351 replies to this topic

[gregmacpherson]

Re: http://libgen.org/sc...3.268680&open=1

Quote : our results suggest a pivotal role of mitochondria-related signalling and mtROS in modulating endothelial function with age. This possibility is further supported by previous studies showing a life-extending effect of endothelial cell-specific knockout of p66SHC, a signalling protein involved in sensing and regulation of mtROS production (Camici et al. 2007; Gertz & Steegborn, 2010). We observed a marked elevation in phosphorylation of p66SHC, an indication of its activation (Gertz & Steegborn, 2010), in the arteries of old compared with young mice, and this was accompanied by increased vascular mitochondrial superoxide production. MitoQ normalized p66SHC activation and reduced mitochondrial superoxide production, suggesting that an increase in mtROS-mediated vascular oxidative stress may be a key mechanism contributing to the age-related decline in endothelial function.

This is interesting. How would that dosing relate to humans though? The mice certainly received more than the human equivalent of 10 mg !
I hope that someone performs legitimate longevity studies on wild type mice using MitoQ

 

We have funding for a human studies on this work early next year - watch this space. 

 

Longevity studies are being considered for funding also.  All going well we will have that confirmed by the end of this year. 

 

Thanks

 

Greg

[gregmacpherson]

Some forms of antioxidants have had negative effects on the body, particularly in regards to hormetic adaptations (i.e., exercise & weight lifting).

 

Have there been any studies in regards to CoQ10 or MitoQ, and a reduction in hormesis? I'm particularly concerned for two cases:

 

1. I don't want to risk reduced gains from exercise; I am in very good shape and competitive, and don't want to lose that edge.

 

2. Some theorize that too many antioxidants can prevent our bodies' natural oxidation systems from being able to kill off cancerous cells.

 

Would CoQ10, MitoQ or Ubiquinol/PQQ/Shilajit blends run the risk for either scenario 1 or 2? Would cycling be beneficial?

 

Final question: would MitoQ theoretically be capable of offsetting some of the oxidative damage caused by occasional Adderall usage, as a study aid?

 

Hi,

 

Good questions.

 

MitoQ is a selective antioxidant and allows free radical signalling to continue similar to what we see with CoQ10 therefore it avoids the reduction in hormesis seen with other antioxidant compounds.

 

MitoQ will give you a reasonable boost in exercise endurance from own experience and reports from others. 

 

When we tune up our mitochondria with a compound like MitoQ we see more effective ROS signalling which, in theory, will benefit our natural process in the instance of infections or cancer.  I say in theory because we have not done studies in this area. 

 

There is no evidence that cycling is required with MitoQ. It does not up regulate our natural antioxidant cascades. 

 

Lastly, sorry, I am not sure on the effect of Adderall and oxidative stress on the body.  We have one study showing MitoQ had some beneficial effects on cocaine toxicity which may be relevant to your question.

 

Thanks

[NeuroGeneration]

Thanks for your reply, @gregmacpherson. I'm not going to try out the cocaine, but I'll buy some MitoQ for a test run ;-)

 

Do you think 5mg would be adequate for a very healthy 30 year old (I know 10-20 is best, but I'm asking in consideration of my health & age)? 10mg is quite pricey.

 

Also, should I discontinue CoQ10/PQQ/Shilajit, coadminister, or alternate each day with MitoQ?

Edited by NeuroGeneration, 14 July 2014 - 08:51 PM.

[gregmacpherson]

Smart thinking

 

10mg is best but 5mg will be fine at 30. Consider upping to 10mg when you hit 40 or sooner if your funding situation improves. 

 

I think, feel your way on the CoQ10/PQQ/Silajit front.  Try alternating vs regular MitoQ and see if you notice a difference. 

 

I have tried PQQ with MitoQ and didn't experience the increased benefit I was expecting so went back to just MitoQ.  

