Neutraceuticals: the Latency Period is Over

Twenty five hundred years ago, Hippocrates, the “father of medicine”, the namesake of the oath sworn to by new physicians, stated, “Let food be thy medicine and medicine be thy food”. Forty years ago, Linus Pauling, considered the father of modem chemistry, gave us the concept of “Orthomolecular Medicine”. Simply stated, this means that if you provide cells with the right molecules, the result will be health. As the Don McLean song about Van Gogh goes; “they weren’t listening then, they’re not listening now.” Orthodox medicine has ignored the wisdom of these sages in its insistence on the primacy of pharmaceuticals (synthetic molecules) as the only acceptable way to treat and cure diseases. Traditional medicine has been dismissive regarding the value of natural supplements in part because of educational bias, in part because of pharmaceutical influence upon media outlets, and in part because of faulty studies based on a research paradigm that insists on isolating a single factor and determining its singular effect on disease outcome. Medicine has come grudgingly to accep t the fact that diet plays a major role in the cause of degenerative disease. The question then becomes, if food and degenerative disease are related then why would there not be the same relationship between active factors in these foods and disease states both positively and negatively. If diet modification is accepted as a major underpinning of enhancing health and reducing risk of degenerative disease, then why would highly concentrated supplements of positive food factors, supported by good scientific studies, be dismissed as having no value? Perhaps the answer to this question lies in the economic interests of some of the institutional players

The reality is that cells obey all the laws of physics and chemistry. Quantum physics teaches us that the smallest sub atomic particles do not exist as discrete entities but can only be described by their relationship to neighboring particles.64 This is the universal principle of the inter-connectedness of everything. It is also the nature of the human organism. As Lester Packer stated in his seminal book on anti- oxidants, “Everything is connected to everything else”.65 The laws of chemistry are obeyed by cells that speak to each other in the language of native chemicals, hormones, enzymes, fatty acids, vitamins, minerals, amino acids and neurotransmitters. A chronic degenerative disease that has multifactorial causation, cannot be successfully addressed by a synthetic drug which acts at a single focus. The approach must be multi targeted, involve the providing of substances native to the body in varying amounts dependent upon individual biochemistry and whether the intention is prevention or treatment. There may be a role for select pharmaceuticals in this mix but it is secondary rather than primary.

The term “neutraceutical” was coined by Dr. Stephen Felice, founder of the Foundation for Innovation in Medicine. He defined a neutraceutical as a “food or parts of a food, that provide medical or health benefits, including the prevention or treatment of disease”.66 Dr. David Sample of the Harvard faculty has stated, about healthcare, “an abundance of knowledge already exists, that is not rationally applied to peoples needs”.67 The last 20 years have produced an abundance of new knowledge about the nature of chronic degenerative diseases and the role that neutraceuticals should play both in their prevention as well as treatment. The latency period needs to be declared as over and the American people should be educated by their healthcare providers how best to incorporate these food extracts into a regimen for good health maintenance.

Available Neutraceuticals:

It is not within the scope of this paper to provide in depth information about each named neutraceutical. Each of these substances has been the subject of numbers of research studies. Each will be referenced for readers who wish to learn more.

Antioxidants: Endogenous Systems

• Glutathione (GSH): The GSH molecule will not pass through cell membranes to any degree so intracellular synthesis must be facilitated. The only effective way to raise the intracellular levels of GSH throughout the body is to provide a delivery system for the amino acid L-Cysteine which is the rate limiting factor in its synthesis. The most effective way to accomplish this is to use a highly undenatured form of whey protein.55 A more common method is to supplement N-Acetyl-Cysteine (NAC) which should be dosed several times a day. Lipoic acid and vitamin C are exogenous anti-oxidants which are known to raise GSH.69 Selenium is a trace mineral which is incorporated into Glutathione peroxidase.65
• Super-Oxide Dismutase (SOD): Until the last few years SOD was only available by the intramuscular injection of Orgotein, a porcine derived SOD. Recently it was discovered that by combining SOD with a carrier protein known as Gliadin, it is able to survive the G.I. tract and enter the bloodstream.70 The Life extension product is called GliSodin. More recently it was discovered that the Chinese herb, Lyceum Barbarum, known also as Wolfberry as well as Golgi juice, has significant anti-oxidant activity in scavenging the super-oxide radical. GliSodin and wolfberry can be used synergistically71
• Catalase: There are no supplements which, as yet, deliver catalase directly into the bloodstream. There are indications that the SOD supplements mentioned above may indirectly raise catalase levels.72 Catalase is synthesized in the peroxisome within the cell. Peroxisomes are organelles within the cell. One study suggests that DHEA can act as a peroxisome proliferator and thereby increase levels of catalase.73 Another study demonstrated the fact that Nitric Oxide (NO) can increase catalase activity. This leads to the possibility that Arginine which is an NO precursor may be useful in increasing catalase activity.74

