Blog Article: "Is the era of precision medicine for chronic fatigue syndrome at hand?"

[me/cfs 27931]

This is beyond my knowledge level. But perhaps someone with the right background can comment on this article about an idea for testing and treatment for ME/CFS.

Is the era of precision medicine for chronic fatigue syndrome at hand?
https://luysii.wordpress.com/2017/0...edicine-for-chronic-fatigue-syndrome-at-hand/
September 4, 2017

If an idea of mine is correct, it is possible that some patients with chronic fatigue syndrome (CFS) can be treated with specific medications based on the results of a few blood tests. This is precision medicine at its finest. The data to test this idea has already been acquired, and nothing further needs to be done except to analyze it.

Athough the initial impetus for the idea happened only 3 months ago, there have been enough twists and turns that the best way explanation is by a timeline.

Infections of almost any sort are associated with fatigue, most probably caused by components of the inflammatory response. Anyone who’s gone through mononucleosis knows this. The long search for an infectious cause of chronic fatigue syndrome (CFS) has had its ups and downs — particularly downs — see https://luysii.wordpress.com/2011/0...irus-causing-chronic-fatigue-syndrome-in-lab/

At worst many people with these symptoms are written off as crazy; at best, diagnosed as depressed and given antidepressants. The fact that many of those given antidepressants feel better is far from conclusive, since most patients with chronic illnesses are somewhat depressed.

The 1 June 2017 Cell had a long and interesting review of cellular senescence by Norman Sharpless [ vol. 169 pp. 1000 – 1011 ].

One biochemical characteristic of the senescent cell is increased levels of a protein called p16^INK4a, which helps stop cellular proliferation. While p16^INK4a can easily be measured in tissue biopsies, tissue biopsies are inherently invasive. Fortunately, p16^INK4a can also be measured in circulating blood cells.

What caught my eye in the Cell paper was a reference to a paper about cancer [ Cancer Discov. vol. 7 pp. 165 – 176 ’17 ] by N. Demaria, in which the levels of p16^INK4a correlated with the degree of fatigue after chemotherapy. The more p16^INK4a in the blood cells the greater the fatigue.

If the results of the Cancer paper could be replicated, p16^INK4 would be the first objective measure of a patient’s individual sense of fatigue.

So I wrote both authors, suggesting that the p16^INK4a test be run on a collection of chronic fatigue syndrome (CFS) patients. Both authors replied quickly, but thought the problem would be acquiring patients. Demaria said that Sharpless had a lab all set up to do the test.

There matters stood until 22 August when a paper and an editorial about it came out [ Proc. Natl. Acad. Sci. vol. 114 pp. 8914 – 8916, E7150 – E7158 ’17 ]. The paper represented a tremendous amount of data (and work). The blood levels of 51 cytokines (measures of inflammation) and adipokines (hormones released by fat) were measured in both 192 patients with CFS (which can only be defined by symptoms) and 293 healthy controls matched for age and gender.

In this paper, levels of 17 of the 51 cytokines correlated with severity of CFS. This is a striking similarity with the way the p16^INK4 levels correlated with the degree of fatigue after chemotherapy). So I looked up the individual elements of the SASP (which can be found in Annu Rev Pathol. 21010; 5: 99–118.) There are 74 of them. I wondered how many of the 51 cytokines measured in the PNAS paper were in the SASP. This is trickier than it sounds as many cytokines have far more than one name. The bottom line is that 20 SASPs are in the 51 cytokines measured in the paper.

If the fatigue of CFS is due to senescent cells and the SASPs they release, then they should be over-represented in the 17 of the 51 cytokines correlating with symptom severity. Well they are; 9 out of the 17 are SASP. However although suggestive, this increase is not statistically significant (according to my consultants on Math Stack Exchange).

Suppose the idea turns out to be correct and that some patients with CFS are in fact that way because, for whatever reason, they have a lot of senescent cells releasing SASPs.

This would mean that it would be time to start trials of senolyic drugs which destroy senescent cells on the group with elevated SASPs. Fortunately, a few senolytics are currently inc linical use. This would be precision medicine at its finest.

Being able to alleviate the symptoms of CFS would be worthwhile in itself, but SASP levels could also be run on all sorts of conditions associated with fatigue, most notably infection. This might lead to symptomatic treatment at least.

 

[perrier]

This is fascinating. Someone please forward this to Dr Ron Davis. He is sure not to leave any stone unturned.

 

[Cam Newton]

Not to nit pick, but the fatigue I experienced with mono feels like a very different type of fatigue I feel with ME/CFS. And I only had mono two years ago, which ended up triggering the ME/CFS. So I still remember it fairly well.

 

[Snow Leopard]

I don't really understand what the author of the article is saying - what is the specific hypothesis?

