Alzheimer’s disease (AD) is the most common cause of dementia and results from chronic neurodegeneration as we age. Alzheimer’s amyloid plaques and neurofibrillary tangles (NFTs) aggregates of hyperphosphorylated tau protein are primary markers of Alzheimer’s disease. However, several pathological studies failed to demonstrate an increase in amyloid plaques and NFTs in the brains of AD patients with type 2 diabetes (T2DM) as compared to AD patients without T2DM PMID:194984
In addition to plaques associated with AD, there is also reduced mitochondrial function leading to insulin resistance and inflammation in the brain. Recent evidence points to alterations in the function of neural circuits and mitochondrial homeostasis in AD PMCID:PMC3026092. Aging and Alzheimer’s disease cause disruption in cellular energy metabolism, increase reactivity of cell membranes and result in release of toxic substances which overwhelm compensatory mechanisms. As a result, neuronal microcircuits and brain networks become dysfunctional. Diabetes can lead to accelerated cognitive aging and Alzheimer’s disease through high insulin levels which stimulate metabolic and mitochondrial alterations in the brains of animals with cognitive impairment like AD. PMCID: PMC2703480
Studies link Metabolic Syndrome X (Mitochondrial Disease) to aging changes in brain DNA and mitochondrial function. PMCID: PMC3155249 along with abnormal cognition and neuronal changes. Diabetes reduced memory and new brain cell formation in both insulin deficient rats and insulin resistant mice. The adrenal steroid corticosterone is a glucocorticoid and plays an important role as a mediator of diabetes and Metabolic Syndrome X. At high levels glucocorticoids inhibit insulin receptors and reduce glucose utilization in neurons. Lowering corticosterone levels prevents the diabetes induced impairment of learning and memory in insulin deficient rats and insulin resistant mice. Lowering corticosterone levels in diabetes can restore behavioral function on tasks that recruit both new and mature neurons PMCID: PMC404114.
The ketogenic diet is the most notable example of a dietary treatment with proven efficacy against a neurological condition. The high-fat, low-carbohydrate ketogenic diet is used in patients with medically intractable epilepsy. While the mechanisms through which the diet works remain unclear, there is now compelling evidence that its efficacy is likely related to the normalization of aberrant energy metabolism. PMCID: PMC3321471by allowing the brain to utilize ketones instead of glucose to restore mitochondrial function. The brain still needs glucose, but much of the brain’s energy can be supplied by ketones, so the requirement for glucose is less. In AD neurons lose the ability to use glucose efficiently as a fuel. An energy crisis occurs as connections enlarge, the synapses atrophy and the cells starve. Blood tests may show normal blood glucose and normal hemoglobin A1C because of very high insulin. Alzheimer’s patients may show a normal glycemic response on the blood labs, but have an abnormal insulin response in the brain. Only a PET scan will show the cerebral uptake of glucose.
ALZHEIMER’S DISEASE AND DIABETES
Little is known about the mechanistic between Alzheimer’s disease (AD) and diabetes with altered metabolism, inflammation, and insulin resistance being key features of both diseases. Brain insulin dysfunction is begins at a molecular level and abnormal insulin signaling results in synaptic failure and memory decline PMID:24529521.
Insulin is best known as a hormone secreted by the pancreatic β-cell hormone in response to elevated plasma glucose after meals. Insulin stimulates glucose uptake by adipose and muscle tissue, and inhibits free fatty acid released by adipose tissue and glucose production by the liver. However, insulin is also synthesized in brain neurons PM ID:8132571.
Type 2 diabets (T2DM) is caused by peripheral insulin resistance in the body. We now know that insulin resistance also occurs in the brain in T2DM. T2DM may increase the risk for dementia and AD through brain insulin resistance that induces abnormal hyperphosphorylation of the protein tau PMID:19498432. The most immediate cause of brain insulin resistance in AD appears to be amyloid-β-triggered microglia release of proinflammatory cytokines, which inhibit insulin signaling PMCID: PMC4465775. Peripheral insulin resistance due to obesity and diabetes exacerbates brain insulin resistance in AD PMCID: PMC4484598 .
