351 replies to this topic

[gregmacpherson]

Hi Kevnzworld

 

A good question. We saw the paper this week spoke directly with the study author who assured us he was not concerned at all.  

 

His comment ... 

 

Firstly, MitoQ was protective at low levels and damage occurred at significantly higher dose levels than taken orally and secondly, MitoQ crosses the blood brain barrier at low levels further reducing exposure to the stem cell population studied.   

 

Thanks. 

[mitomutant]

 

Hi Kevnzworld

 

A good question. We saw the paper this week spoke directly with the study author who assured us he was not concerned at all.  

 

His comment ... 

 

Firstly, MitoQ was protective at low levels and damage occurred at significantly higher dose levels than taken orally and secondly, MitoQ crosses the blood brain barrier at low levels further reducing exposure to the stem cell population studied.   

 

Thanks. 

 

 

Hi Greg,

 

I am currently taking 10mg of MitoQ to treat a primary mitochondrial dysfunction. What dosage would be required to achievethe detrimental effects concentration (100nM) ? or the other way around, What concentration am I getting with a 10mg daily dosage ? Haven't found much info about MitoQ pharmacokinetics

 

Thanks

[Mind]

The takeaway from this recent Cell paper for me is that mitochondrial targeted anti-oxidants "work", but have potential side-effects. This would be typical for almost any single-purpose supplement. Always good to asses the positives and the negatives.

 

If the negatives outweigh the positives, it would not be too surprising. Many large epidemiological studies have shown negative long term outcomes with supplements. Mouse studies too.

 

A couple of things I am fond of pointing out: This recent research was "in mice" (rarely translates into anything actionable for humans). And, the majority of medical and supplement research (well over 50%) is false, fraudulent, biased, shoddy, or cannot be reproduced.

 

I am taking MitoQ right now (thanks Greg), and I am not too worried. Will continue to monitor future research in this area to see if anything adds validity (pro or con).

[Davin8r]

Regarding the dismissive attitude of the author (quoted above), this seems to be contradicted to an extent by the paper itself (direct quote follows):

 

"MitoQ comprises ubiquinone......covalently linked to lipophilic TPP cation, which enables MitoQ to cross membranes efficiently and to accumulate several-hundred-fold within mitochondria in response to the organelle’s membrane potential (Murphy and Smith, 2007). Different tissues have been reported to accumulate MitoQ with different efficiencies (RodriguezCuenca et al., 2010), making dose control for a specific cell type, or its mitochondria, difficult."

 

So yes, the human dose may be low and the ability of mitoQ to cross the BBB may be limited, but it seems like a daily supplement taken over months/years could still have considerable potential toxicity to neural stem cells.

[Kalliste]

Can you elaborate the "dismissiveness" part David? My english is not capable of picking out every subtlety

 

With MitoQ, unlike C60, there are human studies that have gone on for a long time, according to Greg they have been using large dosages (large when considering the cost for every 5mg pill, please give us 50mg MitoQ pills ) with 80mg/day for adults. So with this new information they should be able to run some additional tests and see if these poor humans have no new neural cells because of inhibition of neural human stem cell activity or whatever.

 

My bet is this is not gonna be an issue in vivo for whatever reason, it's not like we are running out of sources of endogenous ROS. But maybe that is just wishful thinking.

Edited by Cosmicalstorm, 14 June 2015 - 06:19 AM.

[Davin8r]

By dismissive, I meant a few posts earlier where someone contacted the author of the paper and he seemed to downplay any danger (if I understood that post correctly).

Yes, I understand MitoQ has been around a while and tested at higher doses (also failed to help delay or improve Parkinson's, right?). I just wouldn't be taking chances with something as crucial as my own neural stem cells, at least until we know more. Killing off a number of them may not show effects for years, but could really come back to haunt you.

Edited by David Sprouse, 14 June 2015 - 04:27 PM.

[aribadabar]

Can you elaborate the "dismissiveness" part David? My english is not capable of picking out every subtlety

 

With MitoQ, unlike C60, there are human studies that have gone on for a long time, according to Greg they have been using large dosages (large when considering the cost for every 5mg pill, please give us 50mg MitoQ pills ) with 80mg/day for adults. So with this new information they should be able to run some additional tests and see if these poor humans have no new neural cells because of inhibition of neural human stem cell activity or whatever.

 

My bet is this is not gonna be an issue in vivo for whatever reason, it's not like we are running out of sources of endogenous ROS. But maybe that is just wishful thinking.