Simply saying that a SASP is involved is too vague - there necessarily need to be extracellular feedback loops.

 

[viggster]

Someone brought this blog post to my attention and I decided to pass it along. He ties an idea he has into the Naviaux PNAS paper and I thought the PR community might have feedback for him/her.

https://luysii.wordpress.com/2017/0...ine-for-chronic-fatigue-syndrome-at-hand/amp/

 

[Learner1]

Cell senescence is a very good area to pursue in solving the puzzle of ME/CFS.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214092/#!po=18.8172

The issue is how to kick the cells out of their senescent state.

 

[MEMum]

@JaimeS This sounds fascinating.

The top reference, ie @viggster is about a guy blogging on fatigue states relating to senescent cells, ie those no longer dividing, but not dying either.
He looks at the 74 pro-inflammatory molecules produced by senescent cells. These are known as SASP (Senescence Associated Secretory Phenotypes)

He then compares the SASPs with the levels of 17 of the 51 cytokines correlated with severity of CFS. (PNAS)
"So I looked up the individual elements of the SASP (which can be found in Annu Rev Pathol. 21010; 5: 99–118.) There are 74 of them. I wondered how many of the 51 cytokines measured in the PNAS paper were in the SASP. This is trickier than it sounds as many cytokines have far more than one name. The bottom line is that 20 SASPs are in the 51 cytokines measured in the paper.
If the fatigue of CFS is due to senescent cells and the SASPs they release, then they should be over-represented in the 17 of the 51 cytokines correlating with symptom severity. Well they are; 9 out of the 17 are SASP. However although suggestive, this increase is not statistically significant (according to my consultants on Math Stack Exchange)."

@Janet Dafoe (Rose49) as well, in case Jaime is still recovering from the amazing conference
@Simon @Jonathan Edwards ...

 

[Wonko]

The issue is how to kick the cells out of their senescent state.

Obviously - give them a good talking to and explain the error of their ways - it's the only approved treatment after all.

 

[Jonathan Edwards]

@JaimeS This sounds fascinating.

@Janet Dafoe (Rose49) as well, in case Jaime is still recovering from the amazing conference
@Simon @Jonathan Edwards ...

I don't quite get how cells can be senescent in ME. If it was most cells then bits of you would die and they don't. If it is blood cells most of them die after a few days anyway. And he seems to have found 9 out of 17 cytokines - which is some but you would expect some I think. It doesn't click into place for me yet!

 

[MEMum]

Thanks for that info. I'm way out of my depth, but it seemed worth flagging it up to OMF/people who know more science than I do.

Thanks for mentioning other thread @AndyPR . I would ask a moderator to merge the threads, but don't think it would be a priority at the moment! Have you ever thought of moderating Andy, you seem to have the necessary skills, technical abilities and understanding?
Though I suspect that volunteers for moderating or being on the Board have nosedived significantly after recent events....

 

[MEMum]

I don't really understand what the author of the article is saying - what is the specific hypothesis?

Simply saying that a SASP is involved is too vague - there necessarily need to be extracellular feedback loops.

I interpreted this as follows:
The PNAS study shows that out of 51 cytokines measured, 17 correlate with fatigue/disease severity in ME.
Of these 17 cytokines, 9 are the same as pro-inflammatory molecules that are produced by senescent cells. These are called SASPs (ie Senescence Associated Secretory Phenotypes). There are 74 of these produced by senescent cells,

It appears that his original investigations into looking at SASPs arose from the fact that cancer cells which have been "zapped" by chemotherapy go into a senescent state and cancer patients who have had chemo are generally pretty fatigued.

I may be getting this wrong, or reading too much into it, but the overlap seems worth flagging up to the OMF team and anyone else on here who is likely to have a better grasp of the science than I do.

 

[Hajnalka]

The issue is how to kick the cells out of their senescent state

Obviously - give them a good talking to and explain the error of their ways - it's the only approved treatment after all.

 

[AndyPR]

Thanks for mentioning other thread @AndyPR . I would ask a moderator to merge the threads, but don't think it would be a priority at the moment! Have you ever thought of moderating Andy, you seem to have the necessary skills, technical abilities and understanding?
Though I suspect that volunteers for moderating or being on the Board have nosedived significantly after recent events....

I've reported the two threads, asking for a merge.

Thanks for the vote of confidence but as things stand currently I wouldn't even consider volunteering, sadly.

