In the last ten years, there has been a revolution occurring in our understanding of human physiology which has deep implications as to how chronic disease conditions have been treated. This revolution has application for how one can extend their lifespan and during this extended life be healthy with full cognitive functions.
Currently, in conventional western medicine, there's a doctor for each different body system. If you have cardiovascular issues then you see a cardiologist, if you have eczema you see the dermatologist, and if you have neurodegeneration you see a neurologist and maybe also an immunologist. All these things are being looked at as separate conditions. For you as a patient, it can be pretty bewildering and you often end up with numerous medications, one or more for each condition. Welcome to the world of western medicine!
The revolution in human physiology is challenging this fundamental construct that you have separate and disconnected disease conditions happening and raises the basic understanding that there is a common root cause that's driving all these pathologies.
This revolution breaks down into three areas:
- The understanding of the significance of our mitochondria as drivers of aging and chronic disease conditions. Mitochondria are small organelles living in each of our cells. They are symbiotic meaning they have their own DNA different from ours and that there is a mutually beneficial relationship between our cells and the mitochondria. That relationship is we supply nutrients to the mitochondria, and they make adenosine triphosphate (ATP) the energy currency of our bodies. Our bodies require ATP to build proteins, new cells, to move muscles, to contract the heart, to move nerve impulses in the brain and down the nerves...all require ATP. Without the mitochondria producing ATP, we would not be alive.
- The understanding that our microbiota (the bacteria that live on us and inside of us) are fundamental to our existence. This microbiota is responsible for the production of some of our essential vitamins, neurotransmitters, immune response (about 70% of the immune cells are in the gut), and short-chain fatty acids which are essential for health. Finally, there is bidirectional communication occurring with the microbiota communities, the brain, and mitochondria. Science has known of the bacteria inside us for hundreds of years, however, the microbiota was not considered important to physiological processes with the body. The microbiota is being referred to as the “forgotten organ” as it takes center stage alongside the other organs.
- The recent discovery of the glymphatic system which is an extension of the lymphatic system and specifically removes debris from the brain. Accumulation of debris (plaque) within the brain goes hand and hand with many of the neurodegenerative diseases.
Let’s look at how we can use this revolutionary information to outsmart a neurodegenerative disease by understanding the root cause and implement lifestyle changes that deal with the underlying root.
Parkinson’s disease (PD), is the second most common neurodegenerative disorder among the 65 years and older population after Alzheimer disease. PD is characterized by a combination of motor symptoms that include muscular weakness, rigidity, slowness of movement, and often resting tremors. Western medicine does not know what causes PD, however, there are pathological changes in several areas of the brain which are mainly marked by the degeneration of dopaminergic neurons.
Proper gut function in the prevention of neurodegenerative disease is highlighted by a study showing that middle-aged men who defecated less than once a day had an over fourfold increased risk for PD diagnosis over the next 24 years compared to men with regular bowel movements (Abbott et al., 2001). Intriguingly, subjects with PD exhibit intestinal inflammation (Devos et al., 2013), and GI abnormalities such as constipation often preceded motor defects by many years.
Clinically, the PD patients are usually treated with levodopa, a dopamine replacement agent, monoamine oxidase B inhibitors and other types of drugs. The clinical symptoms of the disease are mitigated by supplementing dopamine or reducing the degradation of it. The efficacy of these drugs over the long term is not good with unpleasant side effects such as motor complications, nausea, constipation, headache, and sleep disorder, etc. (Borovac, 2016) which would negatively influence the quality of life of the patients.
Drugs don’t typically address the underlying cause of disease. What’s more, they often have adverse effects that can sometimes be as bad as the disease they’re meant to treat. Considering the long-term side effects of these medications, many patients are searching for a more safe and effective alternative treatment for PD.
The Gut Produced Neurotransmitters
Most people think that neurotransmitters such as dopamine, norepinephrine, epinephrine, and serotonin are made in the brain, however, the reality is most of them are made in the gut. In the context of outsmarting PD, it is very important to understand this gut pathway and in particular the production of dopamine.