NEW APPROACHES TO ALZHEIMER’S DISEASE TREATMENT AND PREVENTION
Amyloid protein is normally found in the brain, but is degraded and not allowed to build up in AD. Over time, the accumulation of amyloid interferes with neuronal signals leading to cognitive decline. Insulin-degrading enzyme (IDE) is a major enzyme responsible for insulin degradation. In addition to insulin, IDE degrades many targets including beta-amyloid peptide. IDE represents a pathophysiological link between type 2 diabetes (T2DM) and late onset Alzheimer’s disease (AD) PMID:27320287. The amyloid is not really the cause of the AD, but is involved as part of the overall picture as AD develops.
AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis and a central player in glucose and lipid metabolism, implicated Alzheimer’s disease (AD). AMPK activity decreases in AD brain, indicating decreased mitochondrial renewal and function. AMPK is associated with β-amyloid protein (Aβ) generation and tau phosphorylation. AMPK activation has non-neuroprotective property and may lead to detrimental outcomes, including Aβ generation and tau phosphorylation. Therefore, it is still unclear whether AMPK could serve a potential therapeutic target for AD, and hence, further studies will be needed to clarify the role of AMPK in AD. PMID:22367557
The sirtuins are a family of enzymes involved in many fundamental cellular processes including gene silencing, DNA repair, and metabolic regulation: PMC4203689 The name Sir comes from the description of the action of the yeast gene ‘silent mating-type information regulation of the gene responsible for cellular regulation’.
Resveratrol, a compound found largely in the skins of red grapes, increases mitochondrial function and ATP production through its effect on gene for making sirtuins, SIRT1. Moderate doses of resveratrol stimulate AMPK and improve mitochondrial function. A high dose of resveratrol activates AMPK in a SIRT1-independent manner, demonstrating that resveratrol dosage is a critical factor. Moderate doses of resveratrol are advised as high doses of (≥50 mg) resulted not only in SIRT1-independent activation of AMPK, but toxic effects include a dramatic reduction in mitochondrial membrane potential and cellular ATP levels. PMCID: PMC3545644
The loss of synaptic space between neurons is one of the major pathological hallmarks associated with Alzheimer’s disease (AD) underlying memory impairment. Increasing the brain’s magnesium by magnesium-l-threonate reduces pathologies and cognitive deficits in a mouse model of AD. Magnesium L-Threonate form of magnesium reduces the formation of amyloid plaques. Elevation of brain magnesium related to substantial protective effects in the synaptic space in a mouse model of AD and may have therapeutic potential for treating AD in humans. PMID:23658180
CANCER AS A MITCHONDRIAL DISEASE
The current theory that cell damage to nuclear chromosomes by mutations in the genomes causes cancer has been overturned. Current dogma states that “Cancer is a genetic disease—that is, it is caused by changes to genes that control the way our cells function, especially how they grow and divide” (http://www.cancer.gov/cancertopics/what-is-cancer).
Although cancer metabolism is receiving increased attention, cancer is generally considered a genetic disease New evidence suggests that cancer is a mitochondrial metabolic disease (Hanahan & Weinberg, 2011). Research demonstrates that cancer is a result of damage to the mitochondria in the cytoplasm of the cell rather than from damage to the genome in the nucleus. Damage in nuclear DNA of tumor cells is a result of the disturbances in energy metabolism and disrupted cellular respiration. (Hu et al., 2012) Metabolic changes and reactive oxygen species are the source of stress in cancer cells, promoting tumor development. (Pedersen, 1978)
Otto Warburg first proposed that all cancers originate from dysfunctional cellular respiration. (WARBURG, 1956). Cancer can be linked to impaired mitochondrial function and energy metabolism. Aerobic fermentation utilized by tumor cells results from abnormalities in both the content and composition of their mitochondria. (Fiske & Vander Heiden, 2012) linked to the discovery that ultrastructure of tumor tissue mitochondria differs markedly from the ultrastructure of normal tissue mitochondria (Seyfried & Shelton, 2010). These findings support Warburg’s central hypothesis that respiration is insufficient in tumor cells. (Ferreira, 2010)
Ketogenic diets are being considered in the treatment of disease from cancer to mitochondrial disease. Ketogenic diets are composed of high fat, moderate protein and low carbohydrates, which favor mitochondrial respiration rather than glycolysis for energy metabolism (Branco et al., 2016).
