Chapter Six
Metabolism
The mitochondria are the organelles of the cells that produce energy. Inside each of the mitochondria are electron transport chains that use electrons to move hydrogen across the interior membrane of the mitochondria, creating an electrochemical gradient. This gradient is the electrical charge difference between the inside and outside of the membrane. The electrons transport chains use the gradient to produce chemical energy that powers the body.
Mitochondria create the main chemical energy molecule of the human body, adenosine triphosphate (ATP). Some cells require more energy, such as nerve cells and muscle cells. Therefore, they have hundreds of mitochondria.
If mitochondria problems occur, such as the generation of too many reactive oxygen species, it has a big effect on cells with more mitochondria. Interestingly, the systems often affected in ASD people are the high-energy systems that contain a lot of mitochondria per cell, such as the gastrointestinal system, the central nervous system, and the muscular system (193).
Source Metabolism
The type of energy source affects the rate of reactive oxygen species generation. The two primary sources of energy are fats and carbohydrates. Fats break down into fatty acids, and carbohydrates break down into glucose. The mitochondria use fatty acids and glucose to produce energy. They also use protein for energy, but this process is more active during starvation.
High blood glucose levels increase the release of insulin, a hormone that enhances glucose metabolism and limits fat metabolism (194). This shift makes the mitochondria use a greater amount of glucose for energy to compensate for reduced fat metabolism.
The proportional balance between glucose and fat metabolism affects the ratio of NADH and FADH2, molecules the mitochondria use for energy production. The molecule nicotinamide adenine dinucleotide (NAD+) can accept an electron and a hydrogen to become NADH. The molecule flavin adenine dinucleotide (FAD) accepts two electrons and two hydrogens to become FADH2.
Both NADH and FADH2 are electron carriers and can transport their electrons to the electron transport chains of the mitochondria. These electrons provide energy to move hydrogen atoms across the inner membrane of the mitochondria, creating the electrochemical gradient used to make ATP.
A critical difference between fatty acids and glucose is that glucose generates a higher ratio of NADH to FADH2. Without going into too much detail, the metabolism of glucose, including the glycolysis steps outside of the mitochondria and the citric acid cycle, generates about a 5/1 ratio of NADH/FADH2.
In contrast, the ratio of NADH/FADH2 created from the metabolism of fatty acids is about 2/1.
The higher ratio of NADH/FADH2 generated by glucose metabolism leads to the creation of more reactive oxygen species than the lower NADH/FADH2 ratio made by fat metabolism. This happens because complex I uses NADH and does not use FADH2.
Complex I is a protein complex in the electron transport chain that transfers electrons from NADH to coenzyme Q10 and moves hydrogen across the inner mitochondrial membrane. Complex I makes a large amount of reactive oxygen species. Research found a relationship between complex I and a “substantial part” of the reactive oxygen species generation, and that “complex I is a source of oxygen radicals in mammals (195).” Others found complex I is one of the “main contributors to superoxide production by mitochondria (196).”
Since glucose creates NADH/FADH2 in a higher ratio, then glucose metabolism leads to the generation of more reactive oxygen species than fat metabolism.
In addition, glucose damages proteins by glycating them, which activates a specific receptor that further increases inflammation. This receptor is known as the receptor for advanced glycation end products (RAGE). Activation of this receptor is another reason glucose is more harmful than fat.
Mitochondria and ASD
Interestingly, research examining some ASD people with signs of mitochondria problems found that the most common electron transport chain disorder was a deficiency of complex I, which occurred in 64% of the ASD people (197). Another study of mitochondrial dysfunction in ASD found decreased complex I and complex IV activity (198). Surprisingly, this mitochondrial problem may not appear in the genetic code. Research noted “most ASD/MD cases (79%) were not associated with genetic abnormalities (199).”
Although evident mitochondrial dysfunction exists in just a small subset of ASD people, many more ASD people have less obvious mitochondria problems caused by too many reactive oxygen species. Mitochondrial dysfunction “may be one of the most common medical conditions associated with autism (200).” Many ASD people might have changed metabolism and inefficient mitochondria (201). Others note dysfunctional fatty acid metabolism in ASD people (202). Research also found phospholipid biomarkers, indicating impaired mitochondrial fatty acid oxidation (203).
