A Puzzling Fullerene Study
Permalink | View Comments (28) | Post Comment | | Posted by Reason

A research group is claiming that fullerenes (C60, ingested and injected) greatly extend life span in rats; this is meeting with some considerable skepticism, given the degree of life extension and the lack of a plausible mechanism. "In the current study researchers fed the molecule dissolved in olive oil to rats and compared outcomes to a control group of rats who got plain olive oil. The main question they wanted to answer was whether chronic C60 administration had any toxicity, what they discovered actually surprised them. ... Here we show that oral administration of C60 dissolved in olive oil (0.8 mg/ml) at reiterated doses (1.7 mg/kg of body weight) to rats not only does not entail chronic toxicity, but it almost doubles their lifespan. ... The estimated median lifespan (EML) for the C60-treated rats was 42 months while the EMLs for control rats and olive oil-treated rats were 22 and 26 months, respectively. Using a toxicity model the researchers demonstrated that the effect on lifespan seems to be mediated by 'attenuation of age-associated increases in oxidative stress'." So what might be going on here? The average life span of the Wistar rats used is 2-3 years (24 - 36 months). This was a small study size, but that's not so important in determining whether you have an actual means of life extension if you can show that any of your study group lived much longer than usual - but it is important when it comes to the degree of life extension. If the study group is small, as it is here, using only a handful of rats, then the size of the effect can be much more readily distorted by chance. This line in the paper jumped out at me: "Before C60 administration, the rats were fasted overnight but with access to water." If they failed to fast the control group, then we're looking at yet another study that failed to control for calorie restriction, and this is actually largely an intermittent fasting study - which has certainly been shown to extend life in rats.

Link: http://extremelongevity.net/2012/04/16/chronic-buckyball-administration-doubles-rat-lifespan/

Comments

I don't think it's fasting. Fasting was only done for pharmacokinetics study, not for chronic toxicity study. That two studies were separate is evident from the description, e.g. rats were acclimated for 7 days for pharmacokinetics study and 14 days for chronic toxicity study.

Posted by: Seo Sanghyeon at April 17, 2012 6:16 AM

@Seo Sanghyeon: That is also a plausible reading of the paper. It doesn't look like they go into any great detail as to the protocol for administration in the longer term study.

I'm skeptical of significant antioxidant effects in vivo from a naturally occurring compound given that antioxidants in general haven't done much for longevity without being heavily designed substances (like SkQ1, for example). Simply flooding the body with antioxidants is usually slightly worse for longevity or a null effect - they don't get to the mitochondria where they might do some good.

More information from the authors would be good. All things considered, I'm sure we'll be hearing more on this in the years ahead; people will try to replicate it, the researchers will be grilled on their work, etc.

Posted by: Reason at April 17, 2012 7:18 AM

I read about this study earlier today via another source and immediately thought of you Reason and hoped that you'd do a post on it - thanks! Lets hope someone repeats the study soon, this time with a larger study group and rigorous controls. Confirmation would indeed be intriguing - what could the possible mechanism be!?

Posted by: Mark Bruce at April 17, 2012 9:04 AM

"They also demonstrated that the compound is fully absorbed via the GI tract and totally eliminated from the body in 10 hours."
--I don't understand this line, it does not jive with the results, but it probably doesn't matter much. Possibly they oddest study results I have ever seen on this site.

and, by the way, no so much of a problem with this post, but some posts have so many hyper links that they are hard to navigate on a touch screen mobile device.

Posted by: JohnD at April 17, 2012 12:23 PM

Caloric restriction doesn't double rat lifespans, does it? Increase, yes, but double?

Probably this is just a small sample size and cannot be reproduced, but who knows? Maybe the fullerenes are greasing the mitochondrial wheels in some way, perhaps catalyzing or preventing some chemical reaction, or maybe mopping up toxic byproducts. Metabolism is wildly complex.

Since the effect is supposedly so dramatic, it would certainly be interesting to see other teams try and reproduce the experiment. World's not running out of rats anytime soon, right?

Posted by: Paul at April 17, 2012 8:19 PM

Very interested to see more labs try and replicate these results.

Just for fun, I checked to see if it was easy to buy them.
Here's a website that sells them - https://sesres.com/FullerenesPrices.asp

At $3800 for 100 g at 99.9% purity, you'll probably go broke before making it to old age, given the doses in the study were up to 2 g per 1 kg body weight. That's a pound of these things mixed in oil every few days.

Of course, manufacturing prices will go down, so if they do work, well, I'd just like to say, let them eat buckyballs!