It should be noted that endogenous anti-oxidants are significantly more potent in their ability to scavenge free radicals than dietary anti-oxidants. GSH, SOD and Catalase are all associated in a linear fashion with mean life span.75 In mammals, species with the highest levels of these anti-oxidants live the longest. Their decline with aging is associated with age related degenerative processes and the development of chronic degenerative diseases.

Exogenous Anti-Oxidants

Vitamin C: Major intracellular anti-oxidant; preventive factor for heart disease, cancer, asthma; regenerates GSH and Vit. E.; associated with longevity.76,77

Vitamin E: Family of mixed tocopherols and tocotrionols; major anti oxidant in lipid medium, preventive factor for heart disease and cancer.78,79

Coenzyme Q10 (CoQ1O): (Ubiquinol) Vital anti-oxidant for mitochondrial energy generation; preventive factor for heart disease, cancer and neurodegenerative diseases, supports healthy brain function.81-83

Lipoic acid: The Universal anti-oxidant which functions in both water soluble (cell cytoplasm) and fat soluble (cell membranes) media; regenerates GSH, potentiates the effects of vitamins C and E; protects mitochondrial energy production; supports brain function.65,83

These 4 neutraceuticals along with GSH are called by Lester Packer, the “network anti-oxidants”. He uses this term because they enhance the power of one another. GSH recycles vitamin C which recycles vitamin E, Lipoic acid enhances vitamins C and E and along with vitamin C, regenerates GSH. Each has a multiplicity of effects with the end result that the whole becomes much greater than the sum of its parts. (65) There is integration and synchronization which produces the result and not the action of a single isolated unit. This is why so many of the studies on nutrients, using the typical research model which tests the actions of a single isolated unit, have produced faulty results.

Carotenoids: This group consists of about 400 different, naturally occurring plant pigments, only 30-50 of which have pro-vitamin A activity. Carotenes are associated with reduced risk of epithelial cell cancers which include, lung, skin, uterine, cervical, respiratory tract and G.I. tract84

• Alpha & beta carotene: Cancer preventive factors, enhancement of thymus mediated immune functions.84,85
• Lycopene: Potent anti-oxidant most associated with reduced risk for prostate cancer, possible preventive for breast and lung cancer, possible cardiovascular preventive.86-88
• Lutein: Preventive for age related eye diseases (cataracts & macular degeneration), anti-oxidant activity in brain, liver, lung, prostate, skin and breast, possible cancer preventive factor.89-92
• Zeaxanthin: Most significant factor for prevention of macular degeneration, possible cancer preventive factor.91-93

Flavinoids: A group of plant pigments that is responsible for the color of fruits and vegetables. They possess potent free radical scavenging potential and also function as “biological response modifiers”. They have actions which are anti-inflammatory, anti-allergic, anti-viral, and anti-cancer. Studies show that higher intakes of dietary flavinoids are associated with reduced risk of many chronic degenerative diseases. They are all variants of phenol mixtures, hence the name polyphenol might be more appropriate.94,95