Excess reactive oxygen species damage mitochondria and cause mitochondria inefficiency. As mentioned, too many reactive oxygen species diminish glutathione levels in the cells. Low glutathione can lead to mitochondria degeneration (204). This causes problems with energy production in mitochondria.
There is more data indicating mitochondrial problems in ASD people. Researchers found an elevation of aspartate aminotransferase in 38% of ASD patients compared with 15% of controls. The same study also found abnormally high serum creatine kinase in 47% of ASD patients (205). In addition, research notes the “extensive abnormalities in specific enzyme activities, mitochondrial structure, and mitochondrial DNA integrity” in those with hypotonia, epileptic seizures, autism, and developmental delay (206).
Researchers also found that 5 of 11 ASD patients classified as having a mitochondrial respiratory chain disorder (207). In addition, researchers found elevated plasma pyruvate levels in ASD children compared with controls, which can be consistent with less pyruvate dehydrogenase activity. The researchers also noticed that ASD children had higher concentrations of hydrogen peroxide, a reactive oxygen species (208). These studies indicate there are problems with energy production in some ASD people.
It is important to know that mitochondrial dysfunction is often not obvious. Therefore, seeing various mitochondria problems depends on parameters used in future research. Less obvious mitochondrial problems are widespread in many health conditions and do not appear on most tests.
Like ASD, metabolic problems exist on a spectrum, some are minor, and others severe. Future researchers should focus more on the less obvious mitochondria issues and reactive oxygen species damage because these conditions affect many people.
Many factors increase the generation of reactive oxygen species, which creates the mitochondrial inefficiency that affects so many people. Mineral deficiencies, pollution, nutrition quality, lifestyle habits, refined carbohydrates, and psychological stress are factors that create too much inflammation and overwhelm the body.
Importantly, neurodegenerative diseases associate with mitochondria problems (209). Mitochondria also likely need consideration in any patient with an unexplained multisystem disorder (210). The condition of mitochondria affects many different health conditions since they are a major source of damaging reactive oxygen species.
This chapter now discusses some of those other health conditions. ASD is still the primary focus of this book and gets more attention in other chapters.
Inefficient Weight
Mitochondria inefficiency strongly affects three common health conditions: obesity, diabetes, and high cholesterol.
If mitochondria cannot metabolize the glucose efficiently because of excess reactive oxygen species, then the liver transforms some of the excess glucose into fat and packs this fat into low-density lipoproteins (LDL) for transportation elsewhere, mainly to fat cells. Transforming glucose into fat increases LDL cholesterol levels, raising the risk of heart attacks when glucose and inflammation oxidize LDL and create plaques in arteries.
Mitochondrial inefficiency also causes type 2 diabetes. This is because mitochondria do not want to metabolize glucose when there are already too many reactive oxygen species inside of the mitochondria. These reactive oxygen species can interfere with insulin signaling, resulting in insulin resistance, limiting the ability of cells to absorb glucose.
This is a purposeful design to prevent cell destruction due to an overwhelming amount of reactive oxygen species. Therefore, healing type 2 diabetes depends on reducing inflammation throughout the body and improving the health of mitochondria.
Besides simply overeating, mitochondria inefficiency also causes obesity. This is because inefficient mitochondria become resistant to both glucose and fat metabolism. Instead, this unused energy gets redirected to storage as fat. Energy redirection is the main cause of the powerful hunger and fatigue experienced by some obese people.
Importantly, inflammation often happens before obesity. Researchers found an “increase in inflammatory mediators or indices predicts the future development of obesity and diabetes (211).” Also, inflammatory-sensitive plasma proteins correlate with future weight gain (212).
Therefore, losing weight may depend on reducing inflammation and improving mitochondria efficiency. Although consuming too many calories is an obvious cause of weight gain, simplistic calorie counting often does not work because inflammation and mitochondrial inefficiency are the actual problems for most obese people. A reason obese people often overeat is because energy redirection makes their bodies not have direct access to enough energy.