 

My read on the reply from the study author is : yes, MitoQ causes issues with neural stem cells BUT at dosages that are probably not reachable in vivo at normal 10mg intake.

 

To err on the side of caution and to save a bit given a fading effect after following regular 10mg dosage for several months, personally I am lowering my dose to one 5mg pill per day.

 

Why do you need a 50mg pill in the light of these study results?

Edited by aribadabar, 15 June 2015 - 04:22 PM.

[Kalliste]

I was getting a bit carried away while writing that. In the light of this study I will definetly cut back a bit on both MitoQ and C60 for the time being.

[niner]

By dismissive, I meant a few posts earlier where someone contacted the author of the paper and he seemed to downplay any danger (if I understood that post correctly).

Yes, I understand MitoQ has been around a while and tested at higher doses (also failed to help delay or improve Parkinson's, right?). I just wouldn't be taking chances with something as crucial as my own neural stem cells, at least until we know more. Killing off a number of them may not show effects for years, but could really come back to haunt you.

 

I agree.  They found that in vitro, a 50nM concentration of MitoQ was sufficient to cause apoptosis in NSCs.   10mg of MitoQ will make 300 liters of 50nM solution.  I'd like to see the pharmacokinetic data for MitoQ that makes the author think it's really no problem at all, given the doses some people are using.  It's my feeling that mitochondrial antioxidants are amazing drugs that are able to do a tremendous amount of good, but like all drugs, only if you take the right dose.  Do we know what the right dose is?  Even with an expensive long term clinical trial, you wouldn't see an effect that takes decades to show up.  I think the only solution is to do more in vitro work, followed by animal experiments with a variety of antioxidants, with subsequent analysis of the NSC population.

[motorcitykid]

I discontinued using C60 and switched to MitoQ -this was about 8 months ago. I thought MitoQ was the "safer choice" based on its long term safety profile. I've been taking the recommended dose of 2 capsules(5mg of mitoquinol). Until further information surfaces on exactly what the safe dosage might be(assuming there is a safe dosage at all)I'm discontinuing MitoQ.I hope I haven't caused any irreversible damage to my NSC population.

 

[Kalliste]

Same here. I was going to order more but I will discontinue MitoQ until more is known. I will continue with C60 but I am cutting that down to one dose every month or perhaps one dose every 15 days or something like that.

 

On the bright side it looks like stem cell rejuvenation will be one of the first therapies that becomes widely available

[gregmacpherson]

Hi All, 
 
I wanted to follow up on my earlier comment regarding the recent paper and MitoQ’s effect on Neural Stem Cells (NSC) given the recent posts noting concern. 

 

The paper indicates that there is a bell shaped dose response curve to MitoQ to murine iPSC in vitro, with protection at 10 nM and toxicity at 50- 100 nM. 
 
The dose given in this study corresponds to a murine dose of ~ 25- 30 mg/kg/day. 
 
The recommended dose of MitoQ is 10-20 mg/day for humans. For a 70 kg human gives a  dose ~ 0.15-0.3 mg/kg/day. 
 
Using the FDA-recommneded adjustment (x 0.08)  to  convert from a mouse to a human dose, gives 2 mg/kg/day, therefore the oral dosing in the mouse  that causes negative effects is ~ many fold higher than the equivalent dose in humans and well beyond the dose of 10-20mg a day recommended in humans.  Ie the dose at which potentially could cause negative effects (assuming full distribution across the BBB) is going to be upwards of 120mg per day.  

More importantly, these effects in mice in vivo were in embryos and only affected pluripotent stem cells. The uptake into the adult brain is far less for MitoQ than in to other tissues and the importance of adult neuronal stem cells, which are not pluripotent,  in the adult brain is not clear. 

 

Therefore it seems unlikely that oral MitoQ reaches the levels in the adult brain that are of concern for NSC populations and in fact is more likely to be at the level that is supportive of NSC populations and deliver benefit.  

Another key takeaway from this research is that, until we know more, it is prudent for pregnant women and children to avoid taking mitochondrial targeted antioxidants. 

 

Thanks 

 

Greg

[Kalliste]

Nice to hear that Greg. It also goes in line with other mitochondrial antioxidant experiments. I can't find the paper right now but I seem to recall a paper were they found that the animals in the highest dose group died too early, likely due to interference in the ROS signaling. But the other animals did fine and even better than average, I will post it here if I can find it.