 

[Alvin2]

I think the senescence-ME/CFS theory is nonsense, though here is some information and a simple treatment that anyone can try, you can get bioactive quercetin (EMIQ) that has high bioavailability but if it cures your ME/CFS i will be shocked. On the other hand Quercetin is a very interesting nutrient that has many other positive effects and even helps mice suffering from radiation induced damage (not in the article but from other research i have done in the past).
http://www.lifeextension.com/Magazine/2015/SS/Sweep-Away-Senile-Cells/Page-01

 

[Tunguska]

Always struck me as a possibility or contributing factor, e.g. closest I spotted:
https://www.nature.com/onc/journal/v24/n11/full/1208262a.html

TGF bold italic beta1 induces prolonged mitochondrial ROS generation through decreased complex IV activity with senescent arrest in Mv1Lu [lung] cells

Transforming growth factor

1 (TGF

1) is a well-characterized cytokine that suppresses epithelial cell growth. We report here that TGF

1 arrested lung epithelial Mv1Lu cells at G1 phase of the cell cycle with acquisition of senescent phenotypes in the presence of 10% serum, whereas it gradually induced apoptosis with lower concentrations of serum. The senescent arrest was accompanied by prolonged generation of reactive oxygen species (ROS) and persistent disruption of mitochondrial membrane potential (

m). We demonstrated that the sustained ROS overproduction was derived from mitochondrial respiratory defect via decreased complex IV activity and was involved in the arrest. Moreover, we verified that hepatocyte growth factor [HGF] released Mv1Lu cells from the arrest by protecting mitochondrial respiration, thereby preventing both the

m disruption and the ROS generation. Our present results suggest the TGF

1-induced senescent arrest as another plausible mechanism to suppress cellular growth in vivo and provide a new biochemical association between the mitochondrial functional defects and the cytokine-induced senescent arrest, emphasizing the importance of maintenance of mitochondrial function in cellular protection from the arrest.
[...]
Taken altogether, our data clearly exhibit that TGF

1 does not induce apoptosis, but senescent arrest in the presence of serum, implying that the senescent arrest induced by TGF

1 might be a new plausible mechanism to suppress cellular growth due to the ubiquitous presence of serum in vivo.
[...]
we further found that HGF could not only reverse the TGF

1-induced apoptosis in the low serum concentration (data not shown), but also the senescent arrest with high serum concentration (Table 1). Furthermore, we demonstrated that the reversal by HGF was accomplished through protection of mitochondrial respiratory function, and that overproduction of mitochondrial ROS was consequently blocked (Figure 8), implicating the potential role of HGF in maintenance of mitochondrial respiratory function for optimal cellular growth.

(and others, https://www.ncbi.nlm.nih.gov/pubmed/20583212 etc.)
and is involved in forms of muscle damage which is the initial clue.

 

[Tunguska]

Hypothetical scenario:
* p53 is a well-known inducer of senescence (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784259/)
* part of TGF-beta/SMAD effects are mediated with p53 (https://www.hindawi.com/journals/jst/2012/294097/)
* SIRT1 abolishes senescent effects of p53 (http://www.jbc.org/content/282/15/10841.full)
* SIRT1 depends on NAD/NADH ratio (in part via circadian Nampt activity)
* ergo, cells with low NAD/NADH ratio in the presence of elevated TGF-beta are more likely to be induced into senescence
* Result: severely reduced cell turnover

But it could be worse because there appear to exist non-p53 (and non-P16) mechanisms through which TGF-beta can induce senescence: https://www.ncbi.nlm.nih.gov/pubmed/21555587 https://www.ncbi.nlm.nih.gov/pubmed/20583212
This is the most annoying part - it does seem like TGF-beta can override other pathways quite a lot. Means that diagnostic attempts with supplements might be futile.

 

[Tunguska]

Also, it looks as if p16 (the one the guy wrote about in OP's links) is similarly regulated by SIRT1 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2249701/) and can be increased by TGF-beta(2) (https://pdfs.semanticscholar.org/ed3d/9c7257f4a717330c3b6623fd195a97c98f1d.pdf). So the hypothetical could apply to both.

However I can't remember if it was TGF-beta1 or TGF-beta2 that mattered most and I can't find the thread.

 

[Tunguska]

Well anyway, here's a picture that two-thirds represents what I'd pictured and visualizes part of what OP's author described (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253488/):

Senescent state itself is not organ death so I viewed it as a (muscle/etc) cell turnover issue on two levels, and immune system is supposed to do bulk of the clearance of the senescent cells.

That said p53/p16/p21 appear impossibly complicated (cell fate decision is ascribed to p21 downstream of p53, with p16 contributing separately) and some of this picture's article's conclusions might circumstantially contradict some of what I conjured up for fun above with p53 deacetylation. That's without even a mention of TGF-beta that activates all this and more, since it's major mediator in wound healing.

Obviously this is not concrete, but personally I'm with the OP author in feeling this is worth measuring or ruling out (first in severe).

I skimmed the 2017 Cell article he referenced (sci-hub) and it's mostly familiar except some perplexing bits about macrophages themselves expressing senescence state, never thought about that...