“Mitochondria are the energy-producing organelles of the cell, generating ATP via oxidative phosphorylation mainly by using pyruvate derived from glycolytic processing of glucose. Ketone bodies generated by fatty acid oxidation can serve as alternative metabolites for aerobic energy production. The ketogenic diet, which is high in fat and low in carbohydrates, mimics the metabolic state of starvation, forcing the body to utilize fat as its primary source of energy” (Branco et al., 2016).
Malignant brain cancer persists as a major disease of morbidity and mortality despite enormous funding into research for treatments. The failure to recognize brain cancer as a disease of energy metabolism has contributed in large part to the failure in management. Brain tumor cells progress as long as long as the cancer cells have access to glucose and glutamine. The current standard of care does not block brain tumor access to glucose and glutamine. The high fat low carbohydrate ketogenic diet (KD) targets glucose availability and possibly that of glutamine when administered in carefully restricted amounts to reduce total caloric intake and circulating levels of glucose. Dietary changes are effective non-toxic therapeutic option to the current standard of care for inhibiting the growth and invasive properties of malignant brain cancer. (Seyfried, Marsh, Shelton, Huysentruyt, & Mukherjee, 2012)
NEW APPROACHES TO CANCER
Over time mitochondrial stress response leads to abnormalities in DNA repair mechanisms and to the upregulation of fermentation pathways (Guha & Avadhani, 2013). A restriction of total caloric intake reduces blood glucose and insulin levels and an elevation in ketone bodie
(β-hydroxybutyrate and acetoacetate). Most tumor cells are unable to use ketone bodies for energy due to abnormalities in mitochondria structure or function (Seyfried et al., 2012). Ketone bodies can also be toxic to some cancer cells. Nutritional ketosis induces metabolic stress on tumor tissue that is selectively vulnerable to glucose deprivation (Chandra & Singh, 2011). Metabolic stress will be greater in tumor cells than in normal cells when the body switches from glucose to ketone bodies for energy. The metabolic shift from glucose metabolism to ketone body metabolism creates an anti-angiogenic, anti-inflammatory and pro-apoptotic environment within the tumor mass destroying cancer cells.
The high fat low carbohydrate ketogenic diet (KD) therapeutic strategy has been used successfully in cancer patients and in preclinical models. Whole body levels of blood glucose and ketone bodies (β-hydroxybutyrate) metabolically stress tumor cells while enhancing the metabolic efficiency of normal cells.
A protein produced in the liver called GcGoleic or GcMAF (which stands for major macrophage –activating factor /MAF) binds to vitamin D and boosts the immune system to destroy cancer cells. (Ruggiero et al., 2014)
Cancer cells and viruses produce an enzyme called nagalase that prevents the production of your own GcMAF, allowing cancer cells and other diseases to go unchecked. Increased nagalase activity is increased in the blood of patients with cancers, but not in healthy subjects (Thyer et al., 2013). You can purchase an olive oil soluble GcMAF either in a dropper bottle or as injectable vials. At www.lyranara.com.
The future of successful cancer treatment will be found in the recognition of the role of the mitochondria in the origin, management, and prevention of the disease. (Seyfried, 2015)
Mitochondrial structure, function and respiratory capacity is defective in all types of tumor cells. This information should be addressed in discussions of cancer metabolism. (Pedersen, 1978) “Non-toxic metabolic therapy should become the future of cancer treatment if the goal is to manage the disease without harming the patient” (Seyfried, Flores, Poff, & D’Agostino, 2014).
The FDA approved antifungal medicine itraconazole (Sporanox) is being studied as a treatment for cancer due to its potent anti-angiogenic activity. Clinical trials have shown that patients with prostate, lung, and basal cell carcinoma have benefited from treatment with itraconazole, along with beneficial reports of its activity in leukemia, ovarian, breast, and pancreatic cancers. (Pantziarka, Sukhatme, Bouche, Meheus, & Sukhatme, 2015). Itraconazole costs about $8 per 100 mg capsules compared to most FDA anti-cancer drugs are priced above $100,000 according to the Harvard Law website.
Studies done at Baylor University Cancer Treatment Center in Dallas, TX, have discovered that dormant tumor suppressor genes that play an important role in cancer prevention and treatment, respond to curcumin. Curcumin can not only awaken dormant tumor suppressor genes, it can also kill cancer stem cells and prevent them from cancer recurrence (Shanmugam et al., 2015).