Limited
As previously discussed, the body can purposefully limit various functions to protect itself from worse situations. For example, the body can limit metabolism to slow down the generation of reactive oxygen species. When there are not enough antioxidant defenses to control the number of reactive oxygen species, then the body sometimes attacks itself and targets functions affecting metabolism.
This is one reason for autoimmune attacks on the thyroid gland, which affects the speed of metabolism in the body. By attacking the thyroid gland, the body is attempting to limit metabolism when there is too much inflammation. As discussed, metabolism is a massive source of oxygen species.
To support this idea, thyroid hormone production needs zinc and magnesium, which inflammation depletes. By including these minerals in the making of a hormone that raises metabolism, the body has a purposefully designed function that helps limit further inflammation.
Other autoimmune diseases might also be an attempt to limit inflammation. For example, type 1 diabetes is an autoimmune condition where the body destroys the cells that produce insulin. As mentioned, insulin increases the metabolism of glucose, which increases reactive oxygen species creation. By limiting insulin production, the body is attempting to reduce this inflammation associated with glucose metabolism. However, in the modern world, attacking insulin-producing cells causes more harm than good because there are so many foods that rapidly raise blood glucose levels.
Another example of a potential purposeful health condition is multiple sclerosis. In this condition, the immune system damages the myelin sheaths that insulate nerves. In health, the insulation provided by the myelin sheath helps the nerves send electrical signals to each other. As an analogy, think about the coating around a common electrical cord. Damage to the myelin sheaths limits the ability of the nervous system to send electrical signals, which reduces the activity of the areas controlled by the damaged nerves. This reduced activity may limit some of the inflammation associated with metabolism.
Of course, this health condition is not desirable, and often still has high levels of inflammation. However, damaging the myelin may prevent much worse inflammation from occurring sooner.
As with many health conditions, the secret is to reduce inflammation at the source. Some of these sources are incorrect nutrition, pollution, lack of exercise, and stress. After inflammation reduces, the attacks on myelin may stop because the brake is no longer necessary.
Red Flag
Interestingly, other autoimmune diseases, with outward skin manifestations and painful symptoms, might serve as a signal, a red flag, that a problem is happening in the body. Perhaps in the past, this signal resulted in lifestyle changes, such as eating different foods or moving to another environment. These changes might then reduce the inflammation causing the health condition.
It is an important fact that autoimmune diseases affect women more than men. These diseases are more common in women because women have a much stronger immune system than men. Typically, a woman’s immune system has a more powerful inflammatory response and a better ability to regulate the response. This improves the ability to destroy pathogens, increasing her ability to protect her pregnancy. Because of the increased regulatory immune cells in women, their immune systems attempt to find more creative solutions to stop the chronic inflammation. One of those creative solutions is to attack various parts of the body to stop worse inflammation from happening.
Remember, even if an autoimmune condition does not directly limit metabolic activity, the condition increases the likelihood of changing behavior harmful to health.
Like many other health conditions, healing autoimmune disease depends on reducing inflammation from multiple sources, such as the hidden psychological stress caused by emotional suppression.
Cancer
Another disease that may provide a temporary benefit is cancer. Research noticed many decades ago that cancer cells frequently had altered energy production, favoring anaerobic glycolysis, and the very rapid consumption of glucose despite having functional mitochondria (213). More recent researchers found an association between higher fasting blood glucose and increased incidence of multiple types of cancer (214). Also, diabetes and hyperglycemia are “associated with an elevated risk of developing pancreatic, liver, colon breast, and endometrial cancer (215).” A study found hyperglycemia to be a predictor of reduced chances of surviving various cancers (216).
Leukemia, a type of blood cancer, can even cause serotonin loss and incretin inactivation to limit insulin secretion, which could further suppress glucose entry into normal cells (217). Research found elevated expression of a glucose transporter and sensitivity to a glycolysis inhibitor in childhood acute lymphoblastic leukemia cells (218). Also, a risk score based on a distinct glucose metabolism signature correlated to the poor survival of individuals with acute myeloid leukemia (219).