Gut bacteria influence neurological functioning, through its ability to modulate and facilitate neuroinflammation, neurotransmission, and neurogenesis. Gut bacteria are involved in synthesizing neurotransmitters and their precursors (GABA, dopamine, serotonin, and norepinephrine)
To produce neurotransmitters, the gut bacteria need aromatic amino acids which come from plants. The three that are important for neurotransmitter production is phenylalanine, tyrosine, and tryptophan. All three of those are critical for brain function. Most of the amino acids the human can produce in our own cells, but there's nine that cannot be made in the human body, which are called the essential amino acids. Among those are these aromatic amino acids that are produced by plants for ingestion by humans.
The three aromatic amino acids and the neurotransmitter production which they drive.
Phenylalanine is a precursor to:
- Tyrosine
- Dopamine
- Norepinephrine
- Epinephrine
- Melanin.
Tyrosine is a precursor to:
- L-dopa and dopamine
- Catecholamines –epinephrine and norepinephrine
- Coumaric acid
- Melanin.
Tryptophan is a precursor to:
- serotonin
- the hormone melatonin
- and vitamin B3.
Approximately 90% of the serotonin that is produced in your human body, serotonin being a neurotransmitter that modulates everything from sleep to focus to creative capacity, is produced in the gut lining rather than in the brain itself. Furthermore, gut microbes can produce dopamine and its precursors from dietary substrates, with almost half of the body's dopamine generated in the GI tract. The gut is bringing all this information into the brain.
This identifies the first issue we want to correct to outsmart PD. Currently, in western society consumption of plant fiber is down by 50-60%. If you want to increase the production of dopamine then you are consuming substantially more of a plant-based diet (not canned) and fermented vegetables. Plants that are high in these three essential amino acids include soybeans, nuts, seeds, beans, lentils, and whole grains.
You can obtain these essential amino acids from other sources such as dairy, cheese or beef (these animals are grazing on plant matter) however this identifies the second issue you must deal with to outsmart PD.
Drug makers sold nearly 30 million pounds of antibiotics for livestock in 2014 – the largest amount yet recorded, compared to about 8 million pounds of antibiotics for human use that year. Antibiotics are needed due to the crowded conditions the animals are raised in and antibiotics fatten the animals up quickly for slaughter, which means more profit for the agribusiness. The antibiotics given to the livestock will then be passed down into dairy products or ingested with the meat we eat. We have four times as much antibiotic going into the food chain as we do into the humans from their doctors. Antibiotics even in small doses adversely affect your gut microbiota and these are the gut bacteria you are depending on to deliver neurotransmitters to your brain. (Wallinga, 2016)
The smart decision then is to eat more plants and if you want dairy products or occasional meat make sure you are getting certified organic to avoid the antibiotics. Data suggest that consumption of fruits and vegetables will improve the gut’s microbiome composition and result in improved psychological well-being, even in as little time as 2 weeks (Conner et al., 2017).
Keep in mind that the reduced vegetable/fiber consumption affects all neurotransmitters, not just the dopamine. This overall deficiency has cascading consequences which are discussed later in the paper.
Epithelium barrier dysfunction
The gastrointestinal wall surrounding the lumen (the inside space of the intestine, that contains food content and bacteria) of the gastrointestinal tract is made up of four layers of specialized tissue. For this discussion on PD, we are concerned with the epithelium which is the barrier closest to the lumen. Your epithelium is one cell thick about half the width of a human hair and is a cellophane-like layer that separates your immune system from the outside world. All of the single cells are held together by what looks like Velcro strips, they are actually called tight junctions (TJ). If your epithelium membrane starts to leak from the lumen into your body, it shifts you very quickly into inflammatory reaction, which can be acute or chronic as pathogen come from inside the lumen contents into your body. Our immune system certainly anticipated our vulnerability here because we built 60 to 70% of the entire body's immune system right behind that gut lining.
