A Different Approach

Younger’s been taking a very different approach to chronic fatigue syndrome and fibromyalgia than most researchers and he spoke about it in Pandora’s first webinar of the year.

younger me/cfs researchers

Younger and some other ME/CFS and FM researchers are taking a very different approach to these illnesses.

We know that people with ME/CFS and FM regularly leave their doctors appointments with disappointingly normal results. But what if normal results actually spell trouble? What if the results are normal but the patient is not? What if the body is configured so that “normal” levels of a factor are, in fact, a real problem?

This idea has become something of a theme in ME/CFS research and it fits in with fibromyalgia findings as well. Miller’s basal ganglia work in ME/CFS suggests that dopamine depletion in the basal ganglia in the brain may be allowing small amounts of inflammation to cause “sickness behavior”. Gordon Broderick’s models suggest that the strange immune networks found in ME/CFS may be causing small concentrations of some immune factors to have immense results. Younger believes a constant state of activation is causing the microglia in ME/CFS and FM to respond to low levels of inflammatory factors.

The central sensitization found in fibromyalgia practically calls out for a situation like this. The difference with Younger’s research is that he thinks he’s found a substance in the blood that can help explain the central sensitization. If he’s right then he’s made a major breakthrough.

The Study

How to tease out normal test results that are not causing problems from normal tests results that are causing fatigue, pain, etc.?  The answer is to disregard absolute levels of a factor and see if you can  correlate fatigue levels with the levels of inflammatory factors. Younger had his participants measure their fatigue levels and take blood samples for 25 days and then he ran an analysis to determine which of  fifty or more inflammatory factors correlated with fatigue.


He found large fluctuations in day to day fatigue. Energy levels would spike up one day and then crash for a couple of days. Then another relatively good day would come along followed by a crash. Fatigue was always present – but the fluctuations were large.

fatigue levels chronic fatigue syndrome

Fatigue levels that changed from day to day brought up the question: if fatigue can be reduced one day – why not the next?

He found some real hope in these fluctuations. If a person is physiologically strong enough to have a relatively good day then their body should be physiologically capable, after all, of having more of them. If you can figure out what is happening when everything is going right – and then duplicate that state – you should be able to maintain it.

(One wonders what’s going on a very different timescale with the relapsing/remitting group of patients – the patients who get a lot better, sometimes for years, and then suddenly and often dramatically relapse. What switch got turned on or off in them? )

Twenty-five days of blood draws sounds like murder. One can envision needle marks up and down one’s arm but Younger only needs a couple of drops each time and he uses really small needles which leave no marks.

Leptin – A Unlikely Candidate Shows Up

leptin surprised finding

Nobody thought leptin would show up – but it did – and in spades

Younger first tried his twenty-five day fatigue  measurement and blood stick trial on three women with fibromyalgia. Of the fifty or so inflammatory markers one popped out in all three women: leptin – a hormone associated with appetite regulation which on the face of it would seem to have little to do with fatigue or pain. Leptin levels are three times higher in women than men, however, and leptin promotes an inflammatory response: two factors that could explain why it’s having an impact in these disorders.

Leptin promotes the activity of the main immune agents in the brain – the microglia. Once activated the microglia change dramatically: they pull in their arms, assume a rounded shape and start pumping out inflammatory cytokines that produce the similar symptoms (fatigue, pain, sleep problems, cognitive problems, etc.)  to those found in ME/CFS and FM. Younger believes the microglia in ME/CFS and FM are activated all the time.

Primed For Action

“It’s like you keep getting the flu without having an infection”


The microglia: from monitors to inflammation producers

Animal research is showing that besides being in a resting or an activated state the microglia can also exist in a “primed” or hypersensitive state – ready to flood, at the slightest hint of danger, the body with fatigue and pain-causing chemicals. They can be put into this hair-trigger state in a number of ways: aging, immune insults, pathogens, taking opioids over long periods and chronic stress all appear able to put the microglia into a hypersensitive state

The microglia can get so tweaked that they can begin to react negatively to endorphins, the body’s own feel-good chemicals, that get pumped out during exercise.

The Hypothesis

Leptin sensitizes the microglia. Hitting the microglia with leptin and then exposing them to a potential danger causes to them to start spewing out inflammatory cytokines like there’s no tomorrow. Younger’s hypothesis is that leptin in ME/CFS and FM is tweaking the microglia in the brain putting them in a flu-like fatigued, painful and cognitively challenged state all the time.

Next Step

First there were three – then there were ten. Younger’s next good-day, bad-day trial had 10 women with ME/CFS and more immune factors. Interestingly he excluded women with positive ANA’s (sign of autoimmune disease) and ESR and C-reactive protein (CRP) – two signs of inflammation.