• Epigallocatechin-3-gallate (EGCG): Derivative of green tea; cancer preventive factor, cell membrane protection, cardiac preventive, brain protective.96-99
• Quercetin: Anti-oxidant scavenger of hydrogen peroxide; heart disease and stroke preventive factor, neuro-protective.99-101
• Curcumin: Widely used yellow spice; powerful anti-oxidant and anti- inflammatory, cancer preventive factor, cardiovascular preventive, neuro protective factor.102-104
• Pycnogenol: From bark extract of the maritime pine tree, a powerful anti oxidant scavenger of super oxide and hydrogen peroxide, anti-inflammatory, cardiovascular preventive; helps lower blood glucose.105,106
• Berry Extracts (blueberry, blackberry, cranberry, bilberry): Potent anti oxidants, cancer preventive factors, cardiovascular preventives, neuroprotective, anti-inflammatory.107,108
• Resveratrol: Found in grapes and red wine, powerful anti-oxidant, appears to be a mimetic for calorie restriction with positive anti aging effects on gene expression, enhances mitochondrial function, cardiovascular preventive, cancer preventive.109 -111
• Pomegranite: Tropical fruit native to Asia; very powerful anti-oxidant, contains ellagic acid, a polyphenol associated with anti cancer and anti atherogenic effects, significant inhibitor of atherosclerosis, reduces risk of heart disease in Diabetics.112,113
• Melatonin: A hormone secreted by the pineal gland in the brain that regulates the biological clock, a powerful anti-oxidant with potential for both cancer prevention and treatment, brain protective 114,115

It should be noted that dietary anti-oxidants operate most effectively when synchronized in complimentary groupings. Carotenoids as well as Flavinoids are most effective in groupings which provide the benefit of synergism.

Anti-Inflammatory Neutraceuticales

Eicosopentanoic acid (EPA): Omega 3 essential fatty acid, from fish oil, precursor to the series 3 anti- inflammatory prostaglandins, cardiovascular preventive.116,117

Docosohexanoic acid (DHA): Omega 3 essential fatty acid, from fish oil, powerful anti-inflammatory, suppresses TNF-a, 1L-6, IL-lB and IL-8, supports brain function 118,119

Gamma Linolenic Acid (GLA): Omega 6 essential fatty acid, precursor to the series 1 anti-inflammatory prostaglandins, reduces inflammatory cytokines.120

Curcumin: Powerful anti-inflammatory, inhibits both cyclooxygenase and lipooxygenase, blocks activity of Nuclear Factor Kappa-B (NFK-B), cancer chemopreventive.121,122

Dehydroepiandrosterone (DHEA): Most abundant steroid hormone in the body, anti-inflammatory, lowers CrP, suppresses 1L-6 and TNF-a, cardiac protective in men, enhances immune function, counters high levels of cortisol.123-126

Cocoa polyphenols: inhibits the 5-lipooxygenase pathway, reducing the levels of pro inflammatory cytokines.127

Nettle leaf extract: Inhibits the secretion of pro-inflammatory cytokines, lowers CrP, supressess TNF-a.128

Quercetin: Inhibits TNF-a, inhibits NF-KB and histamines.129

Vitamin E: Decreases serum CrP and 1L-6.130

Vitamin K: A family of 3 variants, vit. K1, vit.K2, vit.K3 with primary functions in blood clotting and maintenance of bone density. Anti- inflammatory by reducing levels of pro inflammatory signaling molecules such as IL-6.131

EGCG: powerful anti-inflammatory, blocks cyclooxygenase-2 (Cox-2) and TNF-a.132,133

Berry extracts: (polyphenols) Block both cyclooxygenase-2 and 5-lipooxygenase, reducing levels of prostaglandin E-2 and Leukotrine B4,both powerful pro-inflammatory substances.134

Resveratrol: Inhibits Nuclear factor Kappa beta (NF-Kb) one of the major initiators of the inflammatory cascade. Major cancer preventive factor.135,136

Theaflavin: Extract from black tea, has been discovered to possess anti- inflammatory effects in its ability to regulate gene expression in the group of genes that control inflammation. Cardio protective.137

Anti-Glycation Neutraceuticals:

