Dr Younger has published studies on CFS, Fibromyalgia and pain. He has some unique insights on CFS and chronic inflammation. His study was the one that showed leptin was like a trigger of fatigue in CFS.
- Leptin and Chronic Fatigue Syndrome
- Neuroinflammation and Autoimmunity
- Blood Tests for Pain and Fatigue
- Gut Inflammation
- Blood Pressure
- Visual Contrast Sensitivity Testing
- Leptin, Microglia, and Fatigue
- CFS, Immune Responses, Infections, and Toxins
- Lyme Disease
- Biofilms and Localized Infections
- Alzheimer’s and Fungal Infections
- Therapeutic Application of Leptin Research
- CFS Triggers
- Fungal Infection Treatments and Herxheimer Reactions
- Areas of the Brain Targeted by Dysregulated Inflammation and Immune Responses
- Low Blood Pressure and CFS
- CFS and Inflammatory Markers
- Low Dose Naltrexone
- Closing and Where to Learn More
- Where You Can Find Dr. Jarred Younger
- Health Tools I Wish I Had When I Was Sick
I am very excited to interview Dr. Jarred Younger. He received his PhD in Experimental Psychophysiology at the University of Tennessee-Knoxville. He completed his post-doctoral fellowship at Arizona State University and the Stanford University of Medicine, before taking an assistant professor position at Stanford.
In 2014, he joined the faculty at the University of Alabama-Birmingham. His goal is to end the chronic pain and fatigue caused by the inflammation in the brain. He is currently funded by the NIH, the Department of Defense, and several nonprofit agencies to develop techniques for diagnosing and treating neuroinflammation, pain, and fatigue.
Q: How did you get into this?
JY: It started in graduate school and it actually started with pain and the origins of it are pretty unusual. I was in a graduate program that was really big on hypnosis and I trained under Michael Nash at the University of Tennessee Knoxville. What I saw was hypnosis is extremely effective at blocking pain, in some people, and maybe 25% of the population respond really really well. It’s unbelievable what they can tolerate.
(Me): Above the placebo?
JY: Oh yeah yeah. And it’s not related to placebo at all. You can’t predict it based on placebo response. It’s more about how well they can imagine and how well they can dissociate different parts of their experience because hypnosis is primarily about disassociation. So, it works really well – not a placebo effect. It works averagely well on me, so it was really impressive, but as I went into graduate programs and post-docs and started looking at fibromyalgia, and diseases like that, I realized that the psychological approaches could help people cope, but it wasn’t fixing the source of the pain. And so I switched over to neurological and hormonal, immunological, so I could try to fix the problem, because that’s better, I think, than just trying to teach people how to cope. Gradually, I switched over from Psychology, but I wanted to fix Fibromyalgia, and then I got really interested in that group because they were so desperate for treatments and that led to Chronic Fatigue Syndrome, because most of the people with Fibromyalgia also meet the case definition criteria for CFS. So, I think if we can fix one, we’ll fix the other probably, so those are my two main disorders now.
(Me): Okay, that’s cool.
Leptin and Chronic Fatigue Syndrome
JY: Yeah. What we did originally, we didn’t know, but we suspected it was an immune, inflammatory-driven problem, just from looking at other literature. So we did daily blood draws for 25 days, which no one ever does.
So, as far as I know, we’re the first to ever try this and people thought that we were crazy. You have to use really good nurses and really really tiny needles to pull this off. If you’re good, you can actually get people to come in every day and their arms look pretty okay at the end of 25 days-believe it or not. So we took these blood draws and we looked at 50 different inflammatory markers; and in both chronic fatigue syndrome and in pain, which I haven’t published. In fact, that was just accepted. Probably, that’s going to come out, probably in the next week. So now we see in chronic pain, fibromyalgia as well, the same thing: leptin is the best predictor of good days and bad days. So, if the leptin in your blood is high, you’re going to have a severe fatigue day or a severe pain day. If it’s low, that’s a relatively good day. And that’s probably the case for at least three-fourths of the people in this study. So, the majority show that leptin and pain or fatigue relationship. We weren’t looking for it in particular at first, but it came out in both studies and now it’s something we’re going to start focusing on because it doesn’t look like a coincidence. Something’s going on.
(Me): That’s really interesting.
Question: So, what do you think is the mechanism over there where leptin increases and the fatigue scores increase?
JY: Now, it’s hard to know for sure in humans because we can’t do the types of things you can do in animal models, but based on the basic science, the most parsimonious explanation is: leptin is a known microglia sensitizer. So, if you have microglia cells – these are immune cells in our brain that can easily cause fatigue or pain – if you pretreat those with leptin, and then you introduce those microglia to a trigger, they will activate much more robustly than they would without the leptin.
So, higher levels of leptin lower the triggering threshold of microglia. Leptin itself isn’t enough to activate the microglia. It just sets them up to be more profoundly activated once they are and it lowers their threshold so they may start to react to stuff they ordinarily wouldn’t react to. So, that’s what we think is happening-is that the leptin levels are fluctuating. When they’re high, the microglia sensitivity rises and then they react to something else and that exacerbates the symptoms.
(Me): Uh-huh, ok.
Question: So what causes the leptin to rise? What are big things that cause leptin to rise?
JY: Yeah-there’s a lot of things. There’s a circadian rhythm to it. Eating is huge, you know, you’re going to have a rise of leptin when you eat because the primary purpose of leptin is to suppress your appetite, is to control your weight. Now, people develop leptin insensitivity, where it stops working and they don’t get full, so they get larger. And as you get bigger and you gain more fat, your leptin levels go up. So, obese individuals have much more circulating leptin than non-obese individuals. Now, also, women have three times the leptin levels of men, even when you control for body weight, and body mass, and fat-even when you control for fat. So that’s interesting because, I think women are diagnosed with things like fibromyalgia/chronic fatigue syndrome more than men and that may be one explanation-is that their leptin levels are higher and that starts at puberty. So, eating, obesity, being female, stress-eating (that combination of stress and eating) is a very potent driver of leptin. Also, leptin goes up when you have an infection. So, if you get the flu, your appetite goes down and leptin is actually part of the sickness response because the body is trying to reduce the resources that are going into digestion so they can fight off the infection. So there are a lot of triggers to leptin.
