, ‘Why aren’t we all just taking a bunch of vitamin C?” Gioscia-Ryan said. “Scientists think that, taken orally, antioxidants like vitamin C aren’t getting to the places where the reactive oxygen species are being made. MitoQ basically tracks right to the mitochondria.”

The findings of the study indicate that the strategy of specifically targeting the mitochondria may be effective for improving the function of arteries as we age. In addition to improving endothelial function, the MitoQ treatment increased levels of nitric oxide, reduced oxidative stress and improved the health of the mitochondria in the arteries of old mice. 

Other CU-Boulder co-authors of the study include postdoctoral researchers Thomas LaRocca and Amy Sindler, professional research assistant Melanie Zigler and Seals. Professor Michael Murphy of the Medical Research Council’s Mitochondrial Biology Unit in Cambridge, England, who helped develop MitoQ, also is a co-author. MitoQ is manufactured by MitoQ Ltd., and is available as a dietary supplement and skin cream.

The study was supported by award number T32AG000279 from the National Institute on Aging. The content of the published study is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

http://www.colorado....u-boulder-study

 

These studies are both fairly easy to fund since you can recruit aged animals and give them a few doses and see what happens. I don't see this requiring anyone to house the animals for many years. Ideally it would be done using aged primates although I guess that would be more expensive. I would be delighted to donate to this cause.

[YOLF]

What's involved with using these tests. Can they be used at home or do they have to be processed in a lab? 

 

Is there any kind of rapid testing that could be done? We should focus on making these tests available to everyone.

[Kalliste]

The one for 8-oxo-dG is available as a home test, but might need to send it to a lab. I know too little.

[YOLF]

How hard would it be to develop a home test for this? Maybe that's what we need to work on, or both.

[pone11]

 

Test kits for 8-oxo-dG are available online

http://www.trevigen....xodG_ELISA_Kit/

http://www.rndsystem...elisa_kits.aspx

 

Another one would be to look at blood pressure like they did with MitoQ in mice.

 

 

Those 8-oxo-dG kits look like 96 wells intended to all be tested at the same moment?   It's a kit for a large population study in rats or a large national lab.   Does anyone have a test kit for single dose testing?

 

I doubt blood pressure would be a reliable marker as it is too variable, even over the course of one day.

[Nate-2004]

Wow, this post from 2007 predates Baati's C60 study by many years, and no one picked up on it.   Let me highlight it.   The full text of the study is here:

http://www.sciencedi...197458006003423

 

This study extends lifespan in *wild* mice by about 11%, but also had pretty remarkable affects on sparing neurological impairment during the aging.   Like C60, C3 was thought to have its effects as an SOD mimetic.

 

In looking through the footnotes, this one that explains the C60 derivative C3 was interesting:

http://www.ncbi.nlm....pubmed/15451059

 

The second study on C3 explains: "Here we show that a tris-malonic acid derivative of the fullerene C60 molecule (C3) is capable of removing the biologically important superoxide radical with a rate constant (k(C3)) of 2 x 10(6) mol(-1) s(-1), approximately 100-fold slower than the superoxide dismutases (SOD), a family of enzymes responsible for endogenous dismutation of superoxide. This rate constant is within the range of values reported for several manganese-containing SOD mimetic compounds. The reaction between C3 and superoxide was not via stoichiometric "scavenging," as expected, but through catalytic dismutation of superoxide, indicated by lack of structural modifications to C3, regeneration of oxygen, production of hydrogen peroxide, and absence of EPR-active (paramagnetic) products, all consistent with a catalytic mechanism."

 

Here are the questions I have on the above:

 

* Can any of the chemists among us explain what is the difference between C3 and C60 as Baati used it, in terms of either structure or action?

 

* As I understand it, C60 acts like an SOD2 mimetic that has primary action within mitochondrial membranes.   SOD3 is typically found in extracellular spaces and on the surface of cell membranes, protecting the extracellular area.    Are there any known good SOD3 mimetics that do not decrease endogenous SOD3?   Given that all the C60 studies mention SOD2 and say nothing on SOD3, I assume that C60 is not an SOD3 mimetic?

 

* Was Baati's better result than the above study due to a liposomal formulation, thus increasing bioavailability of the C60?    Or are the differences in the two studies attributable primarily to dosing?   And at some dose of C3 - administered in the same form as the study linked above - might we have seen a similar life extension effect as Baati?

 

At the risk of sounding like a broken record from my other posts, no one has ever done dosing studies on C60.   Recently, a structurally similar antioxidant IAC was studied by an Italian group:

http://biomedgeronto...na.glu160.short

 

See Table 1 in the study.   The dose response of IAC is remarkable!  At specific doses they get 170% lifespan extension, and at slight higher doses more than 50% lifespan REDUCTION.   It may be that these SOD mimetics have very specific ranges of biological usefulness, and lower-than-expected doses of toxicity.    And looking at Table 1, the toxicity is not subtle.   These are remarkable reductions in life expectancy.  The antioxidant had a narrow range of benefit.   It's fantastic that the researcher was thoughtful enough to test at so many concentrations.   

 

It is a very fair question to ask will C60 have a similar limited range of benefit, and will C60 lower lifespan at high doses.    This study result on IAC is cautionary.   Those of you who are megadosing C60 really need to read the above study on IAC, study Table 1, and think about the risks you are taking.

 

The world badly needs some dose response studies on C60 in mice or mammals.

 

That last link is broken now unfortunately. This is a super interesting discussion.

 

You talk about "megadosing" but what technically would you consider to be megadosing for a human?  Let's say I were to take 14mg (20ml C60OO) per day for 5 days is that a megadose? I'm about 72kg.

 

Some people decided like the mouse trials they'd stop dosing altogether after 6 months, following the exact methods in the trial. Unfortunately they were off by 17.5 years. 6 months in a rat's life is about 18 years in a human life. By that same reasoning, two weeks apart is almost a year for a human.

 

The video posted says that there are 3 independent ongoing studies involving 200 rats per group. I imagine that those results won't be out till at least 2019.

Edited by Nate-2004, 31 May 2016 - 06:39 PM.

[gamesguru]

You talk about "megadosing" but what technically would you consider to be megadosing for a human? Let's say I were to take 14mg (20ml C60OO) per day for 5 days is that a megadose? I'm about 72kg.

Some people decided like the mouse trials they'd stop dosing altogether after 6 months, following the exact methods in the trial. Unfortunately they were off by 17.5 years. 6 months in a rat's life is about 18 years in a human life. By that same reasoning, two weeks apart is almost a year for a human.

The video posted says that there are 3 independent ongoing studies involving 200 rats per group. I imagine that those results won't be out till at least 2019.

That's a good point about the 17.5 years lol. I wonder if this stuff starts to backfire at her high doses, or if the classic rat to human conversion of 6:1 still holds