Just a FYI. This does not explain why women get CFS more often than men. Cause the study is done on people that already have CFS, not healthy people. With your assumption that high intracellular levels correlate with low blood levels of trypthophan, both men and women with CFS should have low blood levels of tryptophan with this trap
Community symposium on molecular basis of ME/CFS at Stanford Discussion Thread
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Just a FYI. This does not explain why women get CFS more often than men. Cause the study is done on people that already have CFS, not healthy people. With your assumption that high intracellular levels correlate with low blood levels of trypthophan, both men and women with CFS should have low blood levels of tryptophan with this trap
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Are there any hypotheses being publicly explored that might explain what it is about the triggers of M.E that drives up intracellular tryptophan in the first place? (If that is indeed what is driving up tryptophan)
Does Robert Naviaux's Cell Danger Response make a mention of tryptophan?
Does Robert Naviaux's Cell Danger Response make a mention of tryptophan?
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I'm not sure if I can answer any of your queries.
Basically we have limited information. From Fluge and Mella (Armstrong --) we know there's evidence of a switch to using phenylalanine and tryptophan as energy sources in women with ME/CFS [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/]. In particular plasma levels of these amino acids is significantly lowered.
We know that intracellular levels of phenylalanine are higher in people with ME/CFS
*1) abstract: https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
*2) full paper: https://sci-hub.se/10.1039/C8AN01437J.
We don't know if intracellular levels of tryptophan are higher in people with ME/CFS; however, it appears reasonable, based on phenylalanine, to assume that they are.
Possibly intracellular levels of tryptophan might be high enough to suppress IDO1.
I think if you check out the videos from the Conference then you'll find that Ron Davis/Phair are proposing that the cause of the disease is similar in men/women. Possibly the Davis's HLA/KIR gene work will turn up something to explain gender differences i.e. higher incidence in women (or hormones?).
I've tried to lobby for funding to develop a diagnostic test for ME/CFS i.e. based on the above method* [https://forums.phoenixrising.me/ind...h-theyre-working-for-you.61516/#post-1001161]. Feel free to join in i.e. contact your elected representative to request funding for research into ME/CFS - development of a diagnostic test [https://forums.phoenixrising.me/ind...h-theyre-working-for-you.61516/#post-1001161].
Regarding Naviaux's study ("dauer" state) he appears to be suggesting what Fluge and Mella refer to as a "secondary rescue mechanisms". Also see Chris Armstrong's 2015 (?) paper. Search for things like "tryptophan"; "phenylanine"; "amino acid"; "cellular energy". They're all suggesting the same thing i.e. altered energy metabolism (Krebb Cycle/citric acid cycle?).
In terms of what drives up intracellular levels of these amino acids; this demonstrates that intracellular levels of phenylanine are higher:
1) abstract: https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
2) full paper: https://sci-hub.se/10.1039/C8AN01437J.
No reason to expect that tryptophan will not be higher i.e. follow phenylanane.
In terms of what triggers ME/CFS Phair highlights that substrate [high intracellular tryptophan] suppression of IDO1 may give you the fatigue [cancer drug referred to in presentations] i.e. metabolic trap.
Try your local elected representative for funding https://forums.phoenixrising.me/ind...ch-theyre-working-for-you.61516/#post-1001161
bthompsonjr1993
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Wow, that’s amazing. Every one had a mutation! That is exactly the info I was looking for.
Thanks Ben!
-Brian
What is in the serum that causes the cells to become unhealthy ? Is this connected with the metabolic trap ? Or is it some micro RNA in the serum which is causing the cells to go unhealthy.. So does that mean energy starvation can be due to either metabolic trap or something in the serum (micro RNA). Can any individual have both unhealthy serum and metabolic trap ? Very confusing.
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Both the anti-purinergic drug Suramin, and more recently, the Multiple Sclerosis drug Copaxone, make the cells healthier when tested in the nanoneedle.
Murph
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My guess is that the metabolic trap theory and the 'me/cfs serum makes healthy cells behave like me/cfs cells' observation are not compatible. This is based on the fact Phair was so adamant he was describing something that happens inside the cell. My confidence in this guess is ~ 70%.
Yea kind of disappeared from the discussion this time around. If you check out Ron Davis's presentations on the OMF site then you should find something.
Whatever compound(s) in the blood plasma are causing this; the result is I assume is a switch to burning amino acids as cellular energy e.g. phenylalanine and tryptophan [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/].
Possibly this could be increasing the intracellular levels of phenylalanine; found in this study:
*1) abstract: https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
*2) full paper: https://sci-hub.se/10.1039/C8AN01437J.
On the face of it tryptophan should mirror phenylalanine i.e. intracellular levels of tryptophan should increase. Possibly the intracellular levels of tryptophan could rise to a level where IDO1 is suppressed i.e. you get severe fatigue - metabolic trap.