(Me): That’s super interesting, because the people that I see-I see a lot of people with CFS and these kinds of issues-the issues get worse after meals. It gets worse in the circadian manner also, which fits in. And also, a lot of times, these issues are preceded by a stressful period. And so, stress, eating…and the other thing is carbohydrates make the fatigue worse for various reasons (one is that increases leptin more than fat or protein). I originally had hypothesized that carbohydrates-one mechanism was that carbohydrates, like glucose, you know they break down into glucose, and glucose suppresses the wakeful neurotransmitter orexin. And I figured, you know, orexin is also suppressed by inflammation so these people are having inflammation, in combination with a carbohydrate meal-suppresses orexin, they get tired. But carbohydrates also increase leptin more.
JY: Yes. Perfectly plausible too. In fact, we have at least two separate mechanisms by which having a high carb meal, especially simple carbs (through leptin but two different end points) both causing and ending in fatigue, so yeah definitely.
Neuroinflammation and Autoimmunity
(Me): Yeah, and the interesting thing is that leptin also suppresses orexin. So that combination, that soup, of leptin, glucose, stress, and inflammation-it suppresses orexin. Now, where are these microglia being activated in the brain most? So, people with CFS, I noticed, if you look at their symptoms, and you look at what different parts of the brain does, I noticed the hypothalamus-there were problems there. For example, people are having sleep problems, right? The SCN-the suprachiasmatic nucleus-is in the hypothalamus. Low blood pressure-I mean that’s the hypothalamus and brain stem. And they also did a study that people with CFS had more inflammation in the brain stem and oxidative stress.
Question: So, where’s the microglia, in your research, being activated?
JY: Okay, it’s very very difficult to look at microglia and living humans and that’s-we’re actually trying to battle those technical problems right now. Really, the only option we have right now is positron emission tomography (PET). Where we use a radio ligand or a radio tracer that’s attached to a ligand that can go at receptors that microglia tend to express once they’re activated, but it’s not highly specific or sensitive, so it’s not a perfect marker, so we only have a general idea of what’s going on in living humans. We don’t just want to take what we get from the rat research and rodent research and just assume that’s the case in humans. It may differ. The microglia are very well distributed throughout the brain. I mean they are the primary barrier against infection, and so they have to be everywhere. It’s not like they’re particularly collected anywhere, but the hypothalamus is a prime target of the signals that the microglia are sending out. And that’s because, the microglia-that’s the central immune response. Those microglia need to coordinate their fight with the peripheral, so you want the peripheral and the central systems to work together and that signal back to the body is happening through the hypothalamus. It gets to the brain via the vagus nerve, probably, and there’s a few other channels as well, but you need a quick way of going back and forth. So, multiple chemicals produced by microglia are going to have targets on the hypothalamus and that helps coordinate the sickness response. A lot of that fatigue is going to be via effects on the hypothalamus-some though the amygdala but mostly through the hypothalamus.
(Me): Do you think there’s something going on, like, what I’m trying to figure out is if there’s an autoimmune reaction in the hypothalamus or different regions in the brain, or if it’s just-and leptin is a trigger-so there’s some kind of…you know the autoimmunity works in response to the immune system. If you have an autoimmune condition and you dampen inflammation, you manage it and it’s okay-and so, leptin can trigger that autoimmune response. Or, it’s just a general inflammatory response that’s targeting specific areas of the brain or body and that’s what’s happening.
JY: So, I’m not aware of an autoimmune condition that specifically targets the hypothalamus. Now, it may be-it may exist-I’m not aware of it. However, autoimmunity really anywhere in the body, or inflammation, even if it’s not autoimmune, anywhere in the body. Both of those-just kind of systemically-could still lead to the same effects of microglia having this impact on the hypothalamus, causing the symptoms, so it doesn’t have to be-the disregulation or the pathology doesn’t have to sit at the hypothalamus because it’s designed to really detect the problem no matter where it is. It could happen but I don’t know of a particular condition where that’s the problem.
(Me): Right, yeah, I haven’t either heard of an autoimmune condition that specifically targets the hypothalamus.
Q: The question is, is it the case and we’ll find it out-is it possible and we’ll find it out in ten years? I mean, how advanced do you think we are that we would say no, we would have detected that by now? Or, you know what, there’s so much we haven’t detected that ten years down the line we could see antibodies to the hypothalamus or something?
JY: Okay, yeah, good question. We do not yet have, even as researchers, even outside conventional medicine, even the experimental stuff, we do not yet have the ability to (with high resolution) look at inflammation in a living human being. Like I said, the PET stuff, right now, that is very nonspecific and it also has very poor spatial resolution. So, we can’t say “Oh yeah, look-there’s something going on right here at the hypothalamus.” Now, we’re working towards that, and many groups are, and we might talk about thermometry later, but that’s one way we may get at it-brain temperature. What we need are more specific-we need tracers that we can inject in someone that can go specifically to a site of inflammation in the brain. Now that’s hard. It has to get through the blood brain barrier, it has to get right at the target, and it has to emit some kind of signal that we can pick up. That is really tricky engineering stuff. We’re trying right now-one way we’re getting at that-is we’re trying to find a way to take someone’s T-cells and B-cells out of their body. We then incubate them with a marker that we can then inject, and if someone has severe brain inflammation, those peripheral cells get pulled across the blood brain barrier. They’re normally not supposed to be in the brain but we think they’re getting pulled across and that’s causing a lot of problems. So then we’ll put someone in the MRI and we can see if those peripheral cells are appearing in the brain. If we’re able to show that, that’ll be huge. I mean then that will start to turn into a diagnostic marker.
Blood Tests for Pain and Fatigue
Me: That’s super interesting. This brings to mind-somebody with CFS, or any number of conditions, that are chronic-fibromyalgia-they go to the doctor, the doctor does the standard set of blood tests and they say “Nothing is wrong with you. I think you need to go to a psychiatrist”. You know? And they’re doing that with just general markers. Basically, the doctor looks at them and they see “Well, you’re not going to die tomorrow. I think you’re healthy. Go home.” What do you think of that?
