351 replies to this topic

[Kalliste]

I'm also concerned about derailing this thread, however...

 

I was intrigued by post #207 above, which referenced the MitoQ/MitoE/Melatonin study (attached).

 

So I Googled (well, actually I Bing-ed) MELATONIN and MITOCHONDRIA. There were a lot of hits--many from the early 2000s. But I don't see much discussion of this topic on this forum. (I find a lot on Melatonin and Sleep, Melatonin as a Nootropic, etc..) Am I just missing a major thread, or has this not received much attention?

 

As the authors of the paper point out, MitoQ is rapidly concentrated in the mitochondria, while Melatonin is widely distributed in the cytoplasm, so they are definitely different beasts. Synergistic? Competitive? This aspect of Melatonin is quite interesting to me, but I don't want to cover the ground again if it has already been thoroughly hashed out previously somewhere on this forum.

 

I've read about it. Wondered the same thing. If it's as good as MitoQ then it's really good!

 

 

Br J Anaesth. 2013 Mar;110(3):472-80. doi: 10.1093/bja/aes577. Epub 2013 Feb 4.

Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis.

Lowes DA¹, Webster NR, Murphy MP, Galley HF.

Author information

Abstract

BACKGROUND:

Sepsis-induced organ failure is the major cause of death in critical care units, and is characterized by a massive dysregulated inflammatory response and oxidative stress. We investigated the effects of treatment with antioxidants that protect mitochondria (MitoQ, MitoE, or melatonin) in a rat model of lipopolysaccharide (LPS) plus peptidoglycan (PepG)-induced acute sepsis, characterized by inflammation, mitochondrial dysfunction and early organ damage.

METHODS:

Anaesthetized and ventilated rats received an i.v. bolus of LPS and PepG followed by an i.v. infusion of MitoQ, MitoE, melatonin, or saline for 5 h. Organs and blood were then removed for determination of mitochondrial and organ function, oxidative stress, and key cytokines.

RESULTS:

MitoQ, MitoE, or melatonin had broadly similar protective effects with improved mitochondrial respiration (P<0.002), reduced oxidative stress (P<0.02), and decreased interleukin-6 levels (P=0.0001). Compared with control rats, antioxidant-treated rats had lower levels of biochemical markers of organ dysfunction, including plasma alanine amino-transferase activity (P=0.02) and creatinine concentrations (P<0.0001).

CONCLUSIONS:

Antioxidants that act preferentially in mitochondria reduce mitochondrial damage and organ dysfunction and decrease inflammatory responses in a rat model of acute sepsis.

[aribadabar]

Thanks Greg, that's very helpful.  In the above paper they reported on the PK of MitoQ mesylate (methanesulfonate) complexed with beta cyclodextrin.  This was a human phase I trial, orally dosed at 1 mg/kg.  They found a Cmax of 33.15ng/ml in plasma at ~1 hour.  Expressed in molarity, that's 49 nM.   While this briefly (on the order of minutes) attains a level that caused problems in vitro, the cells in vitro were dosed for some amount of time--  I'm not sure how long, but typically it's on the order of hours.  In addition, while this level was seen at 1mg/kg, most people are taking anywhere from a quarter to a sixteenth that amount.  Thus it appears that we have a reasonable (though not huge) safety margin for adults using 5-10mg.  I feel a little better about this now.  I'd not advise megadosing any mitochondrial antioxidants (MitoQ, c60oo, SkQ1, etc) until we have a better understanding of this phenomenon.

 

Thank you for the insightful post.

 

Would the sublingual route be significantly better than the oral one for mitoQ or it wouldn't make a big difference in the final plasma concentrations?

Edited by aribadabar, 03 July 2015 - 03:35 PM.

[motorcitykid]

 

Thanks Greg, that's very helpful.  In the above paper they reported on the PK of MitoQ mesylate (methanesulfonate) complexed with beta cyclodextrin.  This was a human phase I trial, orally dosed at 1 mg/kg.  They found a Cmax of 33.15ng/ml in plasma at ~1 hour.  Expressed in molarity, that's 49 nM.   While this briefly (on the order of minutes) attains a level that caused problems in vitro, the cells in vitro were dosed for some amount of time--  I'm not sure how long, but typically it's on the order of hours.  In addition, while this level was seen at 1mg/kg, most people are taking anywhere from a quarter to a sixteenth that amount.  Thus it appears that we have a reasonable (though not huge) safety margin for adults using 5-10mg.  I feel a little better about this now.  I'd not advise megadosing any mitochondrial antioxidants (MitoQ, c60oo, SkQ1, etc) until we have a better understanding of this phenomenon.

 

Thank you for the insightful post.

 

Would the sublingual route be significantly better than the oral one for mitoQ or it wouldn't make a big difference in the final plasma concentrations?

 

 

I still can't help but wonder... What might be the total health effect of taking 1/16 or 1/4 the amount considered harmful on a daily basis for a lifetime? According to the info available, daily dosing at 1/16th or 1/4 the amount considered harmful puts us on the happy side of the bell curve. The only issue for me is that there are no long term studies. Might we at some point(five or ten years down the road of daily dosing) find ourselves around the ugly side of that bell curve? 