Amazingly, out of “26,743 total cancer deaths in men and women, 848 were estimated as attributable to having a fasting serum glucose level of less than 90 mg/dl (220).” That means that less than 4% of cancer deaths associate with a low fasting blood glucose level. Therefore, cancer has an important relationship with glucose that requires further investigation.
The temporary benefit of most cancers is they rapidly remove excess glucose from the bloodstream. Cancer cells accomplish this removal by depending on glycolysis, even in aerobic conditions. Usually, normal cells only depend on glycolysis when there is not enough oxygen to use the aerobic energy production ability of the mitochondria.
By depending on glycolysis for energy production, even in aerobic conditions, cancer cells need about 19 times “more glucose uptake to obtain equivalent amounts of energy as normal cells (221).” This removes more glucose from the bloodstream at a quicker rate. Researchers note that “a near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging (222).”
Amazingly, most cancer cells consume glucose at such a high rate that doctors use specific trackable glucose and positron emission tomography (PET) scans to locate the tumors by following where the glucose is going.
This removal of glucose by cancer cells is useful because too much glucose in the blood can cause a lot of damage. For example, excessive glucose in the blood can glycate LDL cholesterol, making the LDL much more vulnerable to oxidation (223). Both oxidized and glycated LDL can contribute to atherosclerosis, the buildup of plaque in the arteries (224).
Increased plasma levels of oxidized LDL were found to be one of the strongest predictors of acute coronary heart disease (225). Other researchers found inflammation raised heart disease risk (226). There is also an association between multiple glucose-related factors and an elevated risk of heart disease (227). The impact of glucose on heart disease is also important because heart disease increases the risk of having heart attacks.
As an important side note, some types of contraceptives raised glucose levels following a glucose tolerance test (228). Research found an association between high estrogen levels and more insulin resistance in vitro (229). Therefore, be cautious when selecting contraceptives.
Glucose in the bloodstream also leads to the formation of advanced glycation end-products (230). These activate AGE receptors (RAGE), further increasing inflammation (231) (232).
Multiple researchers also note the association between diabetes, a condition of excess blood glucose, and heart disease risk (233) (234) (235). Diabetes also increases the risk of stroke (236).
These examples are but a small representation of the link between excess glucose in the blood and serious health problems. By removing large quantities of glucose from the bloodstream, many cancers are providing additional time to correct problems with inflammation, metabolism, and nutrition.
Whereas most cancers provide this extra time, high blood glucose levels can cause immediate critical damage, like strokes or heart attacks, resulting in sudden death.
In the evolutionary history of humans, continual sources of foods that spiked blood glucose levels were uncommon. There were periods of higher glucose availability, such as the periodic fruiting of wild plants and occasional heavy dependence on roots. However, most of the time, there were no foods that skyrocketed blood glucose levels. In that situation, cancer may have simply come and gone in vulnerable individuals, as glucose availability naturally shifted with the seasons. In the past, most cancers were rare anyways because of the active lifestyles and food quality available to ancient humans.
Unfortunately, in modern society there is constant access to refined foods that rapidly increase blood glucose levels. This raises insulin levels, which limits fat metabolism, causing cells to excessively metabolize glucose. This increases reactive oxygen species generation, damaging the mitochondria and worsening inflammation. Cancer is not designed to manage the modern-day continual access to refined carbohydrates. Therefore, many cancers are now deadly, which is especially influenced by the higher levels of chronic psychological stress in the modern world.
Interestingly, cancers tend to appear where there was a past injury or infection. This is because both conditions increase inflammation and damage normal cell function in a specific area of the body. The damaged cells cannot metabolize efficiently, leading to higher levels of glucose around the area of damage. This damaged area also has increased inflammation, which affects cancer by slowing the methylation cycle, activating cancer-promoting genes already built into the DNA.