JY: Right, so here’s the tricky part. We do this for pain-let’s just say fatigue for right now. So people think of fatigue and they think of it as a disease or they think of it as a symptom and it’s really neither one of those things. A fatigue is an incredibly general alarm system for our body. And I mean it is really general. I mean, basically, if you’re fatigued, the only thing you know is that something, somewhere is dysregulated. It gives you no information about where or what system. And the truth is that basically every system dysregulation can eventually lead to fatigue-circulatory problems, it can be neurological, it can be endocrine, it can be immune, you can have an infection, you can have anemia. There are hundreds of things that can lead to fatigue. The physicians, to test all of those, would probably have to spend three hundred thousand dollars to test for everything that could be causing it and they can’t do that so they test for five things, ten things. They do the best they can. They test for the big things that can easily explain fatigue. So, some people, they’re like, “Oh, yeah your T3 and your T4 are low. You’ve got a thyroid problem.” And that will fix some people. So they try to catch those big things, but-
JY: So right. So I think eventually- and I think that has a lot to do with cost. I think, in the medical system now, they’re taught not to overtest. That’s actually a force that’s put on clinics is don’t-because it can be seen by insurance companies as a way to drive up costs and charges. So, they don’t like to see you do a hundred different tests, but the truth is, if you want to know what’s going on, you have to do a lot of different tests. And there are programs-I don’t do many call outs- but I think at the Open Medicine Institute, from what I’ve heard from patients, is a group that would test for a lot of stuff, trying to find where that problem is. So, for the future, as the tests get cheaper, I like that model of testing everything, because, you know, the problem is somewhere. If you do the right tests, you’ll probably find it.
Question: Right. So what tests would you do? If your friend came to you and said, “I’m just fatigued all day”. What are the top tests? I know, like you said, and I agree, if you really want to find it, you gotta look for a lot of things, but what tests will give the most bang for their buck in trying to find the cause of fatigue?
JY: Ok. One we talked about-we’d definitely check every element of the thyroid system, so T3, T4, TSH-that’s probably going to do it. Major antibodies for thyroid processes-so looking for like Hashimoto’s, so some major antibodies-ANA (antinuclear antibody), C-reactive protein-those are very general but those are going to tell you something inflammatory and/or autoimmune is happening. So, we’d get those general inflammatory markers; erythrocytes sedimentation rate as well. We’d definitely do complete blood count, so you’re looking for signs of infection. Also, that would give you anemia, and some things like that, if it’s an iron deficiency. You’ve gotta check your sleep. I mean some people out there-they think they have chronic fatigue-they have disrupted sleep and they don’t know it. And that doesn’t necessarily mean you’re snoring too, so they may not be catching. That can explain a lot. Those are the big ones. I guess there’s kind of a secondary list, but you have to at least get those looked at.
(Me): One hundred percent. Yeah. I actually agree with all of those and I think that that’s a really good list. What about like somebody who wants to- they check that stuff and it comes back pretty normal-and the truth is most people with CFS will have normal hs-CRP. And the thyroid, in my experience, the thyroid levels will normally come back low, like the T3-but that’s just from general inflammation and oxidative stress-can lower the T3 levels. So, again, that’s not either very specific. So even if you test that, and a lot of these people take thyroid hormones-maybe they’ll get 5% better, but they don’t really significantly improve.
Question: So then, would you check for like interleukin-6 or different cytokines? Would you check for leptin? What else would you check for?
JY: So, um, it’s a little tricky. A lot of the analytes we’re looking at-the fluctuations, clearly for that individual, are driving symptoms, or at least are tightly correlated with their symptoms. But, their overall levels do not necessarily have to be elevated over someone who doesn’t have the condition. So, a single blood test may not do it, because I think a lot of the dysregulation may not be the chemical itself. It may be the target. And so, you know, you can have a lot of a neurotransmitter, but if you don’t have the receptors for it, that neurotransmitter’s not gonna work, and we don’t have good tests for the receptors. So right now, we may not have a lot of good tests for hitting what the problem is. So if everything comes back normal-basically, at that point, you’re moving to nonconventional extended testing, which would be the extended list of inflammatory things. IL-6 can catch some stuff. Of course, you know, you’d want to do a rheumatoid factor. So a lot of people may get sent to a rheumatologist and they get some extended tests there. But yeah IL-6 can be helpful. That might tell you something. Tumor necrosis factor alpha-if it came back super high, that may tell you something. But, that’s kind of getting to the edge of what we know and now you’re getting into kind of experimental research tests; because there’s not norms for a lot of these inflammatory things.
(Me): Right, right. So, I’ve had some people who came back with super high interleukin-6. Right? So now, interleukin-6 is not supposed to be detectable in the blood in healthy people. I’ve seen study where it said if it’s over two picograms per ml, your risks for heart disease, or some conditions, go up dramatically. Your risk of dying in ten years goes up, you know? And that’s a really low level-two picograms. If it’s tested over two picograms two times in a five year period, your risk of dying in like a ten year period is a lot higher. But then I see some people with an interleukin-6, you know, of like a thousand.
Question: What does that tell you- if someone has a very high interleukin-6? Does that-I mean obviously something’s going on-but does that tell you that someone has an infection? I mean, the question is, how do you take that information and then you try to figure out an underlying cause?
JY: Yeah. And I think the really progressive clinicians will probably do a better job at doing that because they have a lot more flexibility. In our research, we have to stay very strict with our protocol, so we don’t get to play around with kind of branching things. But, in general, I can say if somebody came up with that high of a level of IL-6, that tells us something serious is going on. We’d have to run some more tests, so we’d run more interleukins, tumor necrosis factor; have to run all the IGs and look for some antibody stuff. I would start to look at gut inflammation.
Question: How do you test that? How would someone test that?