 

[Kalliste]

Biology usually does not operate in an accumulating manner like that. With most drugs you can stay on the safe side of dosage for a long time without provoking the symtoms that the same drug would give you in an OD situation.

[Kalliste]

Well I take Curcumin (Turmeric roots and dried curcumin powder for most of the time) along with MitoQ

 

 

Conclusions Every mammal has stem cells in different organs, being particularly important in the brain, and nowa days these cells are believed to play a role in cell substitute after birth [23]. The existence of neural stem/progenitor cells in the mammalian mature brain that are capable of forming new neurons continues to push the developments of new approaches to brain repair after ischemia. In particular, the modulation of impaired neurogenesis in the hippocampus is associated with the amelioration of cognitive deficits and better outcomes related to brain ischemia (Table I) [66,75]. Therefore, the latest focus has been concentrated on the development of new natural drugs that can simulate proliferation of ischemic neural stem/progenitor cells after birth. The mechanisms and factors that control the formation of new neurons in the animal and human brain after ischemia are by and large unknown, and finding such factors is likely to lead to new ways of treating brain ischemia [10,58]. This review presents the neurogenic and neuroprotective properties of curcumin and provides a new basis for a possible reparative strategy whereby endogenous neural stem/progenitor cells are recruited by dietary stimulation to address ischemic neuronal loss [1,39]. Curcumin improves the survival rate of newly generated neurons and stimulates impaired neurogenesis after ischemia by elevation of neurotrophic factors [30,39]. However, curcumin triggers the mitogenic property of neural stem/progenitor cells and stimulates their proliferation by BDNF and MAP kinase activation [30,39]. Collectively, understanding the neurogenic mechanisms after ischemia and curcumin neurogenic activity could provide a neurorestorative strategy that stimulates dysregulated endogenous neural stem/progenitor cell activity and as a result prevents neuropathological changes and neurological deficits after ischemia. There are, however, some encouraging results suggesting that curcumin could be of therapeutic relevance in these kinds of diseases (Table I) [12,13,23,63]. Amid all the optimism surrounding the potential of ischemia-induced neurogenesis, there remain a variety of significant concerns. Postischemic epilepsy is a fairly common morbidity after an ischemic episode [22]. It has been suggested that aberrant neurogenesis triggers the epileptic activity [22]. Clearly any research aimed at enhancing neurogenesis might result in this and other unwanted side effects. In addition, enhanced neurogenesis would stimulate cell growth; it is possible that increased proliferation could result in tumor development [22]. In this situation many issues regarding specificity, mechanism and potential toxicity need to be more carefully studied before clinical trials can occur [13,23]. Undoubtedly, more investigations are needed to explore hippocampal neurogenesis and the effects of curcumin in long-term natural interventions [12], and the fact that curcumin seems to be innocuous in animals and humans could prompt additional studies on the effect of curcumin in the onset and progression of postischemic brain neurodegeneration with Alzheimer phenotype. Our review also points out the limitations of available data and potential directions of research into the role of curcumin in hippocampal neurogenesis and neuroprotection in ischemic brain neurodegeneration with Alzheimer phenotype course.

http://www.termedia....,25332,1,1.html

Edited by Cosmicalstorm, 04 July 2015 - 03:22 PM.

[motorcitykid]

Biology usually does not operate in an accumulating manner like that. With most drugs you can stay on the safe side of dosage for a long time without provoking the symtoms that the same drug would give you in an OD situation.

 

I hear what you're saying but many of those drugs that are approved have a long term safety profile as a result of phase 1,2, and 3 trials. Safety profile has been established and I would imagine that any long term adverse effects-whether due to the substance directly accumulating in the system which I believe does sometimes occur, or due to a seemingly minor drug toxicity issue that causes wear and tear overtime leading to a potentially major health issue way down the road(phase 3) - would be identified at some point during the study.   

 

The MitoQ people reached their conclusions at the level of phase 1 (which I have to say is one phase more than most supplements are tested). But, MitoQ is a very potent supplement that has the potential to breach our normal NSC signaling and function and that makes me a little uncomfortable.

 

I was taking pyridoxomine at the suggested daily dose for about six months without any problem (pyridoxomine had already been on the market for a few years) and one morning I woke up with tingling in my fingers. 

Well,I thought my hands fell asleep but it lasted throughout the day and night and after about a week of tingling I went through my supplement stack, did some digging and found that pyridoxomine could potentially cause neuropathy at higher doses. But I wasn't taking a higher dose, I was taking the recommended.  I discontinued the supplement and the tingling dissappeared within several days.

 

I'm not a chemist, so I don't know if it would be correct to say that the pyridoxomine "accumulated" in my system. But at 2 months there was no problem, at 4 months there was no problem and at 6 months-BAM!! A problem. I was fortunate that the problem was not irreversible, but  I'm not so sure about the prospects of reversing damage to our precious limited colony of NSC.

[Kalliste]

Maybe you were getting tainted Pyridoxomine? Sometimes there is a lot more in some capsules. Maybe it did accumulate.

 

Personally I have taken MitoQ and C60 but I have made several breaks in my usage lasting up to 15 days. I have fasted for three or four days on water/salt only once every month for 12 months for the obvious IGF-1 lowering reason, but also because fasting improves chemoresistance, it also starts production of ROS that seems to be positive. Might balance some damage from this stuff.