Even in a situation of injury or infection, cancer may be simply stepping in to help reduce the excess glucose until metabolism improves and inflammation drops. Once the original problem heals, then cancer may slowly disappear as the healed regular cells take the glucose away and the methylation patterns shift due to reduced inflammation.
If many cancers thrive on glucose, then a ketogenic diet, which is low in glucose, might have anti-cancer effects. A review noted that 72% of animal studies found evidence for an anti-tumor effect on ketogenic meal plans (237). Other researchers also note that keto diets may reduce tumor growth (238). In contrast, increased intake of high glycemic foods that spike blood glucose associate with a higher risk of multiple cancers (239).
Ketogenic diet applications for cancer need to be aware of both protein and phytochemical intake. Some ketogenic followers eat excess protein rather than eating more fat. Research, which did not look at the ketogenic diet, found low protein intake associated with a lower risk of cancer if the individual was under 65 years of age (240). The same research found protein did not have that effect in people over 65 years old (240).
This difference could relate to higher insulin-like growth factor 1 (IGF-1) levels at a younger age. Increased protein intake amplifies IGF-1 activity and increases cell growth, which can cause cancerous cells to grow. Therefore, not eating too much protein may help lower cancer risk.
IGF-1 also negatively affects autophagy, which is a self-eating process performed by the cells. Autophagy often improves metabolic efficiency because cells eat the most inefficient and damaged parts of themselves. Autophagy is critical because inefficient cell components, especially inefficient mitochondria, increase inflammation and the risk of many health problems. There is further discussion of autophagy later.
The other consideration on a ketogenic diet is consuming plenty of phytochemical-rich foods. Inexperienced people begin the high-fat food plan and remove many plants that have beneficial phytochemicals. Vegetables, such as the dark green leafy types, are the most critical part of any food plan because of their impressive phytochemical and mineral content.
In general, the ketogenic approach may be most helpful when protein consumption is moderate, and dark green leafy vegetable intake is high. Adding various spices may also benefit health because of their phytochemical content.
Unfortunately, because of the technology-driven trend to focus on genetics, the view of many people is that genetic mutations cause cancer. They think most types of cancers are primarily because of genetic inheritance. People often declare they simply have the wrong genes and suspect an inherited cancer is only a matter of time. However, “the vast majority of human cancers show no obvious familial inheritance (241).”
Many people that excessively focus on genetics may also believe the increased glucose uptake of cancer is a side effect of these genetic changes. However, research has found a “direct role of increased aerobic glycolysis in inducing the cancer phenotype (242).” The increased uptake of glucose occurs before many cancers start to grow.
Despite frequently still having functional mitochondria that can create much more energy than glycolysis, many cancers will over activate glycolysis to rapidly metabolize glucose for energy. As mentioned, the rapid metabolism of glycolysis allows cancer cells to quickly remove glucose from the blood, which may help protect the body from an immediately worse health problem.
Rather than the old paradigm of most cancers occurring due to accidental genetic mutations, this new paradigm sees most cancers, not all cancers, as having a purposeful and temporarily helpful function. This function is the removal of glucose from the blood when there is too much inflammation and inefficient metabolism.
Typically, the metabolic problems occur because of excess reactive oxygen species caused by many different factors, such as injury, infection, pollution, psychological stress, and consuming too many refined carbohydrates. These problems are usually present for a long-time for cancer to develop to the point of symptoms and seeing cancer on medical scans.
However, the purposeful design of cancer is not meant for an environment that has continual access to foods that spike blood glucose levels. Stopping refined carbohydrate and processed food consumption is critical for reducing inflammation and cancer risk.
In addition, psychological stress, even if hidden from the conscious mind, also needs healing. This is because stress powerfully affects inflammation. Unfortunately, stress if often ignored since stress can hide from awareness and involve confronting intense energy and emotions. Do not overlook the importance of reducing psychological stress.
As mentioned, inflammation and reactive oxygen species can lead to mitochondria inefficiency, which often causes insulin resistance and higher blood glucose. If inflammation raises blood glucose levels, and glucose feeds most cancers, then inflammation increases cancer risk.
