“It’s all in your head.”

“There’s nothing wrong with you.”

“All tests come back negative.”

If you’re someone battling a chronic illness, statements like these from your healthcare provider likely cut at you like a finely sharpened razor.  Then, of course, come the subtle remarks from your friends and family.  It’s not that they don’t care about you or think you’re crazy.  It’s that we have a long history of minimizing things we don’t understand, they make us feel stupid.

Acute infection is easy to identify, easy to treat, and easy to point to a resolution.  Treating acute infection is directly in the wheelhouse of our current healthcare system.  Chronic disease…not so much.  Thus, we criticize what we don’t understand and can’t fix.

Part of the problem with chronic diseases such as autoimmune conditions, fibromyalgia, “adrenal fatigue”, systemic inflammatory response syndrome(SIRS), chronic fatigue syndrome, and persistent parasitic infections is that we have no underlying paradigm for defining or addressing them.  That is, perhaps, until now.

Chronic disease as a positive feedback loop

A review/hypothesis recently published in the journal Mitochondrion appears to be a giant leap forward in approaching chronic disease.  The way our healthcare approaches the treatment of acute illness has saved countless lives and suffering by identifying causes of acute illness such as a bacterial of viral infection and eliminating them.

This approach fails repeatedly for treating chronic disease because often times a chronic disease is a perfect storm of several events.  Even though many people can point to some sort of infection or traumatic event as being the chronological “trigger” of chronic disease, other factors must be there to get “trapped” in the chronic disease state.

In the review mentioned above, the authors make mention of the Epstein Barr Virus(EBV) being a triggering event for Myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS).  The problem is, by the age of 19, 82% of the US population has been exposed to EBV, yet <1% of the population develops ME/CFS.  With such a dramatic difference between these 2 groups, how could EBV cause ME/CFS?

Rather than focusing on the trigger that causes the initial injury, the authors make the case that we need to focus on why the systems in the body are allowing a disease state to persist indefinitely.  Then and only then can we approach chronic disease with a valid paradigm that will lead to resolution.  In their hypothesized model, the primary issue  involves being trapped in one of the 3 stages of the healing cycle.

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The 4 stages of the healing cycle

Ideally, we spend our entire life in stage 1 of the healing cycle, called the health cycle.  The health cycle involves periods of wakeful activity followed by restorative sleep to promote adaptation and recovery.  In this stage, we’re metabolically flexible, being able to metabolize energy via any of the energy systems.  When our internal harmony becomes disrupted due to infection, injury, stress, or some other noxious external factor, we enter the first stage of the cell danger response(CDR).

In the first stage of the CDR, damaged or infected cells are sequestered from healthy tissue and the inflammatory response initiated to begin removing damaged cells, toxins, and foreign invaders.  This stage is marked by increased extracellular ATP and a reliance on glycolysis for energy production.  In this stage, cells too damaged to be repaired are removed via programmed cell death or get gobbled up by the immune system.

In stage 2, we get a proliferation of stem cells to eventually replace the cells that were lost.  Cells with damaged DNA enter senescence, which is a state where they no longer replicate, but still contribute to tissue function.  Unfortunately, they also secrete factors that interfere with tissue function as well, called the senescence associated phenotype(SASP).  In this stage, aerobic glycolysis is the predominant form of energy metabolism.  Ideally, in stages 1 and 2, communication between cells involved in the injury and healthy cells is cut off so that the damaged cells don’t cause collateral damage.

In stage 3, we see resolution of the healing process.  If everything goes properly, stem cells secrete healing factors and the daughter cells created by stem cells differentiate in to specific cell types that are incorporated back in to the tissue.  Oxidative phosphorylation is the predominant form of energy metabolism as inter- and intra-organ communication is restored and extracellular ATP levels decrease.  The result: you re-enter the health cycle.

The problem with chronic disease, as this paradigm goes, is that people with chronic disease don’t progress along the healing cycle.  They’re exposed to some triggering event that initiates the cell danger response and, somewhere along the way, get trapped in to one of the 3 CDR phases due to other contributing factors.  This leads to a system that maintains the disease state, waiting for a signal or signals to progress along that may never come.

Normally, the triggering event is a highly stressful event.  But since you never fully recover from the triggering event, lower level stressors are able to trigger a disproportionately large response. It’s effectively damage, followed by incomplete recovery, followed by more damage.

Over time, the damage accumulates and the bottom falls out.  People become sensitive to things they were never sensitive to before because they’re in a persistent state of incomplete recovery.  Maybe they develop multiple chemical sensitivities, food intolerances, cold intolerance, an autoimmune condition, or they get sick all the time.  As an added bonus, this throws off the HPA axis which causes a massive over-responsiveness to even the mildest stressors.  Then, depression ensues.