 

I have also eaten Turmeric roots/curcumin,  creatine, been drinking green tea, and exercised a lot. Many of these things also interfer with mitochondrial activity, most of them actually increase ROS, creatine seems to increase other antioxidant markers.

 

All of this to balance this new MitoQ/C60 stuff if it has some harmful unknown effect.

Edited by Cosmicalstorm, 04 July 2015 - 08:30 PM.

[motorcitykid]

Maybe you were getting tainted Pyridoxomine? Sometimes there is a lot more in some capsules. Maybe it did accumulate.

 

Personally I have taken MitoQ and C60 but I have made several breaks in my usage lasting up to 15 days. I have fasted for three or four days on water/salt only once every month for 12 months for the obvious IGF-1 lowering reason, but also because fasting improves chemoresistance, it also starts production of ROS that seems to be positive. Might balance some damage from this stuff.

 

I have also eaten Turmeric roots/curcumin,  creatine, been drinking green tea, and exercised a lot. Many of these things also interfer with mitochondrial activity, most of them actually increase ROS, creatine seems to increase other antioxidant markers.

 

All of this to balance this new MitoQ/C60 stuff if it has some harmful unknown effect.

 

I doubt the pyridoxamine was tainted, Life Extension is a pretty reliable source and I think it would be too coincidental that a tainted substance would mirror the effects of neuropathy(tingling in the fingers).
 

[Kalliste]

Here is an interesting paper from China on antioxidants and ROS-burst illnesses like Avian Flu, Ischemia. They mention a few interesting things.

 

 

Mitochondrion-Permeable Antioxidants to Treat ROS-Burst-Mediated Acute Diseases

http://downloads.hin.../aip/346827.pdf

 

 

Attached Files

•  netnytn.jpg   153.49KB   3 downloads

[Kalliste]

 

G10

MITOCHONDRIAL-TARGETED ANTIOXIDANT MITOQUINONE

REDUCES PORTAL HYPERTENSION IN CCl4-CIRRHOTIC RATS

BY DECREASING INTRAHEPATIC RESISTANCE

M. Vilaseca Barcelo´ 1, C. Lo´ pez-Sanjurjo1, M.P. Murphy2, J. Bosch1,

V. Hern´andez-Gea1, J. Gracia-Sancho1, J.C. Garc´ıa-Pag´an1.

1Barcelona Hepatic Hemodynamic Laboratory, Institut d’Investigacions

Biom`ediques August Pi i Sunyer (IDIBAPS) – Hospital Cl´ınic de

Barcelona – CIBEREHD – University of Barcelona Medical School,

Barcelona, Spain; 2MRC Mitochondrial Biology Unit, Medical Research

Council, Cambridge, United Kingdom

E-mail: mvilaseca7@gmail.com

Background and Aims: Increased intrahepatic resistance (IHR)

due to both architectural alterations of the liver parenchyma as

well as to dynamic increase in the hepatic vascular tone, is the

primary factor in the development of portal hypertension. Hepatic

Stellate Cells (HSC) are the main cells contributing to disrupt liver

parenchyma by promoting fibrogenesis when activated. We have

shown that cirrhotic livers have an increased production of reactive

oxidative species (ROS), and that antioxidant therapy decreases

portal pressure. It is also known that part of these ROS is produced

within mitochondria. The aim of this study was to asses if the

mitochondrial-directed antioxidant Mitoquinone was able to reduce

oxidative stress, decrease intrahepatic fibrosis and attenuate portal

hypertension.

Methods: In vitro: The expression of col1, a-SMA and pdgfrb (qPCR)

was determined in human activated HSC (LX-2) in response to

Mitoquinone (1nM for 24 h; n = 3). Proliferation and viability were

also assessed.

In vivo: CCl4-cirrhotic Wistar rats were treated with Mitoquinone

(MIT: 25 mg/kg/day p.o.; n = 9) or its vehicle, DecylTPP (Veh:

25 mg/kg/day; n = 9) for 2 weeks. Cellular and mitochondrial

oxidative stress was assessed by DHE and MitoSox staining.

Systemic and hepatic hemodynamics were determined in vivo. Liver

fibrosis was determined by Sirius Red staining and HSC phenotype

by gene expression of col1, col1a2, pdgfrb, timp1, timp2 (qPCR) and

a-SMA and desmin expression (IHC).

Results: In vitro: Mitoquinone induced a significant deactivation of

HSC (col1 [-67%], a-SMA [-65%] and pdgfrb [-48%]), and decreased

proliferation (−43%). No effects on viability were observed.

In vivo: Mitoquinone markedly decreased mitochondrial (−34%)

and cellular (−34%) oxidative stress. These effects were associated

with a significant reduction in PP (Veh: 13.6±0.9 vs MIT:

10.9±0.6mmHg; −20%) without affecting PBF resulting in a decrease

in IHR (−34%). MAP was not significantly modified. Livers from

Mitoquinone-treated rats showed significantly lower fibrosis (−36%)

and expression of col1, pdgfrb and timp2 (−68%, −54% and −31%,

respectively) without significant changes in a-SMA and desmin.