 

No need to take CoQ10 if you are on MitoQ unless you are on a Statin and then you should take a small dose (to cover the loss of non-mitochondrial CoQ10 activity). 

[NeuroGeneration]

@gregmacpherson - can you please discuss the practical implications of the following quotes (the good & the bad, in relation to MitoQ, even if just theoretical):

 

 

 

"However, recent reports suggest that MitoQ can actually increase superoxide production at Complex I [189,190] and both MitoQ and SkQ were reported to inhibit mitochondrial bioenergetics [191,192]. Thus while these TPP+-conjugated antioxidants can reduce mitochondrial ROS, they may also reduce oxidative phosphorylation and ATP production."

Source: http://www.ncbi.nlm....les/PMC4013820/

 

 

"Another compound tested in clinical trials is the coenzyme Q10. Coenzyme Q10 is required for mitochondrial bioenergetics and can inhibit lipid peroxidation in mitochondrial membranes. Its effects in delaying the progression of Parkinson’s disease showed promising early results which could be confirmed in later trials [90,91]. To improve the targeting of coenzyme Q10 to the mitochondrion, the mitochondrially targeted coenzyme (MitoQ) was synthesized, and shown to be protective in the MPTP animal model [92,93], but ineffective in a human trial [94]."

Source: http://www.ncbi.nlm....les/PMC3909266/

 

 

"Finally, antioxidant therapies use very high doses of antioxidant which can potentially perturb physiological redox signaling. As many studies demonstrated, redox signaling is important for cellular function. Oxidants can regulate different activities, including Keap1-Nrf2 signaling [95,96], and cellular differentiation [97]. Furthermore, antioxidant compounds such as the polyphenolics can bind and reduce transition metal ions and then perturb redox signaling within the cell through the formation of superoxide or hydrogen peroxide [98]."

Source: http://www.ncbi.nlm....les/PMC3909266/

[mitomutant]

@gregmacpherson - can you please discuss the practical implications of the following quotes (the good & the bad, in relation to MitoQ, even if just theoretical):

 

 

 

"However, recent reports suggest that MitoQ can actually increase superoxide production at Complex I [189,190] and both MitoQ and SkQ were reported to inhibit mitochondrial bioenergetics [191,192]. Thus while these TPP+-conjugated antioxidants can reduce mitochondrial ROS, they may also reduce oxidative phosphorylation and ATP production."

Source: http://www.ncbi.nlm....les/PMC4013820/

 

 

I can talk about this one based on my personal experience. I do have a primary mitochondrial dysfunction (mitochondrial myopathy) and my experience with both CoQ10 and mitoQ is, in both cases, very positive. If we take "vitality" as a proxy for ATP production, then these compounds increase ATP production without doubt.

 

Nowadays, I am alternating 300mg Ubiquinol and 10mg mitoq every during weekdays; nothing during weekends.

[gregmacpherson]

Hi NeuroGeneration - apologies for the slow reply - I have been on a break. 

 

Comments embedded below. 

 

KR

 

Greg

 

@gregmacpherson - can you please discuss the practical implications of the following quotes (the good & the bad, in relation to MitoQ, even if just theoretical):

 

 

 

"However, recent reports suggest that MitoQ can actually increase superoxide production at Complex I [189,190] and both MitoQ and SkQ were reported to inhibit mitochondrial bioenergetics [191,192]. Thus while these TPP+-conjugated antioxidants can reduce mitochondrial ROS, they may also reduce oxidative phosphorylation and ATP production."

Source: http://www.ncbi.nlm....les/PMC4013820/

 

 

Superoxide production at complex I only occurs in vitro and does not seem to occur in vivo. Inhibition only occurs at high concentrations of TPP compounds, above those used in vivo.  There is no evidence of increased superoxide production in any of our research in live disease models. 