Posted by: Patrick at April 17, 2012 10:36 PM

I researched the pricing also. I suspect high purities are important to those doing lab research for electronics or something similar and that molecular weight purity would not be important if you are ingesting them (a guess of course). I found similar pricing, but I used the 50g for $525 ($10.5/g=$0.01/mg)) for a fullerene extract of 68% C60 (and the balance being slightly higher weight fullerenes) for my calculations. The post says 1.7mg/Kg of body weight per day. I calculate a 170 lb. person would require 131mg/day to match the dose in the study, which would be $1.31/day. Where is my calculation off?

Posted by: JohnD at April 18, 2012 7:35 AM

One would expect fullerene to be toxic, it looks very foreign from anything animals have had to metabolize over the eons of evolution.

One possible explanation is that animals fed fullerene are capable of detecting contamination in their food supply and as consequence self-restrict their caloric intake resulting in extended life-span.

Although the researcher claims the animals were not calorically restricted, he may mean the scientists did not intend any restrictions, it is totally feasible the animals self-restricted.

Posted by: Brian at April 18, 2012 10:19 AM

JohnD,

I understand they did try various doses. I don't see how many times/day they did the 1.7 mg dose, but I guess that's the one they're making their EML claim on.

If you pull up the full text: "But we then used an aqueous suspension and the most efficient doses were about 2500 times higher (2 g/kg bw), which are considerably higher than those observed for its derivatives as well as those used for most biomedical applications."

Posted by: Patrick at April 18, 2012 12:20 PM

Brian, just a guess here, but if the fullerines are "very foreign from anything animals have had to metabolize over the eons of evolution", I have to wonder if the immune system would just not acknowledge them. Implant metals, like titanium, do not stop any kind of immune response; they are just neutral or ignored by immune system.

Posted by: Patrick at April 18, 2012 12:25 PM

Patrick,
It is not clear if there was just one or more than one 1.7mg/kg o.g. dose per day, but I must believe, because of the grief involved in doing an o.g. on a mouse, that there would not be more than two per day, and probably only one. When reading the full text, of the interpretation of the quote you post is that it is in reference only to a 2005 study, not the current study.

Posted by: JohnD at April 18, 2012 4:00 PM

They do specify the frequency for the chronic toxicity portion of the study, on page 2:

2.3. Chronic toxicity and effects of C60 on survival of rats
The rats were housed three per cage and acclimated for 14 days, before dosing. 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.

Regarding self-limitation of caloric intake, this is in section 3.3 on page 4:

As the growths of all surviving animals showed no significant difference until M30 (Fig. 3b) indicating that the treatment did not alter their food intake, we continued observing their survival.

Posted by: Arcanum at April 18, 2012 5:45 PM

thanks for the input Arcanum, the fonts in that section on pages 2 and 3 on my full page print out are so small that it makes reading that section very difficult for me. I have to believe that the small font was a printing error.

Posted by: JohnD at April 19, 2012 8:43 AM

@ Brian - they were fed C60+oil by gavage

The 42 months is an estimate for extrapolation of study results.

Of note is the actual survival times of the C60 fed animals in the chart on page 6 of the study.
100% of the c60 rats were alive at 59 months
50% of the C60 rats were alive at 62-63 months
1 rat survived to 66 weeks

Those lifespans for male wistars are unheard of -- I can't find any citations in any literature that approach such lifespans -- outside of this study, even in rat lifespan extension studies.

Posted by: karl heuer at April 19, 2012 11:04 AM

A prior study also showing lifespan extension with fullerene, but less dramatic; this time in mice starting at 12 months of age and with much larger control and treatment groups:

1. Neurobiol Aging. 2008 Jan;29(1):117-28. Epub 2006 Oct 31.

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 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/17079053

http://thebronxproject.com/Articles/7.)%20%20Neurobiology%20of%20Aging%202006.pdf

Posted by: Chimi at April 21, 2012 8:08 AM

In the Pipeline points out a duplicate image problem with the paper, which can be added to what look like some other errors in the life span numbers between different sections. Hard to say what's going on here.

http://pipeline.corante.com/archives/2012/04/20/buckyball_longevity_theres_a_problem.php

But on the whole, it still doesn't look plausible. There are plenty of ways this study could have been messed up without intent on the part of the researchers, of course. The one thing that means people will try to replicate this research regardless of general suspicion as to its validity is the length of life of the longest lived Wistar rat, which at 66 months is just far and way out beyond anything else that people have been finding in the records.

That long-lived rat, and those that were nearly as long lived, is somewhat hard to explain away by any form of error or experimental oddity if it is actually accurate data for the life span.

Posted by: Reason at April 21, 2012 8:28 AM

Hypothetical scenario that I unfortunately find more plausible than the study results: Student assigned to perform o.g. on rats accidentally kills rats at the 18? month old mark, fearing loosing credits/faculty approval to graduate, somehow swaps in younger (6? month old) rats, figuring that he/she would graduate before the study was concluded.