These data suggest Mitoquinone evokes a change in HSC to a more

inactive form.

Conclusions: Mitoquinone significantly reduces mitochondrial ROS,

PP and IHR, mostly by decreasing collagen deposition due to

inactivation of HSC. We herein propose directed mitochondrial

antioxidants as a novel treatment against portal hypertension and

cirrhosis.

 

[Kalliste]

Can anyone get a hold of this article?

http://www.fasebj.or...275404.abstract

 

 

Mitochondrial-targeted antioxidants

1. Anne O. Oyewole and
2. Mark A. Birch-Machin¹

+ Author Affiliations
 

This Article

1. Published online before print August 7, 2015, doi: 10.1096/fj.15-275404 fj.15-275404

1. Dermatological Sciences, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom

1. ↵1Correspondence: Dermatological Sciences, Institute of Cellular Medicine, Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom. E-mail: m.a.birch-machin@ncl.ac.uk

Abstract

Redox homeostasis is maintained by the antioxidant defense system, which is responsible for eliminating a wide range of oxidants, including reactive oxygen species (ROS), lipid peroxides, and metals. Mitochondrial (mt)-localized antioxidants are widely studied because the mitochondria; the major producer of intracellular ROS, has been linked to the cause of aging and other chronic diseases. Mt-targeted antioxidants have shown great potential because they cross the mt phospholipid bilayer and eliminate ROS at the heart of the source. Growing evidence has identified mt-targeted antioxidants, such as MitoQ and tiron as potentially effective antioxidant therapies against the damage caused by enhanced ROS generation. This literature review summarizes the current knowledge on mt-targeted antioxidants and their contribution to the body’s antioxidant defense system. In addition to addressing the concerns surrounding current antioxidant strategies, including difficulties in targeting antioxidant treatment to sites of pathologic oxidative damage, we discuss promising therapeutic agents and new strategic approaches.—Oyewole, A. O., Birch-Machin, M. A. Mitochondrial-targeted antioxidants.

1.  

 

Here is a very long e-book that covers  coq10, creatine, MitoQ, Skq1 and more.

http://www.researchg...92e9663caf1.pdf

Edited by Cosmicalstorm, 15 August 2015 - 12:33 PM.

[Kalliste]

MitoQ used in conjunction with several other compounds to treat bone loss in type 2 diabetes.

 

This study evaluated the association between free fatty acid (FFA), ROS generation, mitochondrial dysfunction and bone mineral density (BMD) in type 2 diabetic patients and investigated the molecular mechanism. db/db and high fat (HF)-fed mice were treated by Etomoxir, an inhibitor of CPT1, MitoQ, and PFT-α, an inhibitor of P53. Bone metabolic factors were assessed and BMSCs were isolated and induced to osteogenic differentiation. FFA, lipid peroxidation and mtDNA copy number were correlated with BMD in T2DM patients. Etomoxir, MitoQ and PFT-α significantly inhibited the decrease of BMD and bone breaking strength in db/db and HF-fed mice and suppressed the reduction of BMSCs-differentiated osteoblasts. Etomoxir and MitoQ, but not PFT-α, inhibited the increase of mitochondrial ROS generation in db/db and HF-fed mice and osteoblasts. In addition, Etomoxir, MitoQ and PFT-α significantly inhibited mitochondrial dysfunction in osteoblasts. Moreover, mitochondrial apoptosis was activated in osteoblasts derived from db/db and HF-fed mice, which was inhibited by Etomoxir, MitoQ and PFT-α. Furthermore, mitochondrial accumulation of P53 recruited Bax and initiated molecular events of apoptotic events. These results demonstrated that fatty acid oxidation resulted in ROS generation, activating P53/Bax-mediated mitochondrial apoptosis, leading to reduction of osteogenic differentiation and bone loss in T2DM.

 

 

http://www.nature.co...icles/srep12724

 

Here is the conclusion of the study I asked about in my previous post, it was a bit of a disappointment (going by the name I expected it to be more exhaustive), it did not teach me anything new about MitoQ and mostly rehashed what was already known about Tiron. Or maybe I failed to understand it's core message, I have only read it once.

 

CONCLUSIONS AND PERSPECTIVES

Although a growing body of evidence has demonstrated

the beneficial effects of exogenous antioxidants, in particularmt-

targeted antioxidants in human and animal skin

models (14, 43, 67, 68), controversy still surrounds the use

of these agents to prevent or delay age-associated chronic

diseases and UVR-mediated oxidative damage. Results

from some intervention studies have not consistently

shown beneficial effects of antioxidants, with some even

reporting harmful effects (69). One explanation for the

discrepancies observed may be the differing doses of antioxidants

used in studies. Differences in the basal level of

oxidative damage, the disease stage, or the sensitivity and

tolerance of the agents being assessed in human subjects

can add to the variability observed in the responses (67).

Furthermore,many studies are unable to directly compare

the efficacy of antioxidants because of the different

methodologies used. There is at present a clear unmet

need for a uniform standard of measurement of the efficacy

of antioxidants. The development of such a system

would enhance our knowledge of the potency and usefulness

of antioxidants, which is at present an important goal.