JY: I don’t test that, but there are groups, like Nancy Klimas, I think, at Nova Institute, has a series of tests where they can look at the leakage of inflammatory markers from the gut, and I don’t know what tests they do. I should know that, but they have a process to do that. There are also-simpler than that-there are groups that can test for imbalances of gut bacteria. There are a few that tend to be more inflammatory and they can tell you if-so you basically do some swabs like in your mouth and other places and they’ll tell you if there’s a dysregulation there. So it could be something where probiotics or something may fix it. So, once you get past the major stuff, there’s so many different directions you could go, that it’s really hard to advise, in general. But, IL-6, yeah, if I had that, I would start to test a lot of different things, and try to figure out-what is the source of this inflammation? And you have to test it again because it is kind of an acute thing as well. You wanna make sure you didn’t have a transient infection. So I’d retest in-probably wait a month or so-give everything a chance to calm down. And if it comes back high again, yeah, I’m going start trying to investigate that.
(Me): That’s really interesting.
Question: What about the vagus nerve, right? There’s a researcher who thinks that CFS is caused by an infection or inflammation in the vagus nerve. What do you think of that hypothesis?
JY: Yeah, um, so the vagus has a direct line from the periphery to the hypothalamus and amygdala and other aspects of the sickness response. So, we know, if you uh, if you cut the vagus in an animal, and you give them an infection, you cut off the sickness response. So, and that includes profound fatigue, that’s the core of the sickness response-so absolutely that’s a possibility. That allows peripheral infection to make you feel supremely fatigued. So if there’s an infection, systemically or in the vagus itself-I mean the vagus nerve in the periphery branch has receptors for all-for IL-6 and TNF-alpha and interleukin 1 beta, I think. So it could be systemic, or it could be in the vagus itself. If that were the case, that would be a major problem, because then it’s sending those-“hey, there’s an infection”-almost in an amplified way. So absolutely, theoretically, that’s a plausible idea. We have not confirmed that in humans. It’s hard to test, but it’s definitely plausible.
Question: So that would mean-if you take out the vagus nerve, the sickness response is cut off. So that means that if they are having the inflammation it’s stimulating the vagus nerve? Which would make sense, because people with these conditions have lower blood pressure and lower heart rate, a lot of times. Sometimes they have higher heart rate.
JY: Yeah, that gets complicated. I mean, you know, so you’re right. And if someone has low blood pressure, especially if they have really low blood pressure, you have to make sure that that’s not the driver of the fatigue, because if you’re not getting adequate circulation to the CNS, and adequate oxygen, you’re gonna feel fatigued. You should also probably feel dizzy and maybe have some balance things, and then maybe something would happen with your vision. So, it would probably be more than just fatigue, but that’s the primary one. So, you have to check blood pressure. Now, if that gets below, like a hundred over sixty or lower, especially much lower than that, that could be what’s causing the problem. And then increasing your liquids and there’s approaches to handling that. You have to drive up blood pressure. So yeah it starts to branch into a lot cause-effect relationships. It gets complicated.
(Me): How would you drive up blood pressure? Through salt or what?
JY: Yeah, I’m trying to think…this is a known condition and it’s not something I look at but there are saline solutions that they can take. I think you can drink them and a certain balance of electrolytes so it holds on to it, instead of just being eliminated very rapidly. So try to increase the volume of your liquids-that’s going to push up blood pressure. And then, yeah, I think sodium and some other electrolytes will hold onto that more. I’m sure there’s other solutions, um, I don’t know of a pharmaceutical, though there may be one. I’d have to look into that.
Visual Contrast Sensitivity Testing
(Me): Right. Have you ever heard of the test called Visual Contrast Sensitivity?
JY: I don’t know it.
(Me): Okay, so it’s a test that tries to measure your ability to discern shades of color. And it’s supposedly a test that-you know, it’s testing like if you’re affected by toxins and that’s affecting, let’s say blood flow to your brain and your optic nerves or whatnot-and so, your contrast sensitivity goes down. So I was curious of what you thought about that kind of marker.
JY: It’s an interesting thing. I mean, when your blood pressure to your brain goes down, you do lose color discriminatory abilities. In fact, things tend to get washed out, and in extreme cases, everything goes gray. So I’m not familiar with the test but I mean it certainly makes sense. If you get a blood draw and you have a vasovagal reaction, which means all your vessels dilate and your blood pressure drops, what people usually report is that their field of view narrows. It’s like a circle coming in and the color fades from everything and things turn black and white or gray. So, certainly-not that extreme-but the inability to discern between colors could indicate a lower level of the problem.
(Me): That’s really interesting. Now, back to leptin. In your study you mentioned that people-when the leptin raised, they got more tired-but you also mentioned that the leptin levels weren’t even different from healthy controls. But within the people with CFS, when it raised, people got more tired.
Leptin, Microglia, and Fatigue
Question: Question is, then, what is happening in the brain that causes one group of people to get tired and one group of people not to. And, even more, there’s obese people that obviously have very high leptin levels and they’re not tired. So, what is happening in the hypothalamus, likely, that’s causing one group of people to get tired and one group of people not to get tired.
JY: Yeah, that’s a good question. So the first thing I would say is since I came up with that publication, I have had a couple of groups come to me and say, “we are detecting higher leptin levels in CFS and maybe fibromyalgia. I think one of those is Jose Montoya, who I worked more closely with but I didn’t know he was doing that. I think after I released that, he was like-“No. Here. We’ve got elevated leptin levels”. And another group-I’m forgetting the name of the PI-of the Principal Investigator-but I’ve heard that twice now. Maybe there is a group difference, but you’re right-we didn’t find that.
I think this goes back to something I mentioned very briefly earlier. It’s not just the levels of something. It’s how many receptors are there, what’s happening at the receptor level, what’s happening down stream. And I think with leptin, in particular, it’s gotta be leptin plus something else to have an effect. And so, the dysregulation may not be the leptin. Maybe the leptin is acting just like it should-it’s fluctuating like a normal person-but because the microglia in chronic fatigue syndrome are dysregulated…For example, let’s say you have a bacterial infection, but low level. So, not high enough to ordinarily activate microglia. We’re all walking around-everyone, whether they have symptoms or not-have some bacteria that they shouldn’t, but it’s not making them feel sick. Now let’s say you’ve got that, your microglia are detecting that, but it doesn’t see it as an emergency. Let’s see-how do I want to say this…Let’s say you have some moderate level of bacteria and then the leptin lowers the triggering threshold of the microglia. So, the microglia only hit that triggering threshold at the times that you have the high leptin-in certain individuals. So that’s one model. It’s so hard to prove that, but that’s one way that it could work. It’s an interaction-it’s gotta be leptin plus lipopolysaccharide from bacteria or leptin plus something else. So it’s probably that something else that’s dysregulated and leptin is just exposing the problem.