Carnosine: A native dipeptide synthesized in the body from the amino acids, alanine and histadine, has the ability to block the cross linking reactions between sugars and proteins. Cardio protective, neuro protective, skeletal muscle protective, helps mitigate the complications of diabetes.138

Pyridoxamine: A form of vitamin B6, can inhibit the formation of advanced glycation end products (AGE,s), acts on several stages in the development of AGE’s, protects against complications of diabetes.139

Benfotiamine: A fat soluble form of vitamin B1 (Thiamine), is able to penetrate cell membranes more efficiently than water soluble B1, supports more efficient glucose handling, blocks several pathways leading to glycation and AGE’s.140,141

It should be noted that the more serious the challenge of glycation, as in the case of exisiting metabolic syndrome or diabetes, one could use all of the anti glycation agents so as to cover the multiple pathways by which glycation takes place.

Methylation Defects Neutraceuticals:

Methyl Donors:

Methionine

S-adenosylmethionine (SAMe)

Tri-methyl glycine (TMG)

Methyl Carriers:

Folic acid

Vitamin B12 (methylcobalamine)

Vitamin B6 (pyridoxine)

Special Mention Neutraceuticals

Vitamin D3 deserves special mention as the last several years have revealed it to be an incredibly versatile protector of our health.  A recent review article in the New England Journal of Medicine reported some startling facts about vitamin D 142. After indicating that a large proportion of our elderly population are deficient regarding their vitamin D status, they showed data that revealed that much higher intakes than the standard recommendation (400 IU/day) are needed to achieve a blood level which affords many benefits among which are:  78% reduction in type 1 diabetes in children taking 2000 IU/day of vitamin D in their first year of life; 200% increase in type 1 diabetes in vitamin D deficient children; 33% reduction in type 2 diabetes with intake of 800 IU/day along with calcium; 72% reduction in the number of falls in elderly people taking higher doses; 42% reduction in multiple sclerosis in women taking more than 400 IU/day.  Most startling of all was the relationship to cancer: 30-50% more cancers in vitamin D deficient people!!  Other studies have demonstrated that in addition to being a strong preventive for Diabetes and Cancer, vitamin D has effects that make it a heart disease preventive as well 143. If there was a drug that could significantly reduce the risk of all of major killer diseases, it would be promoted endlessly in every media outlet, yet this has not been the subject of public education.  In an editorial in the Life Extension Journal, Oct. 2007, William Faloon asked the question, “Should the President declare a national emergency to educate the public about the availability of low cost disease prevention?”  Perhaps no single set of facts in recent times demonstrates the obstacles to meaningful change that have been outlined here!

Neutraceuticals that support mitochondrial function

The mitochondria are the organelles in each cell that are the sites of all the chemical reactions that comprise our metabolism.  They are the seat of energy production, the generation of ATP, which is required to fuel all of our life processes.  Mitochondria are subject to high levels of oxidative stress as well as all the other degenerative molecular pathology that has been described.  Mitochondrial dysfunction and failure have been recognized as a major contributing factor to all chronic degenerative diseases 144.

Acetyl-L-Carnatine: Necessary for the transport of fatty acids through the mitochondrial membrane so they can be burned to generate energy. Works in synergy with Lipoic acid to recharge mitochondrial function 145,146.

Creatine: It serves as a substrate for the generation of ATP (the Universal Energy molecule) in the mitochondria. It is stored as creatine phosphate and donates its phosphorus molecule to ADP to renew ATP 14.

D-Ribose: It is a key component of ATP, works in synergy with creatine to regenerate ATP 148.

Note: Life Extension offers a formulation called “Mitochondrial Energy Optimizer” which combines the proper mix of nutrients in the doses suggested by research studies to address the issue of mitochondrial support. 

Healhcare Implementation, The Paradigm Shift:

In redefining what is meant by healthcare, the emphasis is on pre diagnosis interventions, taking advantage of the large window of opportunity that is created by the recognition that degenerative process proceeds slowly over a period of many years before crystallizing into an end stage chronic degenerative disease. By using a set of biomarkers that inform us about the status of pathology on a molecular level, we are able to implement preventive strategies that counter the root causes of degeneration and by doing so, enhance our health and move us closer to Optimal on the symbolic Healthline. It is not within the scope of this paper to offer an in depth discussion of the complete bevy of applications available to the progressive healthcare practitioner, but a brief outline of highlights is in order.