Posted by: JohnD at April 21, 2012 11:21 AM

Dosage: rats have a higher metabolism than humans, you need to use a conversion factor to get human dosage.
The rats were not dosed every day.

4mg/kg x 6/57 is .42mg/kg human dosage

Posted by: Evan at April 23, 2012 3:17 PM

If the human conversion is correct (I have not checked) then I figure a 220 pound man (100 kilograms) would need 42 mg per day. Since 100 grams contains 100,000 milligrams then I calculate 2381 daily doses out of 100 grams (6 and a half years!) Cost of the buckyballs (and as was pointed out, this is at lab prices so figure one or two orders of magnitude cheaper at least when in full production) would be a $1.60. So figure they will charge a buck forty for the olice oil and two dollars for putting it in a gelcap, and they will charge 5 to 10 dollars a day for them.

Of course, if this is for real then every month they spend testing now (and the FDA will NOT be happy about allowing this on the market and will probably try to make it a controlled substance) means a month less life that you could have had.

I doubt that we will ever see more than 25% of the USA taking the stuff on a regular basis even if it does double life. People forget, don't want to spend the money, choose to "grow old gracefully" (it's really hard to be graceful during a colonoscopy or wearing Depends). Heck, some people even smoke and/or don't exercise or even eat pork rinds!

Even so, my VERY rough spreadsheeting indicated that, if nothing else changed (and yes, something would) then in 2050 (assuming an average crosssection comprising 25% of the country immediately began taking it in 2013) instead of being 392 million the US population might be around 402 million. Hardly debilitating although it could mess up Social Security -- oh wait -- too late. Besides, which, people would be working decades longer.

Oh, and even at the rat level, without adjusting based on human metabolism, a kilo would still buy a large man twenty more years of life -- assuming he had twenty left already.

Posted by: Snaz at April 24, 2012 8:36 PM

Reiterating Arcanum: This was NOT a "daily dose for life" study. They started at 10 months old, for one thing, and the dosing was:

Biodistribution study: once daily for 7 days then sacrifice half the rats.
=7 doses.

Chronic Toxicity and Survival study: Daily for a week (7), weekly until end of second month (+7), then every other week until end of 7th month (+11)
=25 dosing days for the entire study/rat.

Oxidative stress study: once daily for 7 days, then CCl4 and then sacrifice.
=7 doses.

I am also troubled by the picture duplication on page 7, which needs to be explained and corrected.

I am amused by the person in the other comments thread lamenting the supplement industy and the buckyball products for sale... which are magnetic sculpture toys that have been out for years. lol

Posted by: CatDoc at April 25, 2012 1:21 PM

Firstly, caloric restriction is really Methionine restriction. 8% Glycine supplementation causes methionine elimination and can produce a maximum of 50% life extension. So apparently C60 does something more than this.

In the early 1970s, it was shown that BHT produced a 23% life extension. BHT is a powerful antioxident that is readily active and needs no conversions in the body as vitamin E and other "natural" oxidents do. I have been taking 1 gm BHT per day since 1977 and I appear to be about 7 years younger than my age.

I just started taking 25 gm Glycine powder per day. It tastes like sugar and only cost about $0.04 per gm. I use it in place of sugar.

Posted by: Tom Blalock at June 7, 2012 9:18 AM

@Tom Blalock: It is very possible that the BHT studies saw a life span extension due to calorie restriction. BHT causes nausea in high doses, which tends to reduce dietary intake. Very few studies prior to a decade ago or so properly controlled for calorie restriction. See:

https://www.fightaging.org/archives/2005/09/peer-at-every-s-1.php

Posted by: Reason at June 7, 2012 10:15 AM

@Reason: I scaled my BHT intake (1000 mg / day) to match the test intake and have never had the slightest nausea.

Posted by: Tom Blalock at June 7, 2012 11:26 AM

>>25 gm Glycine powder per day

Hi, Tom Blalock, quite interesting, i study Medicine and Surgery, i red some study about meth-restriction and antagonist effect of glycine on methionine. So, i'm very interested, Where do you get the bulk? how does it cost and do you have experienced some sides effect?
Cheers :-)

Posted by: Dario Dall'Agata at July 20, 2012 6:28 AM

The other possibility is these particles take up 'junk' in their internal space, the particles are then extruded taking some of the 'junk' with it. I don't see how plain fullerenes would act as a free radical sink themselves, unless the fat attached somehow and was never digested increasing the hydroxyl groups available which may take a part in the degradation of superoxides etc.

Posted by: Julian Poulton-King at October 14, 2012 7:43 PM

25g if Glycine? How long have you been taking this? I take 5g and I want to take higher does but scared of the risks.

Posted by: Andrew young at May 22, 2013 7:46 PM
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