Note: This paper uses metabolomics to classify more than 100 chronic diseases based on the profile of metabokines, metabolic signaling molecules, seen in the condition.  These metabolites dictate whether they are an illness caused by being trapped in CDR1, CDR2, or CDR3.  This includes adrenal dysfunction, SIRS, mitochondrial dysfunction, chronic parasitic/fungal infections, all autoimmune diseases, IBS/IBD, autism, ME/CFS, PTSD, POTS, PANS/PANDAS, Parkinsons, Alzheimer’s, you name it.  This is a great paper and if you are interested in finding out where you may be “trapped”, check it out here.

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Mitochondrial form and the stages of the healing cycle

Since we see profound changes in the way energy is metabolized in each stage of the healing cycle, it makes perfect sense that we’d see changes in mitochondria as well.  During the health cycle, our mitochondria are in their anti-inflammatory, M2 form.  This form is ideal for the metabolic flexibility of healthy, differentiated cells.  It also optimizes mitochondrial dynamics where fusion and fission promote energy efficiency through teamwork and removal of damaged mitochondria, respectively.

When the CDR is turned on, there’s an immediate switch to a pro-inflammatory, M1 phenotype.  This more or less shuts off oxidative energy metabolism in the mitochondria so that oxygen can be diverted towards making reactive oxygen species and other factors that can be used to increase inflammation, signal damage, cripple foreign invaders, and wall off damaged cells from healthy ones.  This switch in mitochondrial function gives rise to the reliance on glycolysis in CDR1, but it comes at a price in decreased organ function.

In CDR2, mitochondria enter their M0 form, where they now begin generating energy via the TCA cycle/aerobic glycolysis.  This is primarily due to swarming of stem cells to the area to replace damaged cells.  Stem cells rely on aerobic glycolysis so that, in addition to generating energy with oxygen, they can also release intermediates that help promote the healing process.

In CDR3, mitochondria begin re-entering their anti-inflammatory M2 form. Newly born cells from CDR2 must fully differentiate and re-establish cell to cell communication.  This also allows these newly formed cells to be “educated” by neighboring cells to re-establish the proper epigenetic profile of a healthy cell.  To accomplish all of the this, cells require adequate energy which can only be provided by oxidative phosphorylation, which is optimized in M2 mitochondria, and an adequate supply of oxygen from the blood.  The increased blood supply also allows removal of waste products and extracellular ATP.

Ideally, this primes you to re-enter the health cycle where you re-establish full metabolic flexibility and proper mitochondrial dynamics.  Oh yeah, and you feel kickass too.  The problem is, if you don’t progress fully through the CDR cycle and re-enter the health cycle, every thing falls apart.

CDR, metabolism, and symptoms of chronic disease

Probably one of the most provocative aspects of this hypothesis is that it seems to do a fantastic job at defining the underlying cause of symptoms common to all chronic disease.  Simply looking at the mitochondrial bioenergetics gives us a firm grasp of why fatigue would be a common symptom of chronic disease.

The assumption has always been that people with chronic disease experience mitochondrial dysfunction.  In the CDR paradigm, mitochondria aren’t dysfunctional, they’re stuck in a suboptimal state that doesn’t allow metabolic flexibility due to incomplete progression through the CDR cycle.  Oxidative phosphorylation is responsible for generating >90% of the ATP your body uses, so poor metabolic flexibility never provides adequate energy.

Another common suite of symptoms of chronic disease involves hormonal imbalance.  Even though many people suffering from chronic disease complain of symptoms consistent with hormonal imbalance, they’re blood levels may or may not come back normal.  This can be explained, in part, by the loss of communication during CDR1 and CDR2.  Despite adequate hormone levels, if communication is walled off between tissues, a hormonal signaling will never reach its intended target.

Chronic activation of the CDR also has a negative effect on signaling from the vagus nerve.  This can lead to autonomic imbalance and an inability to pull out of the sympathetic, fight or flight response.  This disruption in the ebb and flow of the autonomic nervous system can lead to POTS(Postural Orthostatic Tachycardia Syndrome) or autoimmunity due to HPA axis dysregulation.

Anxiety and other psychological symptoms that come with chronic disease can be explained by all the above as well.  In addition, being stuck in one of the phases of the CDR may potentially lead to a chronic version of the sickness response, where sufferers lose their appetite, detach from social engagement, become shut-ins, and fall in to a chronic state of low self worth.

Finally, and probably most frustratingly of all, this model helps explain 2 of the most devastating chronic disease symptoms of all: a propensity to relapse after remission and an accumulation of chronic disease.  With chronic disease, people often enter brief periods of health, but these moments are fleeting.  Something may kick them back in to gear and move them out of the stage of the CDR they are trapped in, but somehow they find their way back in.