[Kalliste]

Found it

 

 

The radical scavenger IAC had a dramatic effect on the lifespan of adult zooids, largely extending the mean lifespan from 68 to 182 days (168% increase, p < .01; maximum life-span 207 days; Table 1A). A dose-response analysis revealed that annelids cultured with an external concentration of 1.25 µM IAC displayed the longest prolongation of mean lifespan. Concentrations both below and slightly above this optimum concentration showed shorter extensions, whereas 10-time higher concentrations caused toxicity and drastically reduced lifespan, compared to controls. Similar results were achieved in a second independent experiment (Table 1B). The Kaplan–Meier survival curves, averaged between both experiments, are shown in Figure 1A. To the best of our knowledge, this is the longest lifespan extension recorded in a living organism exposed to a synthetic compound.

http://biomedgeronto...ona.glu160.full

 

[niner]

The dose given in this study corresponds to a murine dose of ~ 25- 30 mg/kg/day. 

 

Greg, do you know how they arrived at this equivalent dose?  Are there published pharmacokinetics results for MitoQ?  (ideally in humans)

[gregmacpherson]

Hi Niner, 

 

This is the best consolidated source of information on MitoQ that I can give you.  It has some reference to human PK.

 

https://www.mitoq.co...-with-MitoQ.pdf

 

In terms of the NSC study and equivalent dose - the investigators are very experienced in researching MitoQ in murine models so you can have assurety of accuracy. 

 

Thanks

 

Greg

[niner]

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.

[airplanepeanuts]

Is Idebenone also a mitochondrial antioxidant that could possibly have this problem?

 

[PerfectSeek]

• I get a somewhat uncomfortable mental stimulation effect from mitoQ without noticeable effects on physical endurance
• I have only taken 2 doses of MitoQ, both 5mg.  
• I have CFS/Me, and c60oo was drastically superior compared to MitoQ in terms of immediate benefit.  c60oo was immediately positive for physical/mental endurance and mood, where as MitoQ gives me the side effect above.  
• I have had bad reactions to higher doses of Coq10 / Ubinquinol in the past

I'm not sure I'll continue with mitoQ or not.  It would be very interesting to see lifespan studies in mice/rats with MitoQ.  

 

On another note, could someone help me understand why we assume c60oo will have the same toxicity to NSCs at high enough concentrations?  Or are we extrapolating from a common MOA with mitoQ.

 

[Kalliste]

Speculation of course, but both are capable of quenching endogenous ROS in some hidden sub-cellular compartments.

 

 

Cell Stem Cell. 2011 Jan 7;8(1):59-71. doi: 10.1016/j.stem.2010.11.028.

Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner.

Le Belle JE¹, Orozco NM, Paucar AA, Saxe JP, Mottahedeh J, Pyle AD, Wu H, Kornblum HI.

Author information

Abstract

The majority of research on reactive oxygen species (ROS) has focused on their cellular toxicities. Stem cells generally have been thought to maintain low levels of ROS as a protection against these processes. However, recent studies suggest that ROS can also play roles as second messengers, activating normal cellular processes. Here, we investigated ROS function in primary brain-derived neural progenitors. Somewhat surprisingly, we found that proliferative, self-renewing multipotent neural progenitors with the phenotypic characteristics of neural stem cells (NSC) maintained a high ROS status and were highly responsive to ROS stimulation. ROS-mediated enhancements in self-renewal and neurogenesis were dependent on PI3K/Akt signaling. Pharmacological or genetic manipulations that diminished cellular ROS levels also interfered with normal NSC and/or multipotent progenitor function both in vitro and in vivo. This study has identified a redox-mediated regulatory mechanism of NSC function that may have significant implications for brain injury, disease, and repair.

 

Edited by Cosmicalstorm, 21 June 2015 - 12:56 PM.

[niner]

• I get a somewhat uncomfortable mental stimulation effect from mitoQ without noticeable effects on physical endurance
• I have only taken 2 doses of MitoQ, both 5mg.  
• I have CFS/Me, and c60oo was drastically superior compared to MitoQ in terms of immediate benefit.  c60oo was immediately positive for physical/mental endurance and mood, where as MitoQ gives me the side effect above.  
• I have had bad reactions to higher doses of Coq10 / Ubinquinol in the past

I'm not sure I'll continue with mitoQ or not.  It would be very interesting to see lifespan studies in mice/rats with MitoQ.  
 
On another note, could someone help me understand why we assume c60oo will have the same toxicity to NSCs at high enough concentrations?  Or are we extrapolating from a common MOA with mitoQ.

PerfectSeek, how long have you been taking c60oo?  Has it continued to work for you?  There was another person here who reacted poorly to both coQ10 and MitoQ, but he also reacted poorly to c60oo. 