 

 

"Another compound tested in clinical trials is the coenzyme Q10. Coenzyme Q10 is required for mitochondrial bioenergetics and can inhibit lipid peroxidation in mitochondrial membranes. Its effects in delaying the progression of Parkinson’s disease showed promising early results which could be confirmed in later trials [90,91]. To improve the targeting of coenzyme Q10 to the mitochondrion, the mitochondrially targeted coenzyme (MitoQ) was synthesized, and shown to be protective in the MPTP animal model [92,93], but ineffective in a human trial [94]."

Source: http://www.ncbi.nlm....les/PMC3909266/

 

The lack of response to MitoQ  with Parkinson's patients is now believed to be because the disease had progressed beyond the point where MitoQ could have an effect.  There are subsequent studies in animal models where MitoQ was given very early on prior to onset and it was shown to have a neuro-protective effect.  It is very hard to determine that in humans as we don't have diagnostics that identify pre-Parkinson's yet. 

 

 

"Finally, antioxidant therapies use very high doses of antioxidant which can potentially perturb physiological redox signaling. As many studies demonstrated, redox signaling is important for cellular function. Oxidants can regulate different activities, including Keap1-Nrf2 signaling [95,96], and cellular differentiation [97]. Furthermore, antioxidant compounds such as the polyphenolics can bind and reduce transition metal ions and then perturb redox signaling within the cell through the formation of superoxide or hydrogen peroxide [98]."

Source: http://www.ncbi.nlm....les/PMC3909266/

 

This is one of the very interested things about MitoQ as there is NO evidence that MitoQ disrupts redox signalling - note that redox signals are predominantly hydrogen peroxide and quinols don't react with hydroge peroxide.  This suggests that we are quite unique as a selective antioxidant that does not interfere with ROS signalling giving you all the benefit of hormesis as well as antioxidant protection of the mitochondrial membrane leading to highly functioning mitochondria. 

 

 

Many thanks

[NeuroGeneration]

Very good and much appreciated response, Greg – just in time for my MitoQ, which arrived in the mail today. Thanks!

[Razor444]

A new MitoQ study: Mitochondria-targeted therapies for acute kidney injury.

 

I've highlighted the most relevant sentences, from the abstract:

 

'Acute kidney injury (AKI) is a serious clinical condition with no effective treatment. Tubular cells are key targets in AKI. Tubular cells and, specifically, proximal tubular cells are extremely rich in mitochondria and mitochondrial changes had long been known to be a feature of AKI. However, only recent advances in understanding the molecules involved in mitochondria biogenesis and dynamics and the availability of mitochondria-targeted drugs has allowed the exploration of the specific role of mitochondria in AKI. We now review the morphological and functional mitochondrial changes during AKI, as well as changes in the expression of mitochondrial genes and proteins. Finally, we summarise the current status of novel therapeutic strategies specifically targeting mitochondria such as mitochondrial permeability transition pore (MPTP) opening inhibitors (cyclosporine A (CsA)), quinone analogues (MitoQ, SkQ1 and SkQR1), superoxide dismutase (SOD) mimetics (Mito-CP), Szeto-Schiller (SS) peptides (Bendavia) and mitochondrial division inhibitors (mdivi-1). MitoQ, SkQ1, SkQR1, Mito-CP, Bendavia and mdivi-1 have improved the course of diverse experimental models of AKI. Evidence for a beneficial effect of CsA on human cardiac ischaemia-reperfusion injury derives from a clinical trial; however, CsA is nephrotoxic. MitoQ and Bendavia have been shown to be safe for humans. Ongoing clinical trials are testing the efficacy of Bendavia in AKI prevention following renal artery percutaneous transluminal angioplasty.'

Edited by Razor444, 12 August 2014 - 10:13 PM.

[gregmacpherson]

A new article on MitoQ on Science 2.0 today as well.  Very interesting research. 