In other words, even in those able to move out of the CDR and re-enter the health cycle, there’s a pretty good likelihood another trigger will trap them right back in or lead to another chronic disease.  This comes down to not building enough resilience to remain in the health cycle.  And that comes down to a single word: lifestyle.

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Lifestyle: Building resilience to chronic disease

There’s a very good reason that the health cycle is defined as wakeful activity followed by restorative sleep: these are the environmental conditions our healing cycle is optimized for.  When we follow the health cycle we’re more robust, and thus, more resilient to chronic disease.

Interrupting the health cycle by getting inadequate sleep or physical activity likely plays a strong role in predisposing someone to chronic disease.  As the authors of this study put it:

“Moderate exercise creates a natural stimulus that facilitates restorative sleep and repair by creating balanced activation of all the stages of the healing cycle. In many important metabolic ways, exercise “reminds” the body how to heal and promotes disease-free health throughout life.”

What they are basically saying is that exercise keeps your immune system trained and ready for anything that comes at it.  There’s a ton of research in the area of exercise and immune function.  Many people likely assume that the changes brought about via exercise are solely relegated to changes in the mitochondria of muscle cells.  This couldn’t be further from the truth.

One study found that regular exercise is associated with greater mitochondrial DNA copy number, a surrogate marker for the amount of mitochondria in a cell,  But the increase in mtDNA wasn’t in muscle cells, it was in leukocytes, cells of the immune system.

Another study found athletes have upregulation of genes involved in mitochondrial biogenesis and oxidative phosphorylation and a downregulation of inflammatory genes in leukocytes.  Simply put, the mitochondria in their immune system resembled the M2, anti-inflammatory form of mitochondria that causes the transition from CDR3 back in to the healthy cycle.   This is what the authors mean when they say exercise “reminds” the body how to heal.

With regard to sleep, the authors state:

“Sleep is medicine. Slow wave sleep (SWS) and the associated increase in parasympathetic autonomic tone are important for healing and recovery during rapid growth in childhood (Takatani et al., 2018). Disruptions in SWS and parasympathetic tone during sleep are risk factors for many chronic illnesses”

One review discusses how sleep loss negatively affects the immune system, causing the release of inflammatory factors and neuromodulators that negatively impact the CNS and HPA axis.  These neuromodulators are the same neuromodulators described as metabokines above and the effect of poor sleep on the HPA axis is identical to that described for chronic disease.  In other words, this data describes this model of chronic disease to a T.

It’s important to not look at sleep and physical activity as separate factors.  They’re complimentary factors that keep our immune systems functioning properly, our HPA axis balanced, and keep us resistant to chronic disease.  Good sleep promotes strong physical activity, and adequate physical activity promotes strong sleep.  This bi-directionality is described in detailed in another review.  But to summarize, exercise improves deep(SWS) sleep, and balances the autonomic nervous system.

Breaks in this cycle likely play a large role in making one susceptible to chronic disease and are the reason most people flounder back and forth between the CDR and health cycle.  But other factors can help you stay in the health cycle or re-enter it.  In fact, they’re just as important as sleep and exercise because they’re all inter-related and affect one another.  This includes optimizing circadian rhythms, managing stress, meditation, remaining socially engaged, and challenging yourself mentally on a regular basis.

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Aging: The greatest risk factor for chronic disease

For the bulk of this blog I’ve described chronic diseases that are more on the fringe and out of the mainstream.  I feel there’s an under-representation of these conditions in much of the literature so I felt impelled to address them.  But let’s not forget the most common chronic diseases we see in our society: Type 2 diabetes, cardiovascular disease, neurodegenerative disease, and cancer.

These more common chronic diseases tell us a lot more about how chronic disease develops because they have a ton of research behind them.  The most common risk factor for these diseases is aging.  In other words, every day you get older, your risk for these diseases increases.  I have no doubt that the same rings true for all of the chronic diseases mentioned throughout this blog.

The reason aging is the primary risk factor for chronic disease comes down to resilience.  As we age, the epigenetic “program” of our stem cells changes from one that promotes optimal function to one that manages oxidative stress.  The only way to avoid or reverse chronic disease is to either maintain or re-enter the health cycle.  The best part about this is that there is literally no argument to be had here.  There is universal consensus that the best way to do this falls in to 3 main categories:

1. Optimize circadian rhythms
2. Maintain adequate physical activity and cardiorespiratory fitness
3. Maintain a healthy weight via calorie restriction

In the study referenced above, the reprogramming of stem cells from the maintenance of optimal function in youth to managing oxidative stress in aging was reversed in aging stem cells via calorie restriction.  This was accomplished by resetting the circadian clock via SIRT1, which functions as the metabolic arm of the circadian clock.  It also regulates multiple steps in the CDR.