The above* is a potential diagnostic test; consider lobbying for funding to develop a diagnostic test and for funding for research e.g. to identify the substance(s) which cause the shift to burning amino acids as cellular fuel [https://forums.phoenixrising.me/ind...h-theyre-working-for-you.61516/#post-1001161].
Scary stuff but if we could get funding then we could get answers.
Murph
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Where did you hear about Copaxone? I had not heard that!
Kind of strengthens the case to find the compound(s) in plasma which cause cells to change their cellular energy production. Do they change to anaerobic energy production i.e. still using glucose or using amino acids?
Really complicated when you don't know the cellular respiration process etc.
I think Ron Davis said (not at 2018 symposium) that you can filter out these compounds (based on molecular weight I guess) and that this was a potential treatment.
Jackb23
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Are any of these doctors, if not other doctors in the field, performing post mortem studies of the brain?
No need to. I was just saying that the study does not show why women get CFS more often than men, which was the question. The study shows that women with CFS has less tryptophan in the blood than men with CFS (and with your assumption higher intracellular levels). If the study has shown that healthy women also had more intracellular levels of tryptophan than men, then it would possibly show that women are more suseptible. But since the study is done on men and women that already have CFS, the intracellular levels of tryptophan should be high for both genders with this metabolic trap, and therefore both men and women with CFS should have lower blood levels of trypthophan with your assumption, which is not the case.
My point is that the assumption that low blood levels of an amino acid automatically means high intracellular levels are questionable, since then men with CFS should also have low blood levels. Didn't even Phair say that tryptophan blood levels could be either high or low?
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Only scanned your post so I may come back to it later.
Men (with ME/CFS) may be different from women (with ME/CFS) i.e. because men can use their larger muscle mass as an energy source. Check out Chris Armstrong's 2015(?) paper he found evidence of men breaking down muscle tissue. I think Ron Davis spoke about this i.e. re his son Whitney. Also, check out Fluge and Mella's paper; they propose that men may be using their larger muscle mass as an energy source [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/].
Intracellular levels of tryptophan may be measurable with this method:
*1) abstract: https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
*2) full paper: https://sci-hub.se/10.1039/C8AN01437J.
Mark Davis said the immune system is getting simpler i.e. because we know more (2017 Symposium).
This is a potential diagnostic test*. Maybe the answer is for us to try to get support for the research and the development of a diagnostic test [https://forums.phoenixrising.me/ind...h-theyre-working-for-you.61516/#post-1001161].
dreamydays
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Looks like coffee is a big no-no
https://www.ncbi.nlm.nih.gov/pubmed/25738401
Saint John's Wort big no-no
https://www.ncbi.nlm.nih.gov/pubmed/30033402
Whereas Ketamine which is sometimes touted as a treatment could potentially help?
https://www.ncbi.nlm.nih.gov/pubmed/30213652
https://www.ncbi.nlm.nih.gov/pubmed/25738401
Saint John's Wort big no-no
https://www.ncbi.nlm.nih.gov/pubmed/30033402
Whereas Ketamine which is sometimes touted as a treatment could potentially help?
https://www.ncbi.nlm.nih.gov/pubmed/30213652
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Murph
:)
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I start the day with big doses of both, and perceive they help a lot!!
Hve never had ketamine and if this pattern holds I probably shouldn't...
BeautifulDay
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In this Q&A interview with Dr. Naviaux in 2016, I found his answers here very interesting.
Q3. You talk about the chemical signature being similar to a state of hibernation. What sort of animals exhibit a similar signature in hibernation?
Dr. Naviaux: "I wouldn’t use the term hibernation to describe Chronic Fatigue Syndrome. Humans do not hibernate. But I can see how it would be a way that people might get a general idea of the chemistry that we found. Hibernation is just one of a handful of hypometabolic states that has been studied in different animals. There are many others that go by names like dauer, diapause, torpor, estivation, caloric restriction, etc. Many environmental stresses will trigger hypometabolism in humans. In our experience, the metabolic signature of dauer is more similar to CFS than some of the other hypometabolic states that have been studied. One of the main points of our metabolomics study of CFS was to give other scientists a new tool to analyze all of these hypometabolic states, developmental stages, and syndromes so that the similarities and differences can be objectively studied, and rational new therapies developed."
Q4. Are men and women really that different in CFS?