The nutraceutical used in the tests was BCM-95 Curcumin, using a blend of curcumin and turmeric essential oils was found to be the most effective agent. For more information visit www.naturalpractiionermag.com.
According to Dr. Hans J. Kempe, winner of the Nobel Prize for the Einstein Award in 2009 for his invention of the GENO62- SONIC technology using ultrasound and digitalized energy information, the brain, glandular systems, autonomic autoregulation including the HPA axis and cell function can be restored to normal functioning. This technology is now used worldwide as an alternative treatment for cancer. Dr. Kempe spent over 20 years researching the modulation of the genetic-biophysical characteristics of the human cell.
The discovery of the 62 frequencies as cell-building blocks and the decoding of the energetic hereditary substance formula (ME) C2 of organic matter, led to the technology now used to treat many diseases including cancer. The information is sent into the cellular fluid connecting every cell within the body. The communication between the cells happens exclusively through the cell fluid. External information triggers the body to activate its internal controlling and supervision functions, including activation of its own self-repair and healing programs .The information delivered to the brain and body make it possible for the body to heal itself by making it easier for the body to track down energetic blockades or communication problems and repair them. The Foundation of Alternative Medicine, Washington, lists Professor Dr. Kempe and his GKA-System as guideline of Alternative Cancer Treatments. See more on this technology at www.lyranara.com.
The physicist Prof. Dr. Hans Kempe’s research projects answered the question about the forces which create new life and bring it into being. He drew the following conclusion:
“Only the forces which can give life, can keep it healthy.”
LOW ATP AND CHRONIC DISEASE
Symptoms of mitochondrial disease resulting in low ATP production include fatigue, a poorly functioning immune system, dementia, depression, ADD, behavior and mood swings, diabetes, skin rashes and hair loss. The production of energy for your body has far reaching implications for your health. Mitochondrial related muscle degeneration and inherited mitochondrial disease both share similar symptoms. Low ATP production, indicating mitochondrial disease, is found in Alzheimer’s, Parkinson’s, Chronic Fatigue Syndrome, many types of cancer, fibromyalgia, epilepsy and diabetes.
Conditions which interfere with the ability of the mitochondria to make energy result in a variety of symptoms. Mild versions of mitochondrial disease is often a cofactor in deafness, impaired growth, low exercise tolerance and migraine headaches. A buildup of lactic acid and free radicals, along with the lack of energy to run the cell processes, are a result of low mitochondrial function.
AMPK RESTORES METABOLIC SYNDROME
AMP-activated protein kinase (AMPK) and the histone/protein deacetylase SIRT1 are fuel-sensing molecules. When a cell’s energy state is low, AMPK activation restores energy balance by stimulating production of ATP and downregulating anabolic processes that use ATP but are not necessary for survival. AMPK and SIRT1 both regulate each other and the dysregulation of their interactions predisposes to disorders such as type 2 diabetes and atherosclerotic cardiovascular disease. Dysregulation of AMPK sets in motion changes in mitochondrial function (Strang, 1991) that could increases the ability of a cell to generate ATP and diminish oxidative stress and other potentially adverse cellular events(Ruderman & Prentki, 2004). SIRT1 and other sirtuins provide the connection between what we eat and how long we live (Arsov, Tomov, Rashkov, Iliev, & Ivanov, 1986).
AMPK RESTORES MITOCHONDIRAL DYSFUNCTION
Pathogenic factors improved by AMPK and SIRT1 are important for improving mitochondrial dysfunction. AMPK and SIRT1 act to rebalance endothelial cell function leading to arterial damage by reducing inflammation and oxidative stress.(Terada et al., 1989). Hormones such as leptin, gherelin, adiponectin, catecholamine and endocannabinoids regulate AMPK; it is AMPK which in turn mediates their actions on individual tissues and regulate whole body fuel homeostasis (Terada et al., 1989).
Regular exercise and calorie restriction have been shown to activate AMPK. Drugs such as metformin and thiazolidinediones are also used to treat metabolic syndrome (Arsov et al., 1986). AMPK is the central target for the metabolic effects of resveratrol (Um et al., 2010), as well as endothelial cell dysfunction that is generally regarded as an early manifestation of atherosclerotic vascular disease (Potente & Dimmeler, 2008). In keeping with this presumption, these treatments also have been shown to diminish the prevalence of metabolic syndrome-associated diseases, including type 2 diabetes, atherosclerosis, certain cancers and possibly even Alzheimer’s disease.
OBESITY AND MITOCHONDRIA DISEASE
Figure 4.9 Mitochondria related disorders (Adapted from (Nel, Xia, Mädler, & Li, 2006)
FATTY LIVER AND MITOCHONDRIA DAMAGE
Your liver responds to food intake that exceeds the body’s nutritional needs by storing that excess caloric load as fat.
Liver cells, hepatocytes, can become overwhelmed and are no longer able to store additional fats. Eventually caloric overload results in a fatty liver (nonalcoholic fatty liver disease = NASH).
WIMPY MITOCHONDRIA AND OBESITY
People who suffer from obesity eat more and tire more easily. Studies show that the mitochondria in obese individuals are smaller and have less content than healthy mitochondria (Kelley, He, Menshikova, & Ritov, 2002).
Mitochondria dysfunction leads to insulin resistance and fat can no longer be burned through oxidative phosphorylation. Fat now stores in the liver and around the waist. This is something most of us already knew, we just didn’t know why (C.-H. Wang, Chi, & Wei, 2012).
Skeletal mitochondria in obese individuals have reduced contents and impaired electron transport activity (Kelley et al., 2002). Muscle cells in obesity are poor fat burners and have lower energy production as a result of mitochondrial disease.
BELLY FAT AND SURVIVAL
Adipose cells are like inflatable fat silos. These fat cells can expand into storage areas such as an enlarged waistline, love handles, and unsightly pot belly. How does this happen?
First of all, fat distribution begins in the liver, your body’s powerhouse for transforming nutrients into fuel under the influence of insulin signaling. Insulin is also one of the hormones signaling adipose cells to store fat. Since your belly has the highest concentration of insulin receptors, central obesity is a big indicator of mitochondrial damage and insulin resistance, known as Metabolic Syndrome.
In the state of Montana, where I grew up, the farmers had large silos used to store grains for winter. Metabolic Syndrome is a condition indicated by an abundance of fat storage the body as the result of unhealthy mitochondria silos, much like those used by farmers to store grain.
KEEPING DOWN INFLAMMATION
Mitochondria are the energy generators in our cells, but during inflammation mitochondria switch roles and instead of making ATP they make toxic products from oxygen using an enzyme called succinate dehydrogenase, which promotes inflammation. The resulting increase in the production of reactive oxygen species can damage cell structures. (Mills et al., 2016)
The following is a list of five nutrients with known anti-inflammatory properties within white adipose tissue:
Quercetin is recognized as a superior nutrient for lowering inflammation within white adipose tissue by a variety of mechanisms, including lowering TNFa, NF-kappaB, IL-6 and MCP-a. Typical weight management dosage is 1000 mg – 3000 mg per day. Quercetin guards against excess formation of new fat cells while enhancing the death rate of old fat cells. It is also a potent antioxidant for white adipose tissue and can improve leptin resistance. Quercetin lowers insulin resistance by assisting the activation of AMPK (an enzyme metabolic master switch), which promotes fat burning.
Precautionary note: avoid quercetin if you have histamine intolerance as it contributes to rebound histamine release.
Green Tea Catechins (EGCG) – EGCG is the active compound in green tea which activates genes in fat cells that prevent excess fat accumulation. Like quercetin, EGCG also activates AMPK to boost fat burning. Typical weight management dosage is 200 mg to 600 mg of EGCG per day (approximately 1400 mg – 4200 mg of green tea, depending on extract potency). Immune cells contained in white adipose tissue exposed to EGCG begin to regulate normally, no longer behaving in an inflamed manner. EGCG helps nerve tone, including the activation of calorie-disposing brown adipose tissue. Numerous human studies show that EGCG is an excellent weight management nutrient.
Curcumin has long been recognized as an anti-inflammatory nutrient, potently reducing inflammatory cytokines including of NF-kappaB, TNFa, and MCP-1. Typical weight management dosage is 200 mg – 600 mg per day. Curcumin helps lower leptin resistance, boost adiponectin and reverse insulin resistance. It also helps turn on fat burning genes which reduces white adipose tissue.