The path to healing from chronic disease

Unfortunately, I’m fully aware that people suffering from chronic disease are trapped in a state where these 3 factors seem like monumental feats.  Nonetheless, the route out of healing from chronic disease goes through these 3 factors whether you like it or not.  But it’s important to realize that there’s a logical progression through these 3 steps that can make the process much more doable and a lot less painful:

1. Start with circadian rhythms because there’s a lot less pain.  I’ve seen highly impressive results doing this with people in my Circadian Retraining Program and working with individuals one-on-one because establishing a robust circadian rhythm optimizes HPA axis function and blood glucose regulation.  It also gooses your stem cells by giving them what they need: a stimulus to promote healing during the active period and a rest period where you allow them to do so.  Skipping this step will make you crash…HARD!  And you’ll need to do a lot more than blocking blue light at night and practicing time-restricted eating(TRE) to prevent that from happening.
2. Once you re-establish the above, working your feeding/fasting window and SLOWLY adding in physical activity to tolerance in the form of walking will begin to build resilience and help you re-enter the health cycle.  Sleep should improve and energy balance should return.  By energy balance I mean you will begin to feel more energetic during the day and more fatigued when it’s time to go to bed.
3. As you re-establish energy balance, you’ll be able to tolerate exercise, a necessary component to the health cycle.  People who don’t tolerate exercise need to re-enter the health cycle before they tolerate exercise.  As you increase your physical activity levels via exercise, sleep will improve, particularly the deep sleep you need to heal and fully enter the health cycle.  In this phase you will notice the most dramatic improvements based on objective measures.

This brings us to another critical component of the process: measuring progress objectively.  Many people may begin down this path to the health cycle, but they subjectively feel terrible.  This is likely due to a change in epigenetic programming from the pro-chronic disease state to the healthy cycle.

I do this with any of the new wearables that at least measure sleep, heart rate, physical activity, and cardiorespiratory fitness.  The 2 big ones are the Fitbit Charge 2 HR and the Oura Ring.  This allows me to individualize the program for people based on how they respond.  Individualization is key to optimizing re-entry in to the health cycle.  Too much too soon will leave you trapped in the CDR.

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Reprogramming resilience

Another fantastic attribute of this model of chronic disease is that it gives the appropriate time frame to expect to see improvement.  With acute illness, people expect to feel better within a week but that isn’t what you should expect with reversing a chronic disease.

There’s a latency period between the implementation of these factors that build resilience and when you begin to feel better and re-enter the health cycle.  It takes 3-4 days to establish the new epigenetic program and at least 3 weeks to see that reprogramming begin to take hold.  All told, expect to spend at least 3-4 months before your metabolism is reset to promote resilience depending on how long you’ve had your chronic illness as well as the number of chronic illnesses you have.

At this point, your body should be well-equipped to re-enter the health cycle.  For some, other therapies may need to be administered.  For example, in the case of persistent parasitic infection, an antimicrobial or antibiotic therapy may be necessary.

Fortunately, since your microbial defense systems are operating at a much higher level, these therapies will be far more effective at this time.  There will be synergy between you and the antimicrobial, and you’ll be metabolically flexible enough to mop up the mess and progress through all stages of the CDR back in to the health cycle.

Administering an antimicrobial prior to this point ultimately ends in failure.  You haven’t yet built resilience, so even if the antimicrobial is effective you’ll rebound or develop some other infection/overgrowth since your internal environment is still primed for it.  We can say this about any of the chronic diseases mentioned.  Without resilience, you’ll fall right back in because you really haven’t changed any of the conditions that caused you to fall in to the chronic disease in the first place.  Thus, it makes the most sense to establish resilience first, then treat.

Conclusion

Chronic diseases suck for many reasons.  First, we don’t understand them.  This makes them extraordinarily difficult to treat.  Second, given that they’re chronic, they persist.  You’re not going to do a “kill phase” and go back to “normal” in a week.  You’re also not just going to meditate for a few weeks and go back to your previous life because many of the lifestyle factors you had prior to your chronic disease led to it.

Probably the biggest reason chronic diseases suck is that, unless we’re talking about Type 2 diabetes, cardiovascular disease or cancer, none of them are being addressed by your healthcare system.  This new paradigm on treating chronic disease is a giant step forward that may be a godsend to people currently experiencing a chronic disease.

While in the throws of chronic disease, people feel miserable and helpless.  But one thing I’ve consistently seen in the people who pull themselves out of chronic disease is a change in perspective due to becoming more robust and resilient.  They understand health and the health cycle in a way a person who has never experienced chronic disease ever will.  And with this comes a strong resistance to future chronic disease.