Triple-ADT Technology: The Next Revolution
In Alzheimer’s Disease (AD) Therapy
December 4, 2017
America’s Aging Population and the Rising Prevalence of Alzheimer’s Disease:
In 2000, Americans over 65 made up 12.4 percent of the population or 35 million. In 2010 there were more than 40 million Americans over age 65. By 2030, this population is expected to grow to 72 million – 19 percent of the U.S. population.
Currently there are 5.4 million Americans who suffer from Alzheimer’s Disease. Gregory Petsko, in his recent TED Talk estimates that in 2050 the US will have 32 million people over the age of 80. Half of these, or 16 million, are projected to have Alzheimer’s Disease (AD).
Looking forward, 25 to 50% of Americans will show signs of Alzheimer’s by the age of 85. When it comes to dementia, we should all consider ourselves vulnerable. No matter what genes we carry, our odds of developing cognitive problems increase as we age.
An expert panel at the NIH has reviewed the research on preventing Alzheimer’s disease by keeping mentally and physically active or by using various dietary supplements, including EPA and DHA in fish oil. The panel concluded that “current treatments provide some symptomatic benefits for a short period of time, maybe a couple of years. But there are no treatments that are currently available that will delay the progression of the disease.”
Even the current tests that assess AD, including (i) PET scans that measure amyloid and how glucose is metabolized in the brain, (ii) MRI scans that measure whether the brain is shrinking or (iii) cerebrospinal fluid tests that measure amyloid and tau as protein markers of dying brain cells are cumbersome in assessing the clinical course of AD. DNA sequencing techniques that identify two copies of a gene variant, ApoE4, while strongly linked to the appearance of AD, is only helpful in a small percentage of AD patients. It does suggest, however, that low density lipoproteins may play a role in the pathogenesis of the disease.
Today, cognitive brain testing remains the easiest method for assessing the advance of Alzheimer’s Disease
The Challenges of Alzheimer’s Disease
Alzheimer’s Disease joins a long list of Chronic Degenerative Diseases that have mushroomed since the introduction of High Fructose Corn Syrup (HFCS) into the American diet in the 1970s. Alzheimer’s Disease now appears to be a multifactorial disease related to the metabolic risk factors that have emerged from dietary changes introduced in the 70s to promulgate low-fat diets. During this era the Food Industry introduced increased quantities of sugar and HFCS to make up for the loss in taste due to the removal of dietary fats. In fact, AD has been described by Mark Bittman as Type-3 Diabetes because the two chronic conditions are so closely linked.
Alzheimer’s Disease leads to progressive dementia states that impair the dignity of AD patients. Not only do they lose their memory and cognitive functions, but they progressively lose their ability to wash, bathe, dress, eat, exercise or even communicate with family members and loved ones. The costs of institutionalizing AD patients is prohibitive at best leading to near financial collapse for younger family members. Some have described this increasing vegetative state in AD patients as the greatest challenge to America’s health moving forward.
Positