Robert Naviaux' Lab - News - from 2019 onwards

I find Naviaux's work interesting and worth pursuing, but probably in the DARPA mould of potentially high-impact but low-probability. For example, his work on ASD is innovative, but I note that all papers on purinergic signalling being involved in ASD are from him; no other research group seems to have picked this up to with follow-up studies to test and confirm this theory. This despite the significantly higher funding and researcher interest in ASD compared to ME/CFS.

Sorry for suggesting that the answer to everything is a GWAS study. I didn't even know what a GWAS study was until @Simon M did an article on Chris Pointing's proposed application (now an application?) for funding for a GWAS study in ME!

Anyway, has there been GWAS study in ASD and if so did they turn up anything linked to "purinergic signalling"?
 
@Simon M,

I was in that replication study and since it’s been like three years since I donated my blood, I emailed the Naviaux Lab to see if and when the Study will be published. I got a reply saying basically that they’re still massaging the data, but they plan to publish some day.

I find this disappointing.

Why don't you also ask OMF or the Ron Davis group why there not concerned about it not being published since they put up the million dollars to fund it. Maybe they can give you better insight? Just a thought.
 
IMHO We need multiple labs trying to identify the blood factor which is why I backed the Prusty fundraiser and hope the OMF will do their own nanoneedle investigations.

What we dont need is people assuming what it is going to be.
 
From a recent email exchange with Robert Naviaux...some comments about the cause of MECFS.


......If you have seen our website on ME/CFS, you know that we don’t think of ME/CFS as an energy deficiency disease. We see it as a probably with reallocation of cellular energy away from housekeeping functions we associated with health and toward cellular defense. ME/CFS is a problem with energy “distribution”, not energy “production.
......
We have more data now showing that ATP outside the cell (instead of inside the cell) is an ancient signal for danger that is released by cells under stress. This squares with an old paper by Lawson, et al. that shows the PBMCs from patients with ME/CFS make MORE ATP, not less.

I posted the Lawson et al. paper here.

https://www.s4me.info/threads/eleva...ue-syndrome-patients-lawson-et-al-2016.16760/

Here is a link to the CFS page on his web site.

https://naviauxlab.ucsd.edu/science-item/chronic-fatigue-syndrome-research/
 
@Jonathan Edwards You previously suggested a problem with housekeeping processes too.

This might explain, e.g., unrefreshing sleep. The body isn't clearing away all those signals that have built up through the day, so they remain for the next day, and the day after that, and the day after that...

It might also explain cumulative PEM, in that the symptoms caused by exertion from yesterday get added to today's, and then tomorrow's, and so on.

The prolonged recovery time and need for regular rest might be the body trying to manage those housekeeping functions in drips and drabs over the longer term. Pacing, therefore, would allow space and time to reset those things.

I'm not sure about the mitochondrial stuff yet, without having seen the evidence, but the general theory of ME as a failure of housekeeping seems like it makes sense.
 
@Jonathan Edwards You previously suggested a problem with housekeeping processes too.

This might explain, e.g., unrefreshing sleep. The body isn't clearing away all those signals that have built up through the day, so they remain for the next day, and the day after that, and the day after that...

It might also explain cumulative PEM, in that the symptoms caused by exertion from yesterday get added to today's, and then tomorrow's, and so on.

The prolonged recovery time and need for regular rest might be the body trying to manage those housekeeping functions in drips and drabs over the longer term. Pacing, therefore, would allow space and time to reset those things.

I'm not sure about the mitochondrial stuff yet, without having seen the evidence, but the general theory of ME as a failure of housekeeping seems like it makes sense.

This sort of concept would really describe my experience. Everything from lactic acid buildup, to problems with brain processing (possibly related to glymphatic system?), to the sleep disfunction.
 
The question that comes to my mind is whether this theory could account for the swapping of plasma(?) that patient-to-control inflicted impairment and control-to-patient cleared it, at least when measured by the nano-needle? (I'm very foggy this morning so if I've mixed anything up there let me know).

If I do have the details right, could it be the raised ATP that the nano-needle is sensing? And/or if raised extra-cellular ATP is a 'danger' signal, then it could explain the immediate effect of swapping the medium that, in patients, it is presumably in. And could immunoadsorption/plasmapheresis, as an unintended side effect be removing ATP? I'll freely admit I don't have the scientific knowledge to know if these are stupid questions or not. :)
 
From 2003, but this abstract summarizes some of the ways extracellular ATP works particularly in connection with the nervous system. From the article
Extracellular ATP and Neurodegeneration.

ATP is a potent signaling molecule abundantly present in the CNS. It elicits a wide array of physiological effects and is regarded as the phylogenetically most ancient epigenetic factor playing crucial biological roles in several different tissues. These can range from neurotransmission, smooth muscle contraction, chemosensory signaling, secretion and vasodilatation, to more complex phenomena such as immune responses, pain, male reproduction, fertilization and embryonic development. ATP is released into the extracellular space either exocytotically or from damaged and dying cells. It is often co-released with other neurotransmitters and it can interact with growth factors at both receptor- and / or signal transduction-level.

Once in the extracellular environment, ATP binds to specific receptors termed P2. Based on pharmacological profiles, on selectivity of coupling to second-messenger pathways and on molecular cloning, two main subclasses with multiple subtypes have been distinguished. They are P2X, i.e. fast cation-selective receptor channels (Na+, K+, Ca2+), possessing low affinity for ATP and responsible for fast excitatory neurotransmission, and P2Y, i.e. slow G protein-coupled metabotropic receptors, possessing higher affinity for the ligand. In the nervous system, they are broadly expressed in both neurons and glial cells and can mediate dual effects: short-term such as neurotransmission, and long-term such as trophic actions.

Since massive extracellular release of ATP often occurs after metabolic stress, brain ischemia and trauma, purinergic mechanisms are also correlated to and involved in the etiopathology of many neurodegenerative conditions. Furthermore, extracellular ATP per se is toxic for primary neuronal dissociated and organotypic CNS cultures from cortex, striatum and cerebellum and P2 receptors can mediate and aggravate hypoxic signaling in many CNS neurons. Conversely, several P2 receptor antagonists abolish the cell death fate of primary neuronal cultures exposed to excessive glutamate, serum / potassium deprivation, hypoglycemia and chemical hypoxia.

In parallel with these detrimental effects, also trophic functions have been extensively described for extracellular purines (both for neuronal and non-neuronal cells), but these might either aggravate or ameliorate the normal cellular conditions. In summary, extracellular ATP plays a very complex role not only in the repair, remodeling and survival occurring in the nervous system, but even in cell death and this can occur either after normal developmental conditions, after injury, or acute and chronic diseases.
 
From the Naviaux’s website:
Does a systems analysis of the metabolic abnormalities found in CFS lead us to a better understanding of the root biology underlying the disease? A: Yes. ME/CFS is a chronic physiologic reaction to a perfect storm of severe environmental threats. It is a dauer-like metabolic syndrome that can be caused by at least 50 different triggers. ME/CFS prevents the orderly progression of the normal steps of healing5, and causes life-long pain and disability4. If ME/CFS is truly like dauer6, then the biological clock of aging is slowed during illness7, but in a perverse twist of medical fate, without relief from long-term disabling symptoms.
As a non-scientist patient this makes sense to me as a possible explanation for how I feel. What I am not clear about is how much is conjecture and how much is established scientific fact. Have Naviaux’s findings which suggest that ME/CFS is a “dauer-like metabolic syndrome” been replicated?

Also, I hadn’t picked up on the suggestion that a dauer-like state would slow the biological clock before, but it is consistent with the observation that others have made (see this thread) that people with ME, and particularly severe ME, often seem to look much younger than their real age.

I don’t know if it is relevant but when my metabolic age* was tested by the ME Biobank it was 25 years younger than my actual age (the same age as I was when my illness began). Does anyone know if there is any published data on the relative metabolic ages of people with ME/CFS?

*From https://tanita.eu/help-guides/understanding-your-measurements/:
Metabolic age “is calculated by comparing your basal metabolic rate (BMR) to the BMR average of your chronological age group. If your metabolic age is higher than your actual age, it’s an indication that you need to improve your metabolic rate. Increased exercise will build healthy muscle tissue, which in turn will improve your metabolic age. Stay on track by monitoring regularly.”

If people with ME (or a subgroup) have a much lower metabolic age than their actual age this would surely tell us something useful as it is the opposite of what one would expect from those who are inactive for other reasons.

If there is subgroup of people with ME with a relatively low metabolic age and a subgroup with a high metabolic age, it would clearly be necessary to look at the distribution of the data rather than simply calculating the mean relative difference between metabolic and actual age in patients v controls.
 
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"If ME/CFS is truly like dauer6, then the biological clock of aging is slowed during illness7, but in a perverse twist of medical fate, without relief from long-term disabling symptoms."

This sounds like nonsense to me

Should do more research before all these crazy theories
 
raised extracelullar atp and mtdna are a definite in me/cfs. I have a limited understanding, that little what I have is telling me that is really bad news.
 
Interesting.
We did the ATP profile test by Acumen.
I know that it has not been replicated.

However.
It was spooky for its correlation with severity.
It also looked at translocator function ( atp out and atp in)

My daughter was chucking ATP out in bucket loads
 
If ME/CFS is truly like dauer6, then the biological clock of aging is slowed during illness
Also, I hadn’t picked up on the suggestion that a dauer-like state would slow the biological clock before, but it is consistent with the observation that others have made (see this thread) that people with ME, and particularly severe ME, often seem to look much younger than their real age.

I don’t know if it is relevant but when my metabolic age* was tested by the ME Biobank it was 25 years younger than my actual age (the same age as I was when my illness began). Does anyone know if there is any published data on the relative metabolic ages of people with ME/CFS?

I'm not sure that is all hanging together. 'The biological clock of ageing is slowed' - One researcher found telomeres were abnormally shortened in people with ME - I'm not sure I believe that either, but it would be a sign of the opposite - biological aging advanced.

https://pubmed.ncbi.nlm.nih.gov/8361073/
The basal metabolic rate decreases almost linearly with age. Skeletal musculature is a fundamental organ that consumes the largest part of energy in the normal human body. The total volume of skeletal muscle can be estimated by 24-hours creatinine excretion. The volume of skeletal musculature decreases and the percentage of fat tissue increases with age. It is shown that the decrease in muscle mass relative to total body may be wholly responsible for the age-related decreases in basal metabolic rate.
If this paper is correct, the decrease in BMR (in healthy people) with age has a lot to do with muscle mass. How was your metabolic age measured @Robert73? Perhaps it wasn't really a measure of what your metabolism is doing, which would be interesting, but actually just a measure of muscle mass? (Which is still interesting, as in, 'how could you retain so much muscle mass with a sedentary lifestyle?', but it's a different question.)
 
How was your metabolic age measured @Robert73? Perhaps it wasn't really a measure of what your metabolism is doing, which would be interesting, but actually just a measure of muscle mass?
The ME Biobank use a Tanita machine for calculating BMR (see: https://tanita.eu/help-guides/understanding-your-measurements/basal-metabolic-rate/). I've no idea how accurate or useful it is. I'm guessing that if low metabolic age had been a common observation in people with ME, and was deemed to be significant, the Biobank would have published something about it by now, but I will ask.

I've managed to find a copy of my results. My ages was incorrectly entered as 34 instead of 43 but that doesn't change the calculation and everything else is correct.

tanita.jpg
 
The ME Biobank use a Tanita machine for calculating BMR (see: https://tanita.eu/help-guides/understanding-your-measurements/basal-metabolic-rate/). I've no idea how accurate or useful it is. I'm guessing that if low metabolic age had been a common observation in people with ME, and was deemed to be significant, the Biobank would have published something about it by now, but I will ask.

I've managed to find a copy of my results. My ages was incorrectly entered as 34 instead of 43 but that doesn't change the calculation and everything else is correct.

View attachment 11984
Tanita scales is somewhat known to be unreliable, at least their lower-end models.
They measure your body composition by using "bioimpedance", a small electric current is sent through the body, and the resistance it meets is then used to calculate how much fat, muscle (and organs, this is "fat free mass", I'm not sure if the model here subtracts some standard weight of your organs to give you the weight of your muscle) and bone you have as these different body tissue have different ability to transport electric currents.

The algorhitm used to turn the resistance measurements into fat/protein/bone can change the results of the test, on many weights you can chose between being "active"/"muscular" or "standard", this changes the algorhitm and can give very different results. They may not be applicaple to pwME. Water retention could increase your protein% (muscle is recognized as having lower resistance than fat due to its high er water content) and is an easy way to get a better result than what you actually have.

Calculating "biological age" based on these measurements is mostly just for fun. Especially if you don't fit into the algorhitm the weight uses to calculate its results.

Besides that, I think its interesting. Though I'd be more worried about increased biological aging (the shortened telomeres @Hutan mentioned, increased oxidative stress, reduced "clean-up" of other stuff..) re people looking younger than their age - I've always done that. Not exposing your skin to all kinds of weather all the time could reduce signs of aging on the face, many pwME are less outdoors for obvious reasons. I'd say low activity could reduce certain byproducts of daily living that would also accumulate and be part of the process we call aging, but then there's the disease process that might change this. Which I guess is what we're discussing :p
 
Almost all of it is conjecture. We are well-justified in being skeptical.
That is what I thought but I’ve not managed to follow the research as closely as I would like and I wondered if I had missed something.

It is very frustrating and concerning to me when scientists present conjecture (and in some cases falsehoods) as facts. I don’t know if this happens more in ME research than other areas of medical research but it is deeply unhelpful.

Besides that, I think its interesting. Though I'd be more worried about increased biological aging
Yes, although, from a research point of view, it would be a mistake to discount a counterintuitive result because it isn’t worrying in itself. The question is whether it can tell us anything useful about the condition.


If research confirmed the observation that a significant number of people with ME (and particularly severe ME) look much younger than their age, it would be interesting to know why. Images of people who have been confined indoors for other reasons (eg Julian Assange, Terry Waite) make me question whether being indoors, inactive and under a lot of stress would be likely to make someone look younger. Similarly, my observations of people who have been unwell for a long time with other types of illness is that having a severely debilitating chronic illness is more likely to make someone look older, not younger.

I’m not suggesting that the observation is necessarily correct or that it couldn’t be explained by something secondary but, as with so much about ME, I would be interested to know more.
 
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