 

http://www.science20..._horizon-142136

 

 

[krillin]

This is one of the very interested things about MitoQ as there is NO evidence that MitoQ disrupts redox signalling - note that redox signals are predominantly hydrogen peroxide and quinols don't react with hydroge peroxide.  This suggests that we are quite unique as a selective antioxidant that does not interfere with ROS signalling giving you all the benefit of hormesis as well as antioxidant protection of the mitochondrial membrane leading to highly functioning mitochondria.

 

PMID: 21445095 found that 200 nM MitoQ impaired muscle differentiation by reducing mitochondrial ROS.

[niner]

 

This is one of the very interested things about MitoQ as there is NO evidence that MitoQ disrupts redox signalling - note that redox signals are predominantly hydrogen peroxide and quinols don't react with hydroge peroxide.  This suggests that we are quite unique as a selective antioxidant that does not interfere with ROS signalling giving you all the benefit of hormesis as well as antioxidant protection of the mitochondrial membrane leading to highly functioning mitochondria.

 

PMID: 21445095 found that 200 nM MitoQ impaired muscle differentiation by reducing mitochondrial ROS.

 

Thanks for that ref, and nice to have you back, btw.  They didn't determine a dose response relationship here, but it stands to reason that one exists.  I don't know enough about MitoQ pharmacokinetics off the top of my head to be sure about this, but 200nM sounds like a pretty tough number to hit in vivo, given the sorts of doses people are using.  

 

Greg, do you have any PK numbers on MitoQ?

[normalizing]

its nice to see all the positive studies, but i still questiona bioavailibity of mitoq. for example, mitoq is sold in powder capsule form and that doesnt sound too reliable to me. wouldnt it be more bioavaible if in capsule gel with some sort of oil?

[Kalliste]

 

"targeting mitochondrial superoxide with inactivators such as mitoTEMPO and MitoQ, repressed metastatic progenitor cells and no metastasis was able to develop."

 

What would the translated dosage for a human taking MitoQ be in this trial, 5mg or 10mg/day? Or did they go super high and dose 50 or 100's of mg/day?

 

[Hebbeh]

I've been using mitoQ sublingually for about a month and the mental energy boast is quite evident within less than 30 minutes.  I've been using 3 capsules spread through the day but recently dropped back to 2 to due to feeling over stimulated at times with a tinge of anxiety which is not normal.  But I do enjoy the focused energy especially in the morning.

[gregmacpherson]

Hi, the short answer is that we don't know just yet.  More research is being done.  I would stick with 10mg per day for now. 

 

Thanks

 

 

"targeting mitochondrial superoxide with inactivators such as mitoTEMPO and MitoQ, repressed metastatic progenitor cells and no metastasis was able to develop."

 

What would the translated dosage for a human taking MitoQ be in this trial, 5mg or 10mg/day? Or did they go super high and dose 50 or 100's of mg/day?

 

 

Hi, good question.  

 

MitoQ is a powder in its raw form and has no issue wrt bio-availability.  Almost all of the absorbed mitoq reaches the mitochondria within a few hours. 

 

Thanks

its nice to see all the positive studies, but i still questiona bioavailibity of mitoq. for example, mitoq is sold in powder capsule form and that doesnt sound too reliable to me. wouldnt it be more bioavaible if in capsule gel with some sort of oil?

 

[gregmacpherson]

 

 

This is one of the very interested things about MitoQ as there is NO evidence that MitoQ disrupts redox signalling - note that redox signals are predominantly hydrogen peroxide and quinols don't react with hydroge peroxide.  This suggests that we are quite unique as a selective antioxidant that does not interfere with ROS signalling giving you all the benefit of hormesis as well as antioxidant protection of the mitochondrial membrane leading to highly functioning mitochondria.

 

PMID: 21445095 found that 200 nM MitoQ impaired muscle differentiation by reducing mitochondrial ROS.

 

Thanks for that ref, and nice to have you back, btw.  They didn't determine a dose response relationship here, but it stands to reason that one exists.  I don't know enough about MitoQ pharmacokinetics off the top of my head to be sure about this, but 200nM sounds like a pretty tough number to hit in vivo, given the sorts of doses people are using.  