Here is an example of how the epithelium and the TJ’s function. Let’s say you get a bacterial infection, a stomach bug. Your immune system senses that and directs the epithelium cells to open their tight junctions. This allows water from the interior of your body to rush into the intestines. Guess what happens next...you get diarrhea, which is the body’s attempt to flush this pathogen out of you.
However, this unique feature of the epithelium renders the gut particularly susceptible to the development of a chronic inflammatory state and resultant barrier dysfunction. Many of the resulting diseases, such as PD, are associated with aging, and given that intestinal inflammation and forms of intestinal permeability have been shown to increase with age (Man et al., 2015), immune mediation of gut-brain interactions is particularly relevant in the pathology of neurodegenerative diseases of aging.
Leakage from the intestine into the peritoneal cavity and into the circulation can then occur, eliciting a systemic proinflammatory immune response (Al-Asmakh and Hedin, 2015). Many microbial pathogenic secretions or components such as lipopolysaccharides (LPS), which are a cell component of some bacteria’s walls that can be found in the microbiome, enter the circulation following increased intestinal permeability. They are immunogenic and can trigger systemic inflammatory responses. Proinflammatory cytokines and oxidative stress have been causally linked to neuron death, including dopaminergic neurons, and neuroinflammation which is now considered a key factor in numerous neurodegenerative diseases.
The gut bacteria also influence obesity by creating a low-grade, systemic inflammation status promoted by LPS, which is considered the link between the gut microbiota and chronic, low-grade inflammation, as it promotes visceral fat deposits, glucose intolerance, and hepatic insulin resistance. This occurs because a high-fat diet and obesity lead to alterations in the gut microbiota, changing the intestinal epithelial barrier and allowing translocation of LPS and antigens into the blood and adipose tissue—stimulating innate and adaptive immune cells in the liver and adipose tissue. Circulating LPS is found in amyotrophic lateral sclerosis (ALS), major depression patients and PD patients early in the sequelae (Maes et al., 2008; Zhang et al., 2009; Forsyth et al., 2011), an indication of leaky gut occurring early in these conditions.
Clinical and pathological data suggest PD may result from an inflammatory process due to LPS beginning in the epithelium due to leakage of TJs that initiates alpha-synuclein aggregation (plaque buildup), reaching the central nervous system. Additionally, the LPS endotoxin, a toxin has been shown to induce parkinsonism in animal models.
There are several factors which can cause the epithelium to become dysfunctional and allow leakage to occur:
- Chronic stress acting through cortisol is one means by which increases in intestinal permeability occur (Vanuytsel et al., 2014), allowing bacterial translocation from the gut to distant sites.
- Chronic consumption of soft drinks and sweets.
- Excessive consumption of red meats.
- Overuse of antibiotics which depletes both beneficial and pathogenic bacteria.
- Some medications and NSAIDs.
- Food additives and desiccants.
- Under consumption of vegetables and fiber which produces SCFAs which can tighten epithelium cell junctions.
This is discussed in the section Gut Microbiota Fermentation of Fiber.
All the above points are within your control to help you outsmart PD. If you are under stress find a way to manage it such as exercise, yoga, meditation. Shop more locally for your food and move out of the center aisles of your grocery store where all the heavily processed foods are. If occasionally you need an antibiotic then ask your MD for a non broad base antibiotic, one that is specific to your pathogen, so that you don’t kill off the beneficial bacteria.
Make this science part of your everyday life, so that this is not a trendy change that fades away after a couple of months. What this means is you understand that there are symbionts living on you and in you (mitochondria and microbiome) and you understand how to support them (nutrients) so that they provide you a long healthy life.
Gut Microbiota Fermentation of Fiber
There is a developing body of literature that shows that the gut microbiota, if it's fed dietary fiber, which is greatly deficient in the Western diet, and then ferments that fiber and creates chemicals known as short-chain fatty acids—those get absorbed into our circulation and go to distant sites such as the brain, liver, and heart and have anti-inflammatory effects.