The foundation of any program designed to optimize health must begin with proper diet. As has been noted, both health and disease are determined at the cellular level. The environment in which cells live is a sea of bodily fluids. These fluids have a PH which makes them acidic, neutral or alkaline. PH is an important determinant of the speed and efficiency of the chemical reactions that comprise our metabolism with a slightly alkaline PH affording the best environment for the metabolic generation of vital energy. Many books and papers have been written on the relationship of acid alkaline balance and ones overall health. 149-151 The primary cause of acid alkaline imbalance in the body is diet. A healthy diet should be weighted towards foods that produce an alkaline residue. This information is readily available on the internet and in libraries. A possible issue in acid alkaline imbalance associated with aging is the decline in digestive enzyme production that is age associated. With incomplete digestion the body becomes more acidic and mineral reserves can become depleted as they are called into action to offset this increased acidity. Supplementing digestive enzymes and ensuring adequate mineral levels can play a role in maintaining a healthy PH. Diet should minimize high glycemic foods so as to reduce the occurrence of insulin surges which over time can lead to insulin resistance, metabolic syndrome and a host of negative health consequences. High fiber intake is important both in glucose control and weight control. An in depth review of diet and health implications are beyond the scope of this paper but there is an enormous amount of information available to the reader who wishes to become well informed.

The biomarkers for oxidative stress, inflammation, glycation and methylation defects which are common to all the chronic degenerative diseases, give us a general sense regarding molecular pathology and risk for degenerative disease. All these factors can be addressed by lifestyle modifications including dietary changes, physical exercise and the use of specific sets of neutraceuticals. The simplest approach that could be implemented with minimal change to the existing system would be to include in every routine blood profile, tests for; homocysteine, HgA1, CrP and Malondialdeyde. Based on these results, a package of neutraceuticals could be designed to counter the areas in which pathology is evidenced. Even if the development of degenerative disease is simply mitigated, delayed for several years, the gain in quality of life and the reduction of cost to the system could be significant.

Fatty Acid analysis results give us the levels and balances between our essential fatty acids. We are led to where intake must be increased or decreased to bring fatty acid levels closer to optimal balance. Fatty acids are one of the vital determinants of ones health as they are the main components of every cell membrane regardless of tissue type. The balance of these acids determines the permeability of the cell membrane and thus what is allowed to enter and leave the cell, which in turn, determines the health of that cell and as we have learned, health and disease begin at the cellular level. Essential fatty acid levels are also the determinants of prostaglandin levels which regulate inflammatory process and other functions in the cell. Cellular toxins are often located in the fatty membrane structure where they are able to compromise membrane functions and damage cells. Renegade fats which are very long chain fatty acids can be detected in the fatty acid panel and are known to be markers for neurotoxins.152 Theraputic steps would involve the use of techniques such as fast IV Glutathione push or phospholipids exchange which are effective means of removing toxins from cell membranes.152 Healing the cell membrane is critical to restoring and improving ones health!

Declining hormone levels are associated with both aging and chronic degenerative disease. The hormone panel gives us the data with which to address the issue by the use of bio-identical hormones to restore levels to what would be normal at a younger age. There are 2 hormones whose levels actually increase with age and are associated with age related degenerative process. These are cortisol and insulin. Cortisol is the adrenal hormone known as the “stress hormone”. It is secreted at times of stress to prepare us to deal with a threat. When levels remain chronically high or simply increase with age it can cause damage to cells and is a factor in neurodegenerative diseases.153  By supplementing with DHEA, cortisol levels can be decreased. Insulin resistence which involves a diminished cell membrane receptivity to insulin with resultant increasing serum insulin levels, is the underpinning of metabolic syndrome, diabetes and the many degenerative changes associated with these conditions. Dysinsulinemia requires an aggressive multifactorial approach which involves dietary changes with elimination of high glycemic foods, high fiber intake, emphasis on burning fats for energy, correction of cell membrane defects by addressing fatty acid balance, use of supplements such as chromium, a trace mineral, that can improve membrane receptivity to insulin and a host of other neutraceuticals to address basic molecular pathology. Physical exercise is very important in improving insulin sensitivity.