CFS, Immune Responses, Infections, and Toxins
Question: So, do you think somebody with CFS is having more of an immune system problem or more of, let’s say, a trigger problem-infection, toxin, or whatever is causing it. Again, because somebody can have an infection and not mount an immune response. What’s better actually? Someone’s mounting an immune response and trying to get rid of it-I mean I guess it’s situation dependent. But what is the bigger problem here?
JY: I think, ultimately, when we figure out all of ME/CFS, we’re going to be calling them different things and we’re going to putting them in different directions. There’s gonna be a subset-a large subset-that have latent, low to moderate level infections-viral or bacterial. And the key there is going to be eradicate that virus, eradicate that bacteria, eradicate that trigger. That’s going to be a big group. There’s going to be another big group that had and infection-maybe they had Lyme Disease or something like that-and that bacteria or that virus is gone but it damaged the immune system response. It basically hyper-sensitized that response. And we know from the basic science models that’s possible. If you slam the immune system with a series of infections or a major infection, you can permanently prime the microglia so they become hypersensitive. So I think another group-their immune system has been sensitized and now there no longer is a bacteria or a virus to fight off. In that case, we want to decrease the dysregulated inflammation. And that won’t hurt them because there’s no virus or bacteria to fight off. So, it’s going to be both. I don’t know the ratios of one to the other. I think both of those groups will be large. Completely different treatment approaches.
(Me): That’s a really intelligent answer.
Question: Now, let’s say, with the subject of viral infections, you have some clinicians who will test for a bunch of viral infections and normally what they find is high IgG, which means a past infection-they got the infection in the past-with a low IgM-it’s not a current infection. If it has low IgM, could that be that the virus is still causing problems in the body? The virus-it could be that the virus is still triggering the immune system and from that point on, their immune system got primed in a different way. Or, it could be that the virus is reactivating in certain tissues and we’re not able to detect it with the IgG or the IgM test. What do you think?
JY: So, I’m not an immunologist-and to go down all the paths with the different Ig’s and kinda what the differences of those would indicate. So, the problem with the tests is that everyone has had one of these major infections. They’ve had Epstein Barr, flu stuff, you know, so I think the specificity of those tests is pretty low. Like you’re saying, what information does that provide? It’s pretty low. That doesn’t tell you what’s going on. I mean if something happened in the past, that doesn’t mean it’s driving the thing, I don’t know how helpful that is. It would be more helpful if somebody came back with a clear viral titer that was positive and so I kind of like the idea of testing for the bacteria and viruses themselves. That gives you more interesting information. So if you come back and you have a high level of current EBV-hey, you’ve got something you need to treat. If you take the test for borrelia, for Lyme’s Disease and it comes back that you have it in your system, that’s more clear stuff. So I encourage people to get that tested if they’re going to go in that direction. After that, I don’t know how to distinguish, you know, with the antibodies. It may or may not be driving the symptoms, so I think what’s interesting, in those cases, is to track in longitudinally, if you can. I’m a really big fan of longitudinal testing. I think one shot-you don’t know if that’s noise, you don’t know if that’s transient-and then try to track your symptoms; and look at periods when you have bad periods and then good periods. Maybe six months later you’re feeling a little better or worse and seeing if that’s predicting or that’s moving with that and then it may give you some information about whether it’s actually related at all to the problem.
(Me): Yeah, that’s a really good idea. The only problem with that is, I guess, the expense. But that’s a problem in general for people that are having these chronic issues that are not clear cut. You have the people who will just live with-that’s it, they’ve just come to terms with it. And there’s the people who wanna do whatever they can-they’ll take whatever test they can but that’s really expensive. It is very difficult.
Question: There’s a lot of people who think they have chronic Lyme and the CDC says there’s no such thing as chronic Lyme, yet the conventional medical establishment does realize that in 10-20% of the people who get Lyme Disease, have residual symptoms even though they get rid of the bacteria. So what do you think is going on there? Do you think the immune system was primed?-and now it’s just not shutting down.
JY: That’s exactly what I would suspect. I agree that maybe the name “chronic Lyme”-maybe they don’t like that name because it suggests that the bacteria itself is dormant (now become resident in the body) and that probably is not the case. It may be possible. Usually, that wouldn’t be the case. So yeah-we kinda need better terms for post-I think there are old terms for this-for kinda post-viral (or bacterial) immune sensitivity or something like that. The thing is that our body reacts very similarly, in terms of the central nervous system, to a huge number of viri and to a huge number of bacteria, and other things as well, can release lipopolysaccharide- so not just viruses or bacteria. So I can’t think of any particular reason to focus just on the bacterias that cause Lyme Disease. I think we need to think broader-let’s not demonize that one thing. It could be the influenza virus you had three years ago, it could be the Epstein Barr Virus you had a long time ago, it could be something we don’t even really think of. So, I do think, and we certainly know from the rodent models, that it’s possible for-like I said, these “immune hits”, especially if they’re severe or repeated too close together, or possibly if you get immunizations. I don’t want to get into the immunizations debate, but experimental immunizations may stress the immune system as well and could do that too. I think it’s definitely possible-some people are walking around, they had a major infection, and now they’re chronically experiencing the symptoms, like they have the flu, because the immune system is sensitized. Yeah, absolutely.
(Me): Yeah. I agree with that one hundred percent.
Biofilms and Localized Infections
Question: What do you think of the idea of people having latent infections that could possibly be covered by biofilm? Do you think that infections could be local in a certain place? And it won’t drive the normal infection response, whereas you’ll have fever or something like that. It’s more low-grade. So you won’t really have fever, but you’ll be getting chronic, low-grade inflammation.