These short-chain fatty acids (SCFAs) are major end products of bacterial fermentation in the human colon and are known to have wide-ranging impacts on human physiology.
The SCFAs break down into the following metabolites:
- Butyrate is important for maintaining health via regulation of the immune system, maintenance of the epithelial barrier, it is used as an energy source by the mitochondria in the production of ATP. It may be protective against several diseases, including colorectal cancer, inflammatory bowel disease, diabetes, and obesity. Therefore, stimulating butyrate production by the colonic microbiome could be useful for sustaining health and treating diseases.
- Acetate helps in the reduction of the luminal pH, which by itself inhibits pathogenic microorganisms and increases the absorption of some nutrients (Macfarlane and Macfarlane, 2012).
- Propionate is a key player in autophagy and mitophagy. Autophagy deals with the destruction of old or damaged cells and mitophagy deals with the destruction of old or damaged mitochondria. Mitophagy has significance in PD due to dysregulation of mitochondria energy production in the neurons.
What this means for outsmarting PD is that if we're not eating fiber, our microbiota is not producing as many short-chain fatty acids, and we don't have the same level of anti-inflammatory compounds floating around in our bloodstream. One of the really common denominators of these chronic Western diseases is inflammation. It's really decades of chronic inflammation due to our lifestyle that sets us up to get one of these diseases, and then it's inflammation that drives it.
Additionally, scientists have shown that there are different communities of gut bacteria in persons with PD compared to those of healthy control, but the studies did not determine whether these differences were just the byproduct of the disease or whether those different communities could actually influence the disease itself. The smart choice then is to work on normalizing your microbiota communities with the inclusion of plants and fibers.
Foods with indigestible fiber include various types of mushrooms, fruits, legumes, whole grains, potatoes, and vegetables—all containing a type of dietary fiber. Another consideration is prebiotics which is compounds in food that induce the growth or activity of beneficial microorganisms such as bacteria and fungi. Generally, prebiotics come as a powder and can be added to water or a smoothie as a morning drink.
An important prebiotic is inulin, a dietary fiber that can be fermented into acetate, propionate, and butyrate by the gut microbiota. Prolonged intake of this prebiotic seems to lead to reductions in body weight, BMI, and energy and fat intake. It can also reduce lipid concentration, LDL cholesterol, and total cholesterol, as well as lower fasting glucose and insulin concentrations. Similarly, arabinogalactan is a dietary fiber that produces short-chain fatty acids. It has been found to increase gut-barrier function and cytokine production (pro- and anti-inflammatory).
Mitochondrial Dysfunction and PD
Mitochondria live inside the human cell and produce ATP, the energy source for all of the cellular functions. More remarkably, mitochondria live within the neurons of the brain and provide the energy to move all of the nerve impulses. A human neuron may have as many as 2000 mitochondria in the single-cell body compared to a heart cell which may have from 5000 to 8000 mitochondria, all continuously producing energy to drive the movement of nerve impulses and expansion/contraction of the heart. Mitochondria are super power packed energy producers to the degree that a cubic centimeter of mitochondria can produce about 10,000 times more energy than a cubic centimeter of the surface of the sun. Mitochondria have an incredible capacity for the production of energy. (Bush, 2019)
Several more points are important to understand about mitochondria function. First, as was previously mentioned mitochondria are symbionts living in us, with a mutually beneficial relationship, we supply the mitochondria with nutrients and they supply us with ATP.
In a situation (such as a couch potato) where there are excess nutrients and low energy demand this causes damage to the mitochondria and the surrounding area. ATP is made from electrons and when there is low energy demand these electrons can punch holes in the mitochondria membrane and surrounding area. These released electrons are referred to as reactive oxygen species (ROS)
There can also be a process of mitochondria damage driven by low nutrient availability. Mitochondria require oxygen and other nutrients such as CoQ10, and L Carnitine to make ATP. Blockages in the intercellular spaces (plaque), as well as insufficient nutrients, can cause inefficiencies in the production of ATP and create excessive ROS which again damages the mitochondria and surrounding tissues.