If there is a link between cancer and inflammation, then males will have an increased risk of cancer because the male immune system is more pro-inflammatory than the female immune system, which has more self-regulation. Unsurprisingly, males have a higher rate of cancer than females (243).
Another critical indication of the link between cancer and inflammation is many localized infection-based cancers may start due to inflammation caused by the infection (244) (245) (246) (247) (248) (249). Also, serum high-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, correlated with cancer risk (250). In addition, “in most cancers, chronic inflammation precedes tumorigenesis (249).”
Amazingly, researchers report “only 5-10% of all cancer cases can be attributed to genetic defects, whereas the remaining 90-95% have their roots in the environment and lifestyle (249).” This is critical because an individual can change multiple environmental and lifestyle factors that reduce inflammation and cancer risk.
Inflammation can also increase cancer risk via epigenetic modifications. As mentioned in Chapter 3, inflammation slows down the methylation cycle in multiple ways, such as disabling enzymes and redirecting cysteine to produce glutathione, which is a powerful antioxidant.
The methylation inefficiency can limit the methylation of genes that control cancer. The reduced methylation of genes is known as hypomethylation. Researchers note a hypomethylation of genes that promote cancer (251). Also, reduced methylation is present in almost all types of human tumors (64).
Importantly, cancer severity correlated to the amount of hypomethylation (252). This means cancer was more severe when there was less methylation. Other researchers also report global DNA hypomethylation in association with cancer, remarking that “unlike genetic alterations, DNA methylation is reversible (253).”
Interestingly, amongst global hypomethylation, there is usually also hypermethylation of specific DNA sections. Research found hypermethylation of tumor suppressor genes (254) (255). Currently, many cancer researchers focus on this limited and specific hypermethylation.
However, this hypermethylation potentially happens as an indirect consequence of the initial, and more common, hypomethylation (252). Research notes “there is often more hypomethylation than hypermethylation of DNA during carcinogenesis, leading to a net decrease in the genomic 5-methylcytosine content (256).” There is also the likelihood something still unknown about tumor suppressor genes makes these areas more susceptible to hypermethylation amongst the more common hypomethylation pattern.
Perhaps CpG islands affect the specific hypermethylation seen amongst the more common global hypomethylation. CpG islands have a unique DNA arrangement that might attract superoxide, a reactive oxygen species, which has nucleophilic properties. Superoxide, acting as a signaling molecule, may affect DNA in a manner that encourages methylation (257). This may occur in specific areas of DNA and lead to site-specific hypermethylation.
Importantly, other reactive oxygen species can also cause specific hypermethylation (257). Therefore, reactive oxygen species explain both cancer features; the frequent global hypomethylation and the limited but targeted hypermethylation of tumor suppressors.
The ability of inflammation to cause hypomethylation is an elegant design. There are unmutated genes built into DNA that promote the growth of cancer, but an efficient methylation cycle usually keeps these genes turned off. Chronic inflammation can cause the hypomethylation of these cancer-promoting genes, which turns these genes on. This prepares the body to create cancer around the time that normal cells have become resistant to glucose because of the same chronic inflammation.
As discussed, excess reactive oxygen species can damage the ability to metabolize glucose, leading to insulin resistance and higher blood glucose levels. Excess reactive oxygen species also disable methylation cycle enzymes, causing the methylation cycle to slow down and become inefficient. Therefore, too many reactive oxygen species first cause chronic inflammation, antioxidant depletion, and sustained methylation cycle inefficiency before many cancers start to grow.
Chronic inflammation also limits immunity. This affects cancer because many cancer cells are normally found by a well-functioning immune system and destroyed. If the immune system is limited, then cancer cells grow more easily and can hide from the weakened immune system.
If inflammation causes most cancers, then reducing the inflammation using many nutrition and life changes may stop most cancers.
For example, eating low-glycemic plants that have many nutrients and phytochemicals may reduce inflammation and increase methylation cycle efficiency. Also, eating more healthy fats gives cells an energy source that makes fewer reactive oxygen species than glucose.