JY: Yeah. It’s an intriguing hypothesis. It sounds possible-definitely nothing that I’m looking at-and there’s other groups that are really looking at the ‘is there a virus or bacteria currently present?’. So I’m glad that there are people currently looking at that, but if it’s not systemic-whew. Just to prove that…because I mean you’d have to find…you’d have to extract material from the place where that problem is. If that’s in the CNS, there’s no way. I mean there’s just you can’t. You can’t justify it. It’s too dangerous. So no one’s going to do that, I mean, unless you have epilepsy and you’re having surgery anyway. That’s just a “no-go”. I’m trying to find a way to tap into-so now we know as of late last year that the brain fluid is being extracted and is draining through the lymph system. It merges with the peripheral lymph system. We have these cervical lymph nodes that contain the brain fluid. And, it may be that important markers, and maybe the viri and bacteria themselves, are being extracted via that. So if we can get to it, then we might be able to pull, assay it. That’s tricky, you know, you don’t want to go around poking lymph nodes, unless you have to, but it may be a better marker than a lumbar puncture. So, we’re trying to find alternative ways, but it’s an intriguing hypothesis…so hard to test in humans because of the invasive nature-poking around and trying to pull stuff-but there are groups working on it, so I hope they come up with something interesting.
(Me): Yeah, and the other problem with that is that even if you find an infection, you don’t know whether that it is the one causing the problem.
JY: Yeah. The approach now is that they’re trying to give potent antivirals and other drugs systemically, thinking wherever it’s hiding, unless its got some kind of robust protection, which could be the case-but the idea is that you just slam the whole system, it gets everywhere, and hopefully you eradicate that invader.
(Me): Yeah, and it could also be fungal or parasitic.
Alzheimer’s and Fungal Infections
Question: In a group of Alzheimer’s patients-in “Nature” they just published-that all of the group of ten that they had, and they had a different group, all of them had fungal infections in the brain. And they were only able to figure that out because they died and they were able to do an autopsy. But how do you figure these things out in someone? You know you can’t do brain surgery or anything like that.
JY: There’s no reason to look at their brain. Fortunately, people virtually never die of anything like fibromyalgia and ME/CFS, so that’s one good thing to say about the disorders. But yes, that means it’s very hard. We can’t really do post-mortem stuff because when you get access to those brains, those people died for other reasons and that can confound-you know, it makes the analysis really tricky. Very tough. Those of us that research this area, we realize that we gotta test things indirectly, we gotta try to build a case with a bunch of indirect stuff. Hopefully, there’ll be a technical break through where we can directly assess these things. We’re trying it, but yeah, it’s tough.
Therapeutic Application of Leptin Research
Question: So, how can the information that you’ve obtained about leptin-how can that be used for therapeutic purposes? I know you’re using it-probably the main purpose-is to try to see-‘Okay. Once we know leptin is elevated, let’s try to figure out the next step’. That’s probably something you guys are looking into, but is there anything that people can do with the information on leptin?
JY: A little bit. It’s nothing that’s going to be a breakthrough. I mean there are behavioral ways you can try to modulate and suppress your leptin swings, which I think would probably be the key. So, there’s some things you could try, but I don’t know if it’s going to make a huge difference. For example, the amount you eat. You talked about the carb balance, so if you do things that have a high glycemic index-so things that are rapidly digested-that’s going to cause these leptin spikes. You’re probably going to want to avoid those leptin spikes and so taking things that metabolize or are broken down more slowly, much less sugar, not taking any inflammatory things at the same time you’re eating, so again low sugar; like hopefully under 20 grams per day, which is really hard in the United States, but that’s probably what you want to go for. I think low omega-6’s, there’s some bad oils-I’m not too familiar with that-so a good balance of oils and taking any anti-inflammatories at the same time; not stress eating-like not eating the junk food because you’ve had a hard day because those things compound each other. Reducing the body fat will lower the leptin levels. That could help, but that’s tough to do. That diet and exercise part may be particularly tricky and maybe impossible for a lot of people, so we’ve lost that kind of typical recommendation. So there are some things, and there are probably more than that, but those are the ones that we know for sure from the research that you can try if you wanna try to reduce the leptin levels.
(Me): Now, I’ve seen an association where people-and this is something that I’ve had to deal with-chronic fatigue, but not anymore-one of the big changes for me was actually changing my diet to take out plant lectins. And lectins are going to be found more concentrated in grains, legumes, things like that. And somebody did a study that showed lectins can cause problems with the leptin receptor.
JY: I did not know that.
(Me): Yeah, that was actually in 2005, someone did a study. But those problems with the leptin receptor were associated with obesity. And then, I actually figured out that lectins were a very significant cause of my issues by doing experiments with diet and looking at ‘what were the common variables here’. And then I found a study that somebody did with 800 people, where the people avoided lectins-these people had autoimmune conditions-and their TNF went down. According to this physician researcher, all of the patients that he studied, that went on this diet, their autoimmune conditions went away. Now, you know, I have my experience, he’s got his experience, I mean obviously this has to be replicated, and obviously it doesn’t work for everybody. Let’s say, again, there could be many many different causes. If someone has a chronic infection, it’s not going to make a difference if they stay away from lectins, you know, so that’s where it gets complex.
Question: Have you seen anything, with regard to lectins and CFS?
JY: No. I wasn’t familiar with that line of research. I would say more globally though, and I’m sure you know this well, that the first place to start checking if you have a chronic disorder is the diet. There are an almost immeasurable number of things that could be triggering. And people may not think to check their diet if their symptoms are not in the gut-so maybe they think diet if their stomach hurts and they have kind of gut problems-but if they have fatigue, they’re like-“that’s too far removed”. There are so many triggers. So again, if it were me, I would start with-I don’t have a particular plan because I don’t research this-but I would start with elimination diets, keep it simple, track in for a few weeks, and then see what happens. I tell ya, I can’t guess, but I would have to imagine, that there are probably tens of thousands-maybe more people-who could probably fix their problem, if they could just correct the problem in their diet.