ROS damaging is a normal byproduct of the production of ATP and if the damage is severe to the mitochondria a process known as mitophagy occurs which initiates the recycling of the damaged mitochondria. For the damaged cells surrounding the mitochondria, there is another process that filters and removes damaged debris.
Our view of the mitochondrial world of cellular biology is probably based on static images from textbooks in high school or college. It is a much more dynamic world of cellular movement. Mitochondria are like little power plants and are often moved around within the cell or neuron to places that have a higher energy demand. That is accomplished by kinesins that pull the mitochondria to sites of higher energy demand.
Let’s discuss how mitochondria affect PD. PD is associated with a loss of dopaminergic neurons that leads to the depletion in dopamine neurotransmission. In the section on Gut Produced Neurotransmitters, we discussed how consumption of plant essential amino acids can be deficient in the gut leading to a lowered production of dopamine.
Dopamine is required in the brain for the firing of the dopaminergic neurons, over time (years) if there is a lowered production of dopamine, one would expect a lowered availability of dopamine to facilitate the firing of the neurons.
Our body is intrinsically beautiful in its redundancy. Mitochondria are transported to areas of the neuron which exhibit a particularly high energy demand, meaning the body tries to keep up with the lowered dopamine availability by distributing mitochondria to the dopaminergic neurons that are firing, thus trying to maintain the body’s muscular functions. This is how mitochondrial redistribution within neurons can be altered to compensate for pathological changes.
Alpha-synuclein (plaque buildup) is also capable of interacting with mitochondria and causing their dysfunction, indeed it has been shown that alpha-synuclein can induce mitochondrial dysfunction within neurons that precedes neuronal loss. This plaque is debris (see the section on the Glymphatic System) in the brain which obstructs the delivery of nutrients and oxygen to the mitochondria.
In the section on Epithelium barrier dysfunction, the protective effect of the epithelium was defined There is also an epithelium barrier around your brain known as the blood-brain barrier (BBB) which is a network of these same Velcro-like proteins, these tight junctions, that tie together the blood vessels anytime it is next to a nerve.
Glucose is the preferred fuel by the brain and the mitochondria. If there is excessive consumption of glucose (sugars, refined carbohydrates, and soft drinks) going through the BBB in an unregulated fashion, it becomes overwhelming to the brain and mitochondria and drives excessive production of ROS. Additionally, the BBB TJs also become susceptible to leakage just like the gut epithelium barrier.
How then does one begin to outsmart PD in the context of mitochondria production of ATP in the brain? First, remember the PD did not occur overnight it is the progression of years of deficiencies in nutrients, SCFAs and epithelium barrier dysfunction. The basic protocols are to:
- consume a plant-based diet to produce more neurotransmitters and SCFAs.
- consume fibers to produce SCFAs which helps tighten the TJs in the epithelium.
- consume fibers aids in the production of propionate from SCFAs which initiates the process of mitophagy to clear defective or old mitochondria.
- stop consumption of sugars and refined carbohydrates to tighten the TJs in the epithelium.
- Mitochondria need oxygen, so mild exercise (walking, biking) coupled with breathing.
- DO NOT SIT ALL DAY! Sitting creates hypoxia a condition of low oxygen content in the body. The mitochondria need oxygen.
Glymphatic System
It wasn’t very long ago that scientists discovered a mechanism for the brain to remove toxins, called the glymphatic system, and now can link its efficiency to the quality of sleep.
New research shows the efficiency of toxin removal from the brain is linked to how deeply we sleep, which has far-reaching implications for depression, neurodegeneration, and PD.