 

The reason for concern about c60oo and NSCs is that we think they have similar MoA.  We think they are both mitochondrial antioxidants.

[PerfectSeek]

I've taken c60oo for about a year.  It's continued to work, although the near miraculous effects have tapered off.  I see increased endurance and capacity to exercise.  It remains the best drug/supplements I've ever tried, using about 4-8mg / week.  Higher doses were not more effective, and I could probably even lower the dose. 

 

The mitoQ feeling is very similar to what I had experienced taking 300mg of coq10, an "out of it" yet stimulated feeling which is not at all comfortable.  My reactions to most supplements are consistent with the general population, so coq10/mitoQ remains an outlier in that respect. 

 

Thanks CosmicalStorm for the abstract, I didn't realize that NSCs were reliant on ROS. 

 

 

[Kalliste]

I suspect it is a matter of dose and perhaps most consumers of C60 and MitoQ are well below that threshold. Hopefully. Nightmare scenario is that we find out that these antioxidants over the time span of years or decades, far longer than the length of life of our brave rodent friends who first tried these compounds, has some bad effect on our beloved little neurons.

Perhaps you would need to dose 10mg/kg of c60 to do this. I suspect there will be some such dose response relationship, the redox regulation cannot be too sensitive to disturbance or smokers of cigarettes would die of acute brain disease after a week or something like that.

 

 Who knows

[BigLabRat]

I just started MitoQ. So far, so good--a mild uplift in energy and mood. I'm not too nervous about the NSC effects for a simple reason: There has been a great deal more research with this compound than with many which are consumed quite casually.

 

Of course, I'm late to the party on all of this. But it's curious to me that C60 seems--from my newbie perspective-- to have been embraced quite enthusiastically despite all the unknowns, while some people seem to be in a slight state of panic over MitoQ based on a single study that really isn't comparable to in vivo conditions. (I do agree with Niner that megadosing any of these compounds is probably not a smart move.)

 

At the risk of going off-topic, I am still trying to get my head around the C60 experience on this forum. I have read through some of the threads, but I'm unable to gather whether there is an emerging consensus on C60 or not. 

[PerfectSeek]

Niner and others mentioned that toxicity to NSCs wouldn't present for many years, so despite MitoQ having been studied in humans it's a valid concern for those planning to take it indefinitely.  c60oo could have the same problem. 

 

The lifespan studies are extremely impressive for c60oo, which is why the forum has embraced it so much.  I think many people would be interested in similar studies for MitoQ, this would solidify mitochondrial ROS scavenging as a mechanism for life extension. 

[Kalliste]

The takeaway from other studies into effective antioxidants is that they seem to have a mode of action that follows a bell curve. For IAC which seems similar to C60 they were able to dose 20-30mg/kg and get good results. I think they went up to 300mg/kg before hitting lifespan-decreasing effects.

[BigLabRat]

The lifespan studies are extremely impressive for c60oo, which is why the forum has embraced it so much.

 

Could you steer me to mammalian studies other than Baati? I've had trouble locating much real science literature on c60oo and benefits for mammals, so I guess I'm looking in the wrong places!
 

[PerfectSeek]

Sorry, that probably should read "lifespan study is".  The longecity sponsored study also showed interesting results in a model of leukemia.  At risk of derailing the thread, see the link here:

 

http://www.longecity...ored-aml-study/

 

 

 

The lifespan studies are extremely impressive for c60oo, which is why the forum has embraced it so much.

 

Could you steer me to mammalian studies other than Baati? I've had trouble locating much real science literature on c60oo and benefits for mammals, so I guess I'm looking in the wrong places!
 

 

 

[BigLabRat]

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.

Attached Files

•  Melatonin, MitoQ, and MitoE.pdf   285.66KB   8 downloads

[mitomutant]

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.

 

3 years ago I was looking at high doses of melatonin to treat my mitochondrial disease. I spoke to a couple of researchers and they both agree that it was a good idea to give it a try. I started at 10mg daily and ended at 50mg daily; maybe 2-3 months in total.

 

I can only measure the effectiveness of a given supp by how it affects to my daily energy levels and in this case, it made nothing for me.

 

Anyway, I keep an eye on melatonin research and from what I read, I see melotinin as a pleitropic hormone, so it's good to make sure you are not deficient. The best reason to be consistent with your sleep patterns.

 

In the mitochondrial context, melatonin is definitively a potent antiox [1]

 

[1] http://www.ncbi.nlm....pubmed/14740000