In a recent review, Murphy (70) described key concerns

regarding the effectiveness of current antioxidant strategies

described. Although a considerable amount of literature

has been published on the origin and generation

of intracellular ROS, current antioxidant therapies lack

specificity for dysfunctional or diseased organelles, cells,

and tissue and may not achieve an effective concentration

at the site of pathologic oxidative stress. Furthermore,

antioxidants target a broad spectrum of reactive oxygen

intermediates and are unable to mediate a response

against a specific intermediate in a pathologic process or

oxidative reaction, with the results that many current

therapeutic strategies are unfocused. Mt-targeted antioxidants

have shown great promise, with compounds

such as MitoQ currently in clinical trials; however, further

investigative work is needed, to improve the potency of

current antioxidants and therapeutic treatments. One

proposal is the establishment and use of validated biomarkers

that can be used routinely in in vivo and in vitro

models, to assess the protective effects of compounds.

The need to assess the role of iron-mediated oxidative

damage via the Fenton reaction is important in further

ascertaining the contribution of iron accumulation andmt

dysfunction to the pathologic development and progression

of various diseases. Very limited evidence is available

on the interactions between antioxidants and chelating

agents, and clearer elucidation may lead to the development

of nontoxic, potent therapeutic agents, as well as and

novel biomarkers of specific diseased tissue and downstream

mediators of oxidative pathways.

http://www.fasebj.or...275404.abstract

Edited by Cosmicalstorm, 18 August 2015 - 09:12 AM.

[docmaas]

mitoq c60oo or both?  

 

I've been off and on NR and just acquired 12 bottles of the HP.  I'm 71, diabetes type 2.  I swim 6 miles a week, 3x 1 mile mild and 1 mile high intensity.  I currently take pterostilbene and creatine and just added berberine.  Unfortunately metformin is not particulary useful for me due to a genetic snp.  I also have potential methylation issues but put those aside after getting some brain fog from some of the supplements.  I will probably pick that up later but being 71 and relatively good health aside from the diabetes I'm not too concerned about that right now.

 

I want to go the next step to something that gets inside the mitochondria.  Is there any synergy between these two options or is it pretty much one or the other.  I've read through the thread and seen no real evidence to support taking them both or to avoid taking them both.  So what are your opinions and experience?

 

thanks,

 

Mike

 

thanks,

 

Mike

[niner]

Mike, I'd certainly advise taking at least one of them (either c60oo or MitoQ).  MitoQ is a lot more expensive, but I've seen a couple reports from people who find that MitoQ works better for them than c60oo.  I don't recall any strong reports of synergy from the few people who have tried both, but I don't know if they really gave it a proper evaluation.  If you can afford MitoQ, then I'd suggest trying both of them, separately and together.  If you experiment with them, bear in mind that there is a very long half life with c60oo, so you should probably try MitoQ first, then add c60oo.  Let us know your experiences. 

[Kalliste]

I've tried them both and tried them at the same time, at high dosage (20mg MitoQ and 25ml of C60oo on one day. once or twice) without feeling any ill effects. I'm 31 though.

Did not feel some godlike superpower either by the way, but that might be because I'm already in good shape.

 

Start with C60 and add MitoQ later on as niner suggests. You can take a lot of c60 at once, the packaging kind of discourages big doses but I usually take 10ml once or twice a week.

[docmaas]

thanks for the input.  Is there a succinct thread of the best guesses for the mechanisms of C60oo?  One of the things that is somewhat more attractive with mitoq is the number of research projects.  In contrast C60oo seems to be more of a collection of anecdotes.  Of course anecdotes can be useful and I do understand the difficulty of reproducing the original work or extending it further when there is no profit to be gained by those with the resources.  But there are a lot of very knowledgeable and smart people on this site and a pointer to a thread or even a few posts would be highly appreciated.

 

I'm not well versed in most of this stuff and a lot of it reads like mesopotamian to me but I like to read it anyway.

 

thanks again,

 

Mike

[niner]

Start with C60 and add MitoQ later on as niner suggests. You can take a lot of c60 at once, the packaging kind of discourages big doses but I usually take 10ml once or twice a week.

 

Because c60oo is so long-lasting, I'd start with MitoQ first, if you want to do a comparison.   I've used a variety of dosing strategies; for a long time it was 30mg, once a month, then 7.5 mg/week, lately ~3.75 mg twice a week.  I'm trying to find a schedule that will keep my eczema at bay.

 

thanks for the input.  Is there a succinct thread of the best guesses for the mechanisms of C60oo?  One of the things that is somewhat more attractive with mitoq is the number of research projects.  In contrast C60oo seems to be more of a collection of anecdotes.  Of course anecdotes can be useful and I do understand the difficulty of reproducing the original work or extending it further when there is no profit to be gained by those with the resources.  But there are a lot of very knowledgeable and smart people on this site and a pointer to a thread or even a few posts would be highly appreciated.

 

I'm not well versed in most of this stuff and a lot of it reads like mesopotamian to me but I like to read it anyway.

 

In our c60health forum, there are several very long threads that collectively contain all truth regarding c60oo.  Unfortunately, they also contain all lies about same, and are not labeled as such.  Such is the nature of the internet...  Given that it reads like mesopotamian, it's probably not worth the trouble.  The explanation that I think makes the most sense and is consistent with all available observations is that c60oo is a potent mitochondrial antioxidant with an exceptionally long half life.  In addition, it has some receptor-mediated activities, like an anti-allergy/asthma effect, and alterations in the way alcohol and certain gaseous anaesthetics are experienced.