Also, making sure to fulfill all daily nutrient requirements by tracking food intake supports enzyme essential for antioxidant defenses and detoxification. These steps and many others reverse overall DNA hypomethylation and reduce blood glucose levels.
Regular exercise, improving sleep, periodic fasting, and caloric restriction also reduce inflammation and help stop cancer.
However, psychological stress is one of the most critical problems that needs improvement to reduce cancer. This is difficult, as cancer is a stressful condition because of pain and confrontation with mortality. There is further discussion about psychological stress later.
As this book hopefully makes clear, reducing chronic inflammation and getting quality nutrition may be the key to improving not only cancer, but also many other health conditions, including difficult ASD symptoms.
Unfortunately, many modern societies have multiple risk factors that increase inflammation. A few of these factors are excess refined carbohydrate consumption, not enough dark leafy green vegetables, eating throughout the day, not exercising, too much psychological stress, using lights late at night, and not sleeping enough.
All these risk factors were not a consistent problem for our ancient ancestors. As simply part of natural living, they consumed low glycemic load whole food, periodically fasted, frequently exercised, and ate plenty of animal fat. Critically, they also ate many fresh, phytochemical-rich vegetables. This ancient lifestyle balances inflammation and maintains mitochondria efficiency.
Improving Mitochondria
A big secret to improving health is better mitochondria. One frequently overlooked way to enhance mitochondrial efficiency is meditation. When done with specific breath styles, meditation greatly improves breathing patterns to better oxygenate the body. Many people do not breathe deeply and evenly enough to be well-oxygenated. Breathe is much better for the body when it comes from the nose and not the mouth.
Not having enough oxygen negatively affects metabolism and increases inflammation. Oxygen is necessary for the mitochondria to produce energy most efficiently. A lack of oxygen causes there to be more glucose metabolism via the glycolysis pathway, which is inefficient and results in a more imbalanced NADH/FADH2 ratio.
Meditation also reduces psychological stress, which can lower inflammation and improve mitochondria efficiency. There is more information about the dangers of chronic psychological stress and the benefits of meditation later.
Another way to benefit mitochondria and energy creation is to increase the ratio of NAD+/NADH. A higher ratio is a signal to the body that energy production capabilities are inefficient. This signal can lead to the creation of new, more efficient mitochondria.
Because of the importance of NAD+, research has been investigating supplements, such as nicotinamide riboside (NR), to increase the levels of NAD+ and stimulate health improvements (258). Unfortunately, there is not as strong of a focus on researching lifestyle changes that reduce both inflammation and the NAD+/NADH ratio.
Mitochondria inefficiency is the primary reason for a low NAD+/NADH ratio to begin with. If mitochondria have too many reactive oxygen species, then they can increase reactive oxygen species production by slowing complex I with various other molecules.
A potential example of this process is the tau tangles associated with Alzheimer’s disease. Researchers found that tau may inhibit complex I in transgenic Alzheimer’s disease mice (259). This inhibition could be a purposeful way to increase the rate of superoxide generation at complex I and speed up removal of inefficient mitochondria.
Also, mitochondria can inhibit complex I activity during glutathione depletion by using nitric oxide. Researchers noted dopaminergic cells use nitric oxide to inhibit complex I when glutathione levels are low (260).
Again, these blocking actions increase reactive oxygen species production from complex I. This may help signal autophagy to remove those damaged mitochondria. Also, limiting complex I raises inflammation for various other purposes.
In general, inhibiting complex I causes an accumulation of NADH and a lower NAD+/NADH ratio because more NAD+ remains in NADH form. This excess NADH can overcharge complex I, causing electron leaks that create significantly more superoxide, a reactive oxygen species. A study found the “ratio and concentrations of NADH and NAD+ determine the rate of superoxide formation (261).”
Interestingly, a review noted how ASD people tended to have a lower ratio of NAD+/NADH (262). This ratio is lower in many ASD people due to inflammation and inefficient mitochondria.
The most natural way to improve the NAD+/NADH ratio is fasting, which limits the generation of more NADH. This also allows the electron transport chain to use the backed up NADH supply, turning them back into NAD+.