Heavy metals if detected at high levels can be removed by techniques such as IV Chelation therapy or by the use of oral chelating agents.154 As mentioned earlier, fast IV Glutathione push is effective in removing heavy metals from their bindings in cell membranes.152

To truly implement a comprehensive healthcare management system is a complicated matter that would require major changes to the manner in which patients are seen in clinical practice. With an emphasis shift from diagnosis to functional molecular medicine, the time requirements necessary for patient evaluation and education would be increased.  When addressing degenerative diseases which have multifactorial causation, it is necessary to design a treatment protocol that is multi targeted in which all components are synchronized for maximum benefit. There is no one size fits all in such a scheme. Patient protocols would have to be individualized in a manner that is not the case with the dispensing of pharmaceuticals. Economic issues regarding time management would have to be resolved. To make what are now more exotic laboratory tests more practical would require routine use to increase the volume of tests for laboratories so that costs can be reduced and the costs of these tests would need to be covered by health insurance providers. The cost of neutraceuticals would need to be made more affordable for all and covered by insurance in the same manner that drug coverage is provided. These are but a few of the considerations that would need addressing for practical implementation of progressive healthcare. We can outline here, what should ideally be done but it is up to the political, economic and scientific forces that have a stake in this arena to resolve these issues so that the costs of “healthcare” can be dramatically reduced and the general health of the people, improved. We have the scientific tools at our disposal to accomplish the task. What we need is the political and economic willingness to address the problem. 

Summary:

We are faced with a major crisis in our healthcare system involving both the delivery of services and the excessive costs to the delivery of these services. The projected costs of healthcare in the next few decades suggest a collision course with bankruptcy. The costs of our Medicare system, which serves the needs of our senior population are said to be unsustainable. Our existing medical paradigm was designed to treat acute illnesses and is poorly designed to handle the management of chronic degenerative diseases which account for the bulk of costs to the Medicare program. We spend more than any other nation on healthcare yet we rank below many countries in the measurable parameters of outcome. What is required are solutions that can galvanize the political, economic and scientific forces, each of which have a stake in the maintenance of our healthcare system, towards action in implementing preventive healthcare. The goal must include improvement of the general level of health in all members of our society, the achievement of which is accompanied by the benefit to our economy of reduced costs of healthcare. Absent a specific dollar amount, it should be clear that by reducing the incidence of all chronic degenerative diseases, by reducing the suffering associated with degenerative processes in different areas of the body, the economic benefit of cost reduction should be quite significant.

This paper addresses the scientific piece of the puzzle.. which can have a significant impact on the economic piece as well. We describe the nature of chronic degenerative diseases as multi-factorial in cause and requiring a multi-targeted treatment approach. We describe the common molecular pathology shared by heart disease, cancer, diabetes and all the neurodegenerative diseases. We note that this pathology develops slowly over many years and allows for strategic interventions in a pre-diagnosis state. This multi-targeted approach employing primarily low cost chemicals native to the body has the potential to mitigate, delay and possibly prevent the occurrence of a chronic degenerative disease. This paradigm shift, by which we redefine healthcare, also challenges the uniqueness of a named disease, implicit in the primacy of “diagnosis” and supports the concept of one treatment approach for multiple conditions.

In order to accelerate this shift towards healthcare we need to create a new kind of research protocol; one that is multi-targeted, with combinations of neutraceuticals that directs itself towards all known underlying causational factors. We can no longer evaluate the benefits of nutrients by a research model that attempts to isolate a single nutrient and determine its treatment value in a specific disease condition. The whole is greater than the sum of its parts and we must create these wholistic models for both preventive and treatment implementation An excellent starting point for structuring such research protocols would be the area of Neurodegenerative diseases which are a major growing health problem globally, for which there are currently no effective allopathic treatment models.