[Kalliste]

thanks for the input.  Is there a succinct thread of the best guesses for the mechanisms of C60oo?  One of the things that is somewhat more attractive with mitoq is the number of research projects.  In contrast C60oo seems to be more of a collection of anecdotes.  Of course anecdotes can be useful and I do understand the difficulty of reproducing the original work or extending it further when there is no profit to be gained by those with the resources.  But there are a lot of very knowledgeable and smart people on this site and a pointer to a thread or even a few posts would be highly appreciated.

 

I'm not well versed in most of this stuff and a lot of it reads like mesopotamian to me but I like to read it anyway.

 

thanks again,

 

Mike

 

There is a wealth of studies on various fullerene compounds with little to no reported toxicity (except when mixed with toxic solvents, when inhaled like dust, when injected in cluster form).

 

MitoQ also has some issues that worry me, a therapeautic index that seems pretty short, probably shorter than C60. And also some problems with stem cells at high dosages. That stem cell bit might go for C60 as well since it might perturb the redox homeostasis in the same way.

 

IMO MitoQ and C60 are safe substances, probably a lot safer than many things you will get at the doctors office like malaria-meds, statins, NSAIDS.

[BigLabRat]

Niner, as a newcomer to the forums I'd have to say I'm in the same boat at docmaas--the sheer volume of material posted on C60 is overwhelming. I've spent some time trying to get a handle on the consensus, or determine if one even exists. (I wish someone would do a "review article" or post a retrospective survey; but I'm sure everyone has better things to do.)

 

That said, I was glad to hear you say that one should try MitoQ first, as that's what I'm doing...largely because I don't seem to be able to get my head around C60!

[Kalliste]

Here are the five most informative papers on C60 IMO.

 

 

Abstract

Countless studies showed that [60]fullerene (C₆₀) and derivatives could have many potential biomedical applications. However, while several independent research groups showed that C₆₀ has no acute or sub-acute toxicity in various experimental models, more than 25 years after its discovery the in vivo fate and the chronic effects of this fullerene remain unknown. If the potential of C₆₀ and derivatives in the biomedical field have to be fulfilled these issues must be addressed. 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 effects of C₆₀-olive oil solutions in an experimental model of CCl₄ intoxication in rat strongly suggest that the effect on lifespan is mainly due to the attenuation of age-associated increases in oxidative stress. Pharmacokinetic studies show that dissolved C₆₀ is absorbed by the gastro-intestinal tract and eliminated in a few tens of hours. These results of importance in the fields of medicine and toxicology should open the way for the many possible -and waited for- biomedical applications of C₆₀ including cancer therapy, neurodegenerative disorders, and ageing.

 

http://www.sciencedi...142961212003237

 

 

Results published in 1999 have shown that fullerenes have a potential as biological antioxidants. The antioxidant property is based on the fact that fullerenes possess large amount of conjugated double bonds and low lying lowest unoccupied molecular orbital (LUMO) which can easily take up an electron, making an attack of radical species highly possible. It has been reported that up to 34 methyl radicals have been added onto a single C60 molecule. This quenching process appears to be catalytic. In other words the fullerene can react with many superoxides without being consumed. Due to this feature fullerenes are considered to be the world’s most efficient radical scavenger and are described as radical sponges (Krusic et al 1991). The major advantage of using fullerenes as medical antioxidant is their ability to localize within the cell to mitochondria and other cell compartment sites, where in diseased states, the production of free radicals takes place.

Experiments on rats done by Najla Gharbi and coworkers proved this remarkable trait. They showed that aqueous C60 suspensions prepared without using any polar organic solvent, not only have no acute or sub acute toxicity in rodents, but also protect their livers against free-radical damage (Gharbi et al 2005). Rats are intoxicated with CCl₄, which led to the formation of trichloromethyl radical CCl₃^•, causing severe damage to the liver on reaction with oxygen. Trichloromethylperoxy radicals CCl₃OO•, a highly reactive species which rapidly initiates the chain reaction of lipid peroxidation (Slater et al 1985), is formed. C60 is able to scavenge a large number of these radicals per molecule leading to the result that rats pre-treated with C60 and intoxicated with CCl₄ showed no liver damage. Considering the histopathological examinations and biological tests, pristine C60 can be considered as a powerful liver-protective agent when used in a dose-dependent manner.

When fullerene is derivatized with polar groups, as in case of polyhydroxylated fullerenes (fullerenol) and C60 tris(malonic)acid, they become water soluble enabling them to cross the cell membrane and localize preferentially to mitochondria (Foley et al 2002; Youle and Karbowski 2005), which generate great masses of cellular oxygen free radicals. This phenomenon makes them useful for a variety of medical applications (Tsai et al 1997; Lotharius et al 1999; Bisaglia et al 2000). These radical scavengers have shown to protect cell growth from various toxins that can induce apoptotic injuries in vitro (Lin et al 1999; Lin et al 2002; Chen et al 2004) in different cell types such as neuronal cells (Dugan et al 1997; Bisaglia et al 2000), hepatoma cells (Huang et al 1998), or epithelial cells (Straface et al 1999).