Having a fasting period lasting 36 to 48 hours once every two weeks also improves the repair processes throughout the body. During fasting, the body switches from metabolizing glucose to metabolizing fat for energy to conserve glycogen stores (263).
Increased fat metabolism reduces inflammation because of the much lower NADH/FADH2 ratio that is generated. As discussed, more FADH2 and less NADH reduces the activation of complex I. Less NADH creation also leads to higher NAD+ levels, increasing the creation of new, more efficient mitochondria.
In addition, fasting activates the important enzyme adenosine monophosphate-activated protein kinase (AMPK). Fasting activates AMPK by raising the ratio of adenosine monophosphate (AMP) to adenosine triphosphate (ATP). This AMP/ATP ratio is like the NAD+/NADH ratio since both ratios are signals that there is not enough energy generation ability. These signals tell the body to enhance overall metabolic ability by creating new mitochondria and destroying old, inefficient mitochondria. Upgrading mitochondria dramatically improves energy and reduces inflammation.
Higher NADH levels inhibit AMPK, while higher NAD+ levels activate AMPK (264). Activation shifts metabolism to more fat metabolism and less glucose metabolism (265). As discussed, increased fat metabolism reduces the number of reactive oxygen species generated by the mitochondria.
Unsurprisingly then, AMPK has an anti-inflammatory effect. Research reported AMPK inhibited IL-6, a major inflammatory molecule (266).
Importantly, exercise can activate AMPK (267). Curcumin can also activate AMPK. Research found that in human hepatoma cells, curcumin activates AMPK at 400 times a greater rate than metformin (268).
Fasting frequently occurred in the past when resources were limited, and hunting was unsuccessful. Therefore, the design of the human body is to not eat for a few days each month.
Fasting has multiple health benefits, such as protecting against “obesity, hypertension, asthma and rheumatoid arthritis (269).” Restricting calories may even enhance the effectiveness of cancer chemotherapy (270) (271). In general, fasting reduces the chronic inflammation that is causing many different health conditions.
However, fasting is dangerous if already in a weak state of health. Therefore, having the guidance of a medical professional when fasting is important. Some people first need to improve overall health by using nutrition and life changes before fasting for longer periods of time.
In addition to fasting for 36 to 48 hours every two weeks, another way to improve overall health is to only eat food within an 8-hour window every day. This is known as intermittent fasting or time-restricted eating.
An example of intermittent fasting is eating a large breakfast at 8 am, a big lunch around 2 pm, and no food after 4 pm. Also, any snacking should only happen within the 8-hour window to maximize the metabolic upgrades.
Amazingly, intermittent fasting regimens “induce the coordinated activation of signaling pathways that optimize physiological function, enhance performance, and slow aging and disease processes (272).” Other researchers note time-restricted eating has many health benefits (273) (274) (275). Circadian rhythms affect these benefits. The rhythms of nature influence the rhythms of the human body.
Circadian rhythms affect up to 20 percent of the human metabolome (276). Insulin sensitivity varies by time of day so much that there is a phenomenon known as afternoon diabetes (276). Many organs in the body operate on rhythmic cycles and function best at specific times in the day (277). Intermittent fasting synchronizes these rhythmic cycles, leading to better overall function and health.
Although glucose metabolism is more inflammatory than fat metabolism, all metabolism creates reactive oxygen species in varying amounts. Eating too frequently does not allow the body to adequately rest from this damaging process and make important repairs. Regularly skipping dinner and instead having a much bigger breakfast and lunch to fulfill nutrition needs gives the body more time to do some repairs. In addition, periodic water-only fasts for 36 to 48 hours greatly improves the repair process and reduces inflammation.
However, the best way to improve mitochondria function is improving nutrition. Avoiding processed foods, refined carbohydrates, sugar, and polluted meats reduces inflammation and protects mitochondria health.
Instead, eating healthy fats, quality grass-fed meats, phytochemical-rich vegetables, and fulfilling all nutrient requirements dramatically benefits mitochondria health and many different health conditions.