(Me): Yeah, I completely agree with that.
Question: So, now let’s look at the broad picture, what do you think are the top triggers, in general, for CFS? There are some alternative physicians who will treat heavy metals, and then some alternative physicians who will treat infections, and then there are some physicians who think that…I spoke to one researcher, Dr. Ritchie Shoemaker, I’m not sure if you’ve heard of him, but he tests people with CFS and he found, in his group of people with CFS, every single one of them had problems with water damaged buildings. Now, I happen to think that the people he’s getting are the people who are gravitating towards his work. So again, these things need to be replicated by different groups of researchers and different cohorts of people, but what do you think of mold or water-damaged buildings as a trigger? Have you looked into that at all?
JY: No. So, I don’t do a lot from epidemiological or trigger-based. I do also research Gulf War Illness and that’s the big question with GWI-what caused all of these soldiers to have these symptoms? Was it the immunizations? Was it diesel fires-because there were all these oil fires? Was it mold in the sand? And there are other groups that really look at the triggers. I’m more treatment. And that may sound not right, like how do you deal with the treatment unless you know what the cause is, but there are some treatments you can do without, necessarily knowing the exact trigger, because they all kind converge at some point. You can treat that bottleneck in the system. So, I don’t know a lot about the causes. I don’t rule anything out because, again, like I said, fatigue is such a general alarm system that if you had high levels of heavy metals, fatigue is probably going to be the first place that you notice that. The mold stuff-yeah, absolutely-if you’re exposed to mold and that’s something you’re particularly sensitive to, that’s going to be treated as a major infectious agent or invader. That’s going to invoke a sickness response, an immune response. So yeah-food, mold…really most of the things I’ve heard are completely plausible. I think they’re going to differ in terms of how many people have their symptoms explained by it, but they’re all worthy. Again, if it were me, those are all things I would try to check, if possible. The building stuff is tough if it’s your work or your home.
(Me): Right. But yeah, you know, you can do relatively cheap tests in your work area to test for mold. A hundred and fifty dollars and it’s a pretty good test. But yeah, I agree with you. The problem with this condition-I mean your focused on the biology of it…what is going on…and so that’s really, super important and then there are other people who are focused on the triggers and that’s also important. Both are really important. Even when you know the triggers, you can’t completely get away from mold, so you have to try to see what’s going on in the body, so that you can fix it in other ways.
JY: Yep, exactly.
Fungal Infection Treatments and Herxheimer Reactions
Question: Now, here are some questions. And again, I’m going to ask you some questions that are a bit outside of your research domain, but you know, you can just say you’re not sure or you can just take a stab at it. Here’s an example: let’s just say somebody takes an anti-fungal drug, let’s say Fluconazole, which is not supposed to cause significant side effects, and they get a severe reaction. People will identify this reaction as a Herxheimer reaction. Do you think that if someone does that and they get a severe reaction-do you think that indicates that maybe they have a fungal problem? How do you know what is a Herxheimer reaction versus a side effect?
JY: I don’t have a lot of experience with the time frame. Here’s my guess-and you have to tell me if you’ve heard stuff that would conflict with this-I mean, the idea behind that is that you get a massive die off and basically you’re releasing a bunch of endotoxins, and maybe some other stuff as well, so for me, if I were seeing that and trying to figure that out, it would be more about the time frame, I think, because if it’s that effective-if the drug you’re giving is causing a massive die-off, then it should be doing a good job at eradicating the problems, so that reaction should be fairly transient. I don’t know how long, but I think if you’re still getting that into your second month, that’s suggesting to me that-I mean, those things should be dead by now and those endotoxins should be eliminated. So, that’s where I’d start to get suspicious that it’s not a die-off, it’s actually some side effect of the drug, but not being a clinician, not dealing with that, I can’t say with 100% certainty, but that’s what would make me curious.
(Me): Yeah, that’s a really smart answer.
Areas of the Brain Targeted by Dysregulated Inflammation and Immune Responses
Question: So, are you aware of any areas of the brain that are particularly hit by these issues? Or, in your research, is it just general microglia activation in the brain, central nervous system?
JY: Uh, there are a few. We talk about the hypothalamus. That’s a major one. The amygdala is probably the second most. Definitely direct connections and interactions of inflammatory cytokines on the amygdala cause a lot of the dysphoria, so mood, motivation-when those go down, when you have high inflammation, that’s via the amygdala. Hippocampus.
(Me): Also, the hypothalamus controls mood and motivation.
JY: Yeah, sure. There’s major hormones related to motivation there, so you get a dual hit there. And then the rostral anterior cingulate cortex is probably the fourth major target of some dysphoria. Probably dorsolateral prefrontal cortex as well, so there’s probably about five places, I think, that are particularly strong targets. And through those five, you can explain basically all of the symptoms-fatigue, pain sensitivity, mood decrease, dysphoria, motivation stuff-through those.
Low Blood Pressure and CFS
Question: And what about the very common symptom that I’ve seen, and you can tell me if you’ve seen this in people with CFS, is lower blood pressure. Is that a marker you’ve seen? And my explanation is that the inflammation in the brain stem-there’s these H1/H2 receptors, the histamine H1/H2, they respond to inflammation and they lower the blood pressure. Is that something you’ve seen though? That people with CFS have lower blood pressure?
JY: Yeah, I looked at a few today. We’re selecting some people for a secondary study and some of the resting blood pressures were ridiculously low. I mean I was asking my research assistant-“Can this person actually stand up with this?”. I would faint. If I had a blood pressure that low and stood up, I would be on the ground. For sure. We’re talking about below 100 systolic and below 60 diastolic. Just-I don’t know how you get blood up to your brain. Sometimes a lot lower than that. So, I don’t know the incident rate or I don’t know what percentage of our participants have abnormally low blood pressure. They certainly don’t have abnormally high blood pressure though, so there’s something going on. They’re either normal or running low. I can tell that for sure, but we could do those analyses and see if it’s statistically significantly different than the general population. There’s something going on though. You’re right. I’m seeing low blood pressure way more than I would expect from the general population, so for some people there’s a relationship.