Apoptosis is of critical importance for variety of physiological and pathological phenomenon which led numerous scientists to design experiments in this regard. Daniela Monti et al investigated the protective activity of this drug against oxidative stress-induced apoptosis. 2-deoxy-D-ribose (dRib) or TNF-αplus cycloheximide were used as agents to trigger apoptosis in human peripheral blood mononuclear cells (PBMCs) by interfering with the redox status of cell and mitochondrial membrane potential. It was found that carboxyfullerenes, also known as C60 tris(malonic)acid, was able to protect quiescent PBMCs against apoptosis by preserving the mitochondrial membrane potential integrity, which is the early stage of apoptosis (Monti et al 2000). Other interesting results showing that fullerenes have potential as biological antioxidants were also published by Dugan et al The authors treated transgenic mice carrying a defective copy of the gene encoding for human superoxide dismutase (SOD1), which led to amyotrophic lateral sclerosis (ALS), with C60 tris(malonic)acid. SOD1 knock out mice treated with C60 developed symptoms of disease 10 days later and lived 8 days longer than untreated control mice (Dugan et al 1997).

Fullerenes are also used for cytoprotective action against UVA irradiation (Xiao et al 2006). The ultraviolet A radiation (320–400nm) generates reactive oxygen species, which have a biological effect on human skin cells, leading to cell damage or cell death. Once again the radical scavenging nature of water soluble fullerene derivative namely Radical Sponge® (C60 with poly(vinylpyrrolidone)) was utilised to protect human ore mammalian cells against oxidative stress, through catalytic dismutation of superoxide. The ability of Radical Sponge® to enter into depth of human skin epidermis due to its stability towards oxidative decomposition makes it more reliable than Vitamin C and enables the prevention of both UV skin-injuries and skin aging, without photosensitization and cytotoxicity.

Water soluble fullerenes namely fullerenols and malonic acid derivatives of C60 have attracted great attention in the field of neurosciences. The brain contains a number of different unsaturated fatty acids, and underlies aerobic metabolism, and has limited ability to regenerate damaged tissues, making it a very sensitive organ towards oxidative damage caused by free radicals. These reactive oxygen species being O₂•^- (superoxide), •OH (hydroxyl) radicals and closed shell H₂O₂ molecules (Halliwell 1992). Fullerene derivatives have the ability to inhibit the chain reaction of lipid peroxidation by scavenging intermediate peroxyl radicals, stopping them from attacking adjacent fatty acid chains ore membrane proteins, which would lead to glutamate-receptor-mediated excitotoxicity and apoptotic cell death. In cell culture experiments, C60 tris(malonic)acid rescued cortical neurons from a broad range of insults and was furthermore found to show robust neuroprotection in a number of other cell culture models of neurological disease including Parkinson’s disease (Dugan et al 1997).

http://www.ncbi.nlm....les/PMC2676811/

 

 

 

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 KL¹, Ali SS, Arch R, Xiong C, Wozniak D, Dugan LL.

Author information

Abstract

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.

 

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

 

 

 

Biomaterials. 2009 Feb;30(4):611-21. doi: 10.1016/j.biomaterials.2008.09.061. Epub 2008 Nov 4.

The scavenging of reactive oxygen species and the potential for cell protection by functionalized fullerene materials.

Yin JJ¹, Lao F, Fu PP, Wamer WG, Zhao Y, Wang PC, Qiu Y, Sun B, Xing G, Dong J, Liang XJ, Chen C.

Author information

Abstract

We demonstrated that three different types of water-soluble fullerenes materials can intercept all of the major physiologically relevant ROS. C(60)(C(COOH)(2))(2), C(60)(OH)(22), and Gd@C(82)(OH)(22) can protect cells against H(2)O(2)-induced oxidative damage, stabilize the mitochondrial membrane potential and reduce intracellular ROS production with the following relative potencies: Gd@C(82)(OH)(22)> or =C(60)(OH)(22)>C(60)(C(COOH)(2))(2). Consistent with their cytoprotective abilities, these derivatives can scavenge the stable 2,2-diphenyl-1-picryhydrazyl radical (DPPH), and the reactive oxygen species (ROS) superoxide radical anion (O(2)(*-)), singlet oxygen, and hydroxyl radical (HO(*)), and can also efficiently inhibit lipid peroxidation in vitro. The observed differences in free radical-scavenging capabilities support the hypothesis that both chemical properties, such as surface chemistry induced differences in electron affinity, and physical properties, such as degree of aggregation, influence the biological and biomedical activities of functionalized fullerenes. This represents the first report that different types of fullerene derivatives can scavenge all physiologically relevant ROS. The role of oxidative stress and damage in the etiology and progression of many diseases suggests that these fullerene derivatives may be valuable in vivo cytoprotective and therapeutic agents.

http://www.ncbi.nlm....pubmed/18986699

[docmaas]

I've ordered mitoQ.  Should get it next week.  Meanwhile my resumption of NR after my supplement issues does seem to have enhanced my swimming.  I was having a hard time keeping up with those I usually do keep up with.  After I resumed my NR I began to regain my edge.  I'm now taking 1/2 g/day and am able to keep up even after swimming an extra mile before the group swim starts.  