In six out of the ten leptin levels strongly predicted how bad or good they felt every day.

The Great Graphic

An entirely different type of analysis (thankfully :)) showed leptin popping out again. This analysis found that only leptin was directly associated with fatigue.

leptin - key inflammatory agent

A very different analysis also found that all roads led to….leptin

Dr. Klimas has done and is doing a different kind of good-day/bad-day study, but leptin didn’t pop out. I asked Gordon Broderick why? They simply hadn’t testing for it before  – and why would they? Nobody suspected that leptin – a hormone usually associated with appetite and obesity – would play a role in ME/CFS.  Leptin doesn’t even make much sense within an immune context – the immune factors it affects aren’t believed to play a role in fatigue. The only thing that makes sense with leptin within the context of ME/CFS is the microglia and leptins association with the microglia is just beginning to be understood.

Tight Fit Leaves Younger Confident

Younger’s “leptin” studies have included all of 13 people with chronic fatigue syndrome or fibromyalgia but the results were so unusually “tight” that he “very confidently” said – right now – that leptin plays a major role in producing fatigue in ME/CFS.

Younger’s “leptin” studies have included all of 13 people with chronic fatigue syndrome or fibromyalgia but the results were so unusually “tight” that he “very confidently” said – right now – that leptin plays a major role in producing fatigue in ME/CFS.

leptin hits bullseye in chronic fatigue syndrome

Leptin has hit the bulls eye enough that Younger is confident it plays a significant role

His hypothesis is that leptin is sensitizing the microglia to trick the brain into thinking an infection is present in ME/CFS. Encouragingly he doesn’t think any damage is being done to the brain – it’s just being tricked into producing these inflammatory products. This process is not producing sore throats or runny noses – that’s an entirely different process; Younger is referring to brain produced symptoms such as fatigue, pain, cognitive, sleep and other issues.

[Why it’s doing this in ME/CFS and FM patients is question Younger did not go into.  Leptin was not correlated with fatigue in the healthy controls; i.e. it’s not causing fatigue in them.  It may be that an infection or stress or whatever has put the microglia in ME/CFS and FM patients in such a sensitized state that leptin is sending them over the edge. Or it may be that leptin is interacting differently in ME/CFS and FM patients than it is in healthy controls. One wonders how leptin fits into Broderick’s immune networks….]


Turning Off Leptin

Younger cautioned that he’s not recommending any potential leptin antagonists. If leptin does turn out to be it in ME/CFS and FM there are a number of ways to block it. The problem is that wiping out leptin could have major implications on our ability to fight cancers and block infections. Besides – you’d feel like you were starving all the time.

There are some ways, though, you may be able to safely reduce your leptin levels – at home.

Reducing Leptin Levels

  • Fasting – for a few days reduces leptin levels dramatically (not recommended for ME/CFS/FM).
  • Meditation/Mindfulness Practices – Since stress increases leptin levels anything that reduces stress should reduce leptin levels
  • Losing weight – since leptin is produced by fat cells reducing the number of fat cells in your body should reduce your leptin levels
  • Low glycemic diet

Calming Down the Microglial Cells

calming microglia chronic fatigue

Calming down the microglia is a better option. Meditation type practices may help

A better approach would be to calm down the microglial cells so that they’re not over-reacting to the leptin in the first place. A long list of potential microglial inhibitors are available and a really intriguing one was just added to the list; the antiviral ganciclovir (valganciclovir or valcyte) was just found to knock down microglial activity.

Younger has a grant to study nine botanicals in Gulf War Syndrome.

Younger’s ME/CFS and FM Studies

New Immune Monitoring Study

The NIH is funding a much bigger 25 day immune monitoring study that will start in a couple of months. You should be within in an hour of Birmingham, Alabama to participate in this study..

Leptin Study

People will be given an injection of leptin to see if it causes more fatigue. Since leptin leaves your system quickly, if it does increase fatigue it will only increase it temporarily. This study probably begins in one month. This is an ME/CFS study, but if you have fibromyalgia and haven’t been assessed for ME/CFS you may be eligible.

PET Scan Study

To assess neuroinflammation in ME/CFS. The study will probably be done at Vanderbilt University in Tennessee.

Low Dose Naltrexone for ME/CFS

This study will probably start later this year.

Neuroinflammation, Pain and Fatigue Lab

The lab at the University of Alabama at Birmingham is growing rapidly with twelve people now working in it. Sign up for updates here.

Support the Research

Donate to Younger’s leptin ME/CFS research in a tax deductible manner by funneling it through Pandora, a non-profit organization here. A hundred percent of your donation goes to Younger’s research.

  • Dr. Klimas is next up on Pandora’s webinar program.

More on Dr. Younger’s ME/CFS and FM Work

The Jarred Younger Pandora Webinar

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