Dr. Naviaux: "Yes. About 40-50% of all the metabolites that we measure in our method have a different normal concentration in males and females. This is not all related to testosterone and estrogen. Literally hundreds of metabolites are tuned to different concentrations in men and women. At the pathway level, we found that men and women shared 9 (45%) of the 20 biochemical pathways that were disturbed in CFS patients. Eleven pathways (55%) were more prominent in males or females. We find that to do metabolomics properly, you need to have an adequate number of age- and sex-matched controls. If healthy males and females are lumped together as controls, the power to see metabolic differences in CFS and many other diseases is much decreased. Likewise, the metabolism of a 25-year old male is different from a 35-year old male, and categorically different from a 25-year old female. In each decade of life there are many metabolic changes that occur as part of normal development and aging. When proper age- and sex-matched controls are used, metabolomics is one of the most powerful new tools available to physicians and scientists to study chronic complex disease."
https://www.omf.ngo/2016/09/09/upda...-fatigue-syndrome-q-a-with-robert-naviaux-md/
It's interesting to see Dr. Naviaux speak at both mitochondrial disease medical conferences and ME medical conferences. I spoke with Dr. Naviaux about my mitochondrial disease/ME family at a mito conference last year. While the women in our family are more likely to have severe bouts of debilitating fatigue (with major fatigue in between) and POTS and many other symptoms, the men in our family are more likely to be on the autistic spectrum and see themselves as lazy (rather than fatigued). Dr. Naviaux mentioned that he sees differences too. Don't get me wrong, the men in our family can get debilitating fatigue and the women when really low energy have symptoms of autistic spectrum, yet it's definitely a pattern we see here in our house.
I should mention that all of us in the family can slip into the negative thinking that each of ourselves as being lazy when there is something to do, but there is not enough energy to get us up and going. I now try to frame it as pacing and not lazy here in our house. But this is the zone of fatigue men in our family are in more often than the women. The zone of "I could really push and do it, but I don't have the energy to push through the lack of energy." So I don't see our men with mitochondrial disease as lazy, but as not enough energy and pacing themselves. Whereas the women more often get into the zone of I am so exhausted that if I take another step my whole body is going to stop working (at times it's just painful to lay in bed).
Q3. You talk about the chemical signature being similar to a state of hibernation. What sort of animals exhibit a similar signature in hibernation?
Dr. Naviaux: "I wouldn’t use the term hibernation to describe Chronic Fatigue Syndrome. Humans do not hibernate. But I can see how it would be a way that people might get a general idea of the chemistry that we found. Hibernation is just one of a handful of hypometabolic states that has been studied in different animals. There are many others that go by names like dauer, diapause, torpor, estivation, caloric restriction, etc. Many environmental stresses will trigger hypometabolism in humans. In our experience, the metabolic signature of dauer is more similar to CFS than some of the other hypometabolic states that have been studied. One of the main points of our metabolomics study of CFS was to give other scientists a new tool to analyze all of these hypometabolic states, developmental stages, and syndromes so that the similarities and differences can be objectively studied, and rational new therapies developed."
Q4. Are men and women really that different in CFS?
Dr. Naviaux: "Yes. About 40-50% of all the metabolites that we measure in our method have a different normal concentration in males and females. This is not all related to testosterone and estrogen. Literally hundreds of metabolites are tuned to different concentrations in men and women. At the pathway level, we found that men and women shared 9 (45%) of the 20 biochemical pathways that were disturbed in CFS patients. Eleven pathways (55%) were more prominent in males or females. We find that to do metabolomics properly, you need to have an adequate number of age- and sex-matched controls. If healthy males and females are lumped together as controls, the power to see metabolic differences in CFS and many other diseases is much decreased. Likewise, the metabolism of a 25-year old male is different from a 35-year old male, and categorically different from a 25-year old female. In each decade of life there are many metabolic changes that occur as part of normal development and aging. When proper age- and sex-matched controls are used, metabolomics is one of the most powerful new tools available to physicians and scientists to study chronic complex disease."
https://www.omf.ngo/2016/09/09/upda...-fatigue-syndrome-q-a-with-robert-naviaux-md/
It's interesting to see Dr. Naviaux speak at both mitochondrial disease medical conferences and ME medical conferences. I spoke with Dr. Naviaux about my mitochondrial disease/ME family at a mito conference last year. While the women in our family are more likely to have severe bouts of debilitating fatigue (with major fatigue in between) and POTS and many other symptoms, the men in our family are more likely to be on the autistic spectrum and see themselves as lazy (rather than fatigued). Dr. Naviaux mentioned that he sees differences too. Don't get me wrong, the men in our family can get debilitating fatigue and the women when really low energy have symptoms of autistic spectrum, yet it's definitely a pattern we see here in our house.
I should mention that all of us in the family can slip into the negative thinking that each of ourselves as being lazy when there is something to do, but there is not enough energy to get us up and going. I now try to frame it as pacing and not lazy here in our house. But this is the zone of fatigue men in our family are in more often than the women. The zone of "I could really push and do it, but I don't have the energy to push through the lack of energy." So I don't see our men with mitochondrial disease as lazy, but as not enough energy and pacing themselves. Whereas the women more often get into the zone of I am so exhausted that if I take another step my whole body is going to stop working (at times it's just painful to lay in bed).
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