 

I think my supplement issue is primarily pterostilbene which I find strange because I tolerated it fine for several weeks up to 400mg/day.  Then I got some royal jelly and everything went to hell in a handbasket.  Thought it might be the RJ but the diarrhea just kept on flowing even after cessation of the RJ.  Had stool labs done and no infectious agents were found.  I've slowly been adding things back to the mix including pterostilbene but I'm still getting pretty urgent and loose stools from that.  Powdered curcumin was irritating as well.  Got some Longvida and that does seem to be better.  Haven't been able to find any lipo pterostilbene though.

 

I'm looking forward to the MitoQ.  BTW saw that the bulletproof coffee guy is selling expiring mitoQ liquid at half price.  

 

Mike

[gregmacpherson]

Hi All, 

 

A bit of an update, some exciting news and some discounts over the Thanks Giving Weekend. 

 

On the research front ... 

 

Further work on MitoQ and Alzheimer's Disease models here. 

 

http://sfn15.hubbian.com/id_8700/

http://www.ncbi.nlm....pubmed/26441662

 

Some interesting work on MitoQ and models of anxiety

 

http://www.ncbi.nlm....pubmed/26567514

 

We are also excited to announce that MitoQ has been selected for the 2015 intake of the NIH's anti-aging Intervention Testing Program.   This is a significant step for MitoQ as it will provide a fully independent view of our anti-aging effect.  You can get detailed information here https://www.nia.nih....ing-program-itp . And a list of all the compounds in testing since the program started in 2004 here ... https://www.nia.nih....mpounds-testing.   

 

Lastly, we have some Thanksgiving specials starting shortly ... 20% off our Serum and Combo (Serum and 5mg caps) - CODE "THANKYOU20" and 30% off our MitoQ Blood Sugar and MitoQ Heart products - CODE  "THANKYOU30".  These will be valid till 30 November 2015. 

 

Wishing you all the best for the Thanksgiving Weekend!

 

Greg

 

 

 

[motorcitykid]

I found a study on Schisandrin B that leaves lingering concerns about continuous long term use of mitochondrial free radical scavengers( Mito Q).

I'm thinking the most judicious approach for healthy individuals in their 30's and 40's might be to cycle Mito Q on and off

so as not to completely eliminate the hormetic response(increased glutothione) that occurs in the mitochondria when exposed to ROS stress: 

 

Here's the link to several papers on the subject:

http://examine.com/s...hinensis/#ref29

4.1. Mitochondria

In isolated heart cells, it was mechanistically demonstrated that mitochondria get an increase in glutathione status and the cell increases Heat Shock Protein expression secondary to ROS-stress from Schisandrin B interacting with P450; basically, Schisandrin B induces oxidation and the mitochondria responds with a empirically greater anti-oxidant response.[

 

 

 

 

Edited by motorcitykid, 25 November 2015 - 10:34 PM.

[bosharpe]

Would quite like to do a group buy if others are interested. I would be looking to stock a 6 month - year supply. Anyone game?

[Graviton]

 

I found a study on Schisandrin B that leaves lingering concerns about continuous long term use of mitochondrial free radical scavengers( Mito Q).

I'm thinking the most judicious approach for healthy individuals in their 30's and 40's might be to cycle Mito Q on and off

so as not to completely eliminate the hormetic response(increased glutothione) that occurs in the mitochondria when exposed to ROS stress: 

 

Here's the link to several papers on the subject:

http://examine.com/s...hinensis/#ref29

4.1. Mitochondria

In isolated heart cells, it was mechanistically demonstrated that mitochondria get an increase in glutathione status and the cell increases Heat Shock Protein expression secondary to ROS-stress from Schisandrin B interacting with P450; basically, Schisandrin B induces oxidation and the mitochondria responds with a empirically greater anti-oxidant response.[

 

 

 

 

There seems to be a study that MitoQ activates Nrf2 (http://www.jbc.org/c...5/45/34447.full). Not sure if it uses a hormetic pathway.

I am concerned about too. Anyone here can answer to this concern? I have posted the rationale in another thread (http://www.longecity...e-6#entry780625).

Furthermore, for someone in 20s, we don't know which dosage of 5mg/day or 10mg/day is better.

 

 

Would quite like to do a group buy if others are interested. I would be looking to stock a 6 month - year supply. Anyone game?

I am interested in group buying of MitoQ if MitoQ can offer a discount promotion.

[tintinet]

1+ for a group buy at a decent discount.

[JJ A]

I would like to be apart of this bulk purchase. +1 to me... please contact me as welll

 

JJ A

[tintinet]

I'd also be interested in a group buy. Thanks!

[bosharpe]

Would have been interested in the bulk buy earlier in the year. Sorry I didn't respond to the above but I was using a 20% discount code. I've stocked up on Mitoq for 13 months but the stuff is really expensive now. Prices have recently risen and there are currently no meaningful discount codes in circulation. I'll probably discontinue and change over to C60oo after my stash runs out. 

[TRUGAN]

Why do you think it went up? I just checked and the regular MitoQ is 59.95 which is the same price that I have been paying since 2014 except for I am using the discount code for members and getting 15% off.