(Me): Right. Cause you would normally see higher blood pressure in people who are on the standard-people in America are suffering from hypertension.
JY: Exactly. I don’t know the percentage but most people probably, over a certain age, are on antihypertensive medication. It’s strange. There’s something there that should be pursued for sure.
CFS and Inflammatory Markers
Question: Now back to this other researcher, Dr. Ritchie Shoemaker, who tests people with CFS. He found certain inflammatory markers elevated in people with CFS and people who are hit by mold. That includes TGF-beta1, MMP-9, C4a, and C3a. Now, have you tested those biomarkers? And what have you found?
JY: Most of those are not part of our panel that we run, though they will be in our panels going forward. So our publications today didn’t, but now we’re expanding the network because I realized that the panel we had was really good at telling us whether there was some inflammatory component, but it didn’t give us enough information to describe the pathways. And you start to get into those complement systems and MMPs and you can start to build something, so we’re going to have an expanded set of analytes. So I can’t tell you if I can replicate that or if I’ve seen that, but it’s something that we’re going to be looking at.
(Me): Mmhmm. Now here’s something that’s contradictory. One group of researchers found elevated alpha MSH in the blood of people with CFS. They found that in 2010. Dr. Ritchie Shoemaker finds lower alpha MSH in people who are hit by mold. Now, alpha MSH causes a whole bunch of effects on the body. It causes you to lose weight and I’ve found that people with CFS generally weigh less. I don’t know if that’s something that you’ve found.
JY: Certainly in the fibromyalgia I think I’m seeing lower body weight so-and we have more experience with fibro than chronic fatigue-but I would probably expect the same thing. We’ll have to check.
(Me): Yeah, and so alpha MSH is a potent anti-inflammatory. I’m curious if you have any thoughts on alpha MSH.
JY: That’s another really interesting one going forward. We need to look at-I’m talking about myself-need to not be so focused on just inflammatory and need to look at the opposing systems as well cause it could be disregulation in the feedback mechanisms. So yeah, no data on it to date, so just something that we’ll look at more from this point on.
(Me): Yeah, the other one would be VIP. Those two, MSH and VIP, are potent anti-inflammatory hormones that he found were low in his cohort.
JY: Interesting. Both of those, again, are in our expanded panel. We’re going to start running our first batch. So now we’ve got thirty people through the protocol, new people. We’re analyzing sex hormones, we’re doing our typical inflammatory and an extended inflammatory panel, so we’ll get to the point, in probably four or five months, where we can start to see if we’re replicating those things that you described.
Low Dose Naltrexone
Question: Okay. Now, you study low dose Naltrexone. And you found that it’s beneficial for some people with CFS and fibromyalgia. Some people have a great response, some people have no response, and a few people don’t do that well with it. How would you identify-and actually you mention this, you say that ESR is a good marker, is one marker, if you’re going to do well with low dose Naltrexone. What would you say? When should somebody think about taking low dose Naltrexone?
JY: Yeah, so it was one marker, but it was the only marker that we had available to try, so I’m not suggesting ESR is particularly good as a predictor of response. We just-we had ESR as a screening measure and I had a hypothesis that it might be predictive as well, so we tried it and it worked. But at that time, we weren’t running the extended panel of tests like we do now. When someone comes in now, they get a hundred different tests to rule out stuff that would give them a different disorder, so now we can test that better. So any low dose Naltrexone (LDN) study I do going forward will have more predictors. So right now, ESR is a predictor, but it’s not like a hundred percent predictor. People had ESRs over 40 millimeters an hour-they were really strong responders to LDN. That didn’t mean people had no response below that. It just meant they had a super powerful response if they were above that. So that alone can’t tell you whether someone’s going to respond or not. We’re looking at IL-6 and things like that now and actually I have a post-doctoral fellow, Luke Parkitney, whose looking at what happens to these cytokines when you start taking LDN, and he’s finding drops of several inflammatory cytokines. I think IL-6 being a big one. I think tumor necrosis factor alpha was another one. He found about six or seven. I’d have to check that to get the list, so there may ultimately be some predictors, but right now it’s too early to say, “Take this test to know if you’re going to respond or not.”.
Closing and Where to Learn More
(Me): That’s super interesting. Yeah. Well, we’re out of time here and you’ve been super helpful and I really appreciated this interview. Where can people find you and read more about your work?
JY: Yeah. So I’m trying to be really good about getting information out as we’re doing it. That’s one of my goals for 2016-is to get the results out to everyone. We do have a Facebook page where I try to post up to date stuff. I don’t have the link here but if you do Neuroinflammation, Pain and Fatigue Laboratory, you can find that. We have a web page. Just search ‘Jared Younger, neuroinflammation, pain, and fatigue”. There’s a newsletter people can sign up for. Those ways people will get the most information. I’m doing Q&A sessions once a month-just people asking me questions…whoever wants to. You can find that on a YouTube channel. Just put in my name and ‘neuroinflammation, pain, and fatigue’. So those are probably the big ways and I’ll start to do little mini videos where we start showing our projects-like here’s the scanner, here’s what we’re getting, so we’ll be putting more stuff like that out. So there’s a few different ways you can follow the lab.
(Me): Awesome. Thanks so much and it’s been really informative. I really appreciate it.
JY: Okay. Thanks Joe.
(Me): Yeah, have a great day.
Where You Can Find Dr. Jarred Younger
- UAB – Neuroinflammation, Pain, and Fatigue Laboratory (Sign Up for Younger Lab News)
Health Tools I Wish I Had When I Was Sick
At SelfHacked, it’s our goal to offer our readers all the tools possible to get optimally healthy. When I was struggling with chronic health issues I felt stuck because I didn’t have any tools to help me get better. I had to spend literally thousands of hours trying to read through studies on pubmed to figure out how the body worked and how to fix it.
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- SelfHacked Elimination Diet course – a video course that will help you figure out which diet works best for you
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- Lectin Avoidance Cookbook – an e-cookbook for people with food sensitivities
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- SelfHacked VIP – an area where you can ask me (Joe) questions about health topics
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