Toxic proteins, like beta-amyloid, tau proteins, and LPS in the brain are linked to neurological dysfunction. It is possible that impairment of the glymphatic system due to disrupted sleep keeps the brain from removing these toxins, which could be driving the dysfunction, once again highlighting the link between sleep, aging and neurological impairment.
There is a massive increase in the exchange of solutes through the glymphatic system during deep sleep. Sleep disturbance is well known to increase with age and PD. Together, this combination may explain the increasing risk of PD, dementia, and cognitive decline with aging and poor sleep.
With the discovery of the glymphatic system, it is now understood that a major function of sleep appears to be that the glymphatic system is turned on and that the brain clears itself of neurotoxic waste products produced during wakefulness.
As was discussed in the section The Gut Produced Neurotransmitters a portion of the neurotransmitters is made in the gut from aromatic amino acids which are derived from the consumption of plant-based foods. The western diet is currently deficient in plant-based food by 50 to 60% which drives deficiencies in the production of the neurotransmitters.
The aromatic amino acid which is specific to sleep is tryptophan which is a precursor to serotonin, the hormone melatonin and vitamin B3 (Niacinamide), all of which are essential to regulate sleep. One would expect that deficiencies in Serotonin, melatonin, and B3 would result in dysregulated sleep.
Regarding vitamin B3 (Niacinamide), the active form of niacinamide in the body is NAD [a coenzyme found in every cell] and this is an intermediary in energy production and when we speak of energy production it is always in reference to the mitochondria. NAD is used in the mitochondria to make our essential energy molecule, namely adenosine triphosphate (ATP).
For outsmarting PD, it is important to understand the root cause which has been reiterated throughout the paper which is reduced consumption of plants and fiber. This reduced consumption has consequences in a lowered production of SCFAs, dysregulation of gut-produced neurotransmitters, the release of toxins into the general circulation through leakage of the epithelium, mitochondria dysregulation, and difficulty in sleeping.
Final Thoughts
In the introduction for this article, I indicated a typical profile for a person with PD, one point being an older adult (65 years or older). What is important to recognize is the discoveries about the significance of the mitochondria, the gut, the microbiota, and sleep have not been viewed as significant in the aging and disease process. Basically, they are recent discoveries and have not been incorporated into the western medicines disease approach. A person who is 65 or older suffering from PD today had no understanding 20 years ago about the significance of these factors. Dietary concerns were minimal.
Essentially, you have a rate of repair and a rate of injury. If a rate of injury outstrips your rate of repair even slightly, you're going to start to degrade in function. You're going to start aging. A current disease then is viewed against the backdrop of ongoing poor dietary consumption over the years rather than the disease condition just happened out of the blue.
Understanding the significance of these new discoveries in relation to human health has profound implications. I think what is apparent is that there are probably some very simple answers to complex disease conditions, some of which I have identified in the paper. Maybe we can get 70 to 80 percent of the way there by just applying these general rules of dietary consideration and then focus on the remaining that will be individualized. I think that would be a productive way to look at this and how you can outsmart PD.
Although this discussion was about a specific disease condition PD, it sets up an opportunity for an internal deconstructive dialogue to challenge some of your beliefs and possible misconceptions about your health. Fundamentally we view ourselves as separate, separate from the environment that we move in. This separateness is defined as the “I” ness which ends at your skin and “other” which would include all of the people and objects you interact with outside of your “I” ness.
However, this discussion has now introduced you to the symbionts (microbiota and mitochondria) which you are totally dependent on for your health and wellbeing. Also, there is direct bi-directional communication occurring with the symbionts and your brain and most amazing for every cell that you consider to be “you” there are 25 or more cells that are not “you” composed of microbiota and mitochondria.
If you are willing to reconsider your belief in separateness, then that gives space to consider the interdependence and interconnectedness of all life on the planet. Your microbiota and mitochondria are totally dependent on you for life just as you are totally dependent on them for your life and wellbeing. Everything on the planet then is interconnected and interdependent in this web of life.
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