Resveratrol activates the Sirt1 gene in fat cells that is highly synergistic with AMPK and increased fat burning. Resveratrol also helps reduce inflammation within fat cells. Typical weight management dosage is 200 mg – 600 mg per day. Resveratrol helps prevent fat accumulation, speeds the release of fat from fat cells, regulates new fat cell formation and clears out old fat cells.
DHA, an omega 3 fatty acid from fish, reduces the accumulation of fat within fat cells, prevents fat cells from expanding in size, regulates the rate of new fat cell formation, reduces inflammatory TNF-kappaB and MCP-1, lowers leptin resistance and boosts adiponectin. Typical weight management dosage of DHA is 500 mg – 3000 mg per day.
DAMAGED METABOLISM AND LOW ATP
To survive a broken metabolism related to mitochondrial damage, the body resorts to a primitive energy production system used by single celled organisms and bacteria. Cells must burn sugar to make a few molecules of ATP and the body doesn’t make enough ATP to function optimally.
Dieting and exercise alone are often not enough to reverse obesity resulting from disordered mitochondrial metabolism. If you can’t reverse this situation you are in big trouble. Exercise becomes difficult for lack of energy, you crave sugar and your body cannibalizes your muscle into sugar for fuel. Do you have these symptoms of mitochondrial damage?
- Lactic acidosis: nausea, vomiting, rapid heartbeat, fatigue, anxiety, abdominal pain, low blood pressure
- Low blood sugar
- Elevated liver enzymes such as ALT (levels over 30)
- Higher levels of conjugated bilirubin
- Elevated ammonia / liver cirrhosis
- Chronic lack of energy
- Strong cravings for sugar
Mitochondria are fragile and can be damaged by toxins. Mitochondrial toxic metals include iron (overload), manganese (overload), mercury, lead and arsenic (Ames, 2010).
Mitochondrial pharmaceutical toxins include:
- Acetaminophen irreversibly inhibits β-oxidation
- Aminoglycoside antibiotics
- Anti-retroviral drugs (NTRIs)
- Aspirin: inhibits & uncouples OXPHOS
- Cancer chemotherapy agents (platinum)
- Complex I inhibitor
- Tamoxifen: inhibits complexes III & IV
- Valproic acid: inhibits complex IV
- Statins deplete CoQ10
BAD BOYS TO AVOID
Mitochondrial dysfunction can result from a poor diet (Parikh et al., 2009). You are well advised to avoid the following if you want healthy mitochondria:
Saturated fat (Dietary fat, fatty acid saturation and mitochondrial bioenergetics (L. Yu et al., 2014).
High glycemic foods, as they create AGES, which is the acronym for Advanced Glycation End Products (Pun & Murphy, 2012).
Fructose: A high fructose diet interferes with mitochondrial ability to function properly. Fructose sugar reduces the ability of the respiratory chain complex I, needed to make ATP during fat burning in oxidative phosphorylation (Sánchez-Martín et al., 2012).
Alcohol damages mitochondria (Manzo-Avalos & Saavedra-Molina, 2010).
AUTOIMMUNE DISEASE DAMAGES MITOCHONDRIA
Immune markers that cause the body to attack itself are indicators of autoimmune disease. When antibodies attack an immune marker protein, called cardolipin, the cristae that comprise the inner folds of the mitochondria can become damaged.
Cardolipin is an important protein to not have become a target of autoimmune attack because it comprises 20% of the cristae in mitochondria, and is a protein that contributes to allowing the cristae to fold. Without healthy cristae there can be no electron transport process to make ATP.
Note the two mitochondria below showing the healthy cristae and damaged cristae:
Figure 4.10 Healthy mitochondrial and damaged mitochondria with cristae damage
Researchers have discovered that most of the time mitochondria join together to form branched networks that are constantly changing shape. In sick and dying cells, the mitochondrial network breaks down and the mitochondria take on a static bean like shape again.
In brain cells the mitochondrial form a network around the nucleus, but in order to be transported to the ends of the nerve fiber they return to the bean shape for purposes of being transported along the axons (Wellcome Trust Center, 2015).
Cristae damage, as the result of inflammatory attacks from the immune system, underlie many complex diseases related to mitochondrial disease, affecting every cell in the body relying on ATP for healing and cell processes.