 

Greg, do you have any PK numbers on MitoQ?

 

 

Hi, this is an in-vitro study and at very high doses so not specifically translatable into in-vivo effect.   

 

At its essence MitoQ is simply a targeted way to get CoQ10 into the mitochondria and will mimic normal CoQ10 effect which has no impact on muscle differentiation and in-vivo levels. 

 

Thanks

[Kevnzworld]

[quote name="gregmacpherson" post="681250" timestamp="1407974988"]


Hi, the short answer is that we don't know just yet. More research is being done. I would stick with 10mg per day for now.

How was the dose of 10mg arrived at?

[gregmacpherson]

Hi, the dose of 10mg is based on our recommended dose for regular use.  

 

This dose was determined as we researched the effective dose to boost energy levels in healthy humans and see health effects.  

 

We do suggest you can take up to 20mg if you have a condition associated with higher oxidative stress and/or mitochondrial dysfunction as you will see additional benefit at this dose. 

 

In terms of the recent study, we don't know the optimal dose for effect but will let you know as soon as we do.  In the mean time our recommended dose of 10mg is a good place to start. 

 

Thanks

[quote name="gregmacpherson" post="681250" timestamp="1407974988"]


Hi, the short answer is that we don't know just yet. More research is being done. I would stick with 10mg per day for now.

How was the dose of 10mg arrived at?

 

[tintinet]

Are any discounts available?

[Kalliste]

I ordered some now, the Longecity code was no more but I knew that already. I'm grateful for the previous courtesy from Greg though.

[tintinet]

I've been taking 10 mg Q AM for a few days now. Haven't noticed any effects, so far. Possibly elevated mood, increased energy, decreased anxiety, but all those could quite easily be short term placebo effects.

[Kalliste]

Yeah same here. Have not felt any super effects after a few days. But then I am 30 and in good shape. I see it as a preventative treatment.

[NeuroGeneration]

I'm also 30, also in good shape, also taking it as a preventative treatment, and also haven't felt anything from it.

[normalizing]

what is supposed to be felt?

[niner]

what is supposed to be felt?

 

If you're young and healthy, not much.

[Kalliste]

Some nice studies were posted by Greg in the other mitoQ thread. Does this mean I can eat like a pig and partially get away with it via MitoQ?

 

A Mitochondrial-Targeted Coenzyme Q Analog Prevents Weight Gain and Ameliorates Hepatic Dysfunction in High Fat-Fed Mice
http://www.ncbi.nlm....pubmed/25301169

The mitochondrial-targeted antioxidant MitoQ ameliorates metabolic syndrome features in obesogenic diet-fed rats better than Apocynin or Allopurinol
http://www.ncbi.nlm....pubmed/25066801

Mitochondria-derived reactive oxygen species mediate caspase-dependent and -independent neuronal deaths.
http://www.ncbi.nlm....pubmed/25239010

[normalizing]

been taking mitoq for a while and i notice zero difference. i try it in the morning empty stomach instead of coffee for wake me up energy booster, but in fact, i have become kind of slower than usual actually. i guess coffee is much more potent in effect than those damn pills.

[gregmacpherson]

been taking mitoq for a while and i notice zero difference. i try it in the morning empty stomach instead of coffee for wake me up energy booster, but in fact, i have become kind of slower than usual actually. i guess coffee is much more potent in effect than those damn pills.

 

Hi Normalizing ... how long have you been taking MitoQ?  We have found a small group of people taking MitoQ that initially feel slightly tired and this resolves within 4-6 weeks before going the other way and delivering significantly increased energy ... we think it comes down to a repair process. Still with it and keep me posted. 

 

Thanks

 

Greg

[Kalliste]

I feel some weird energy showing up a few hours after taking the 5mg pill. Might all be placebo but it happened too often for me to ignore it. I would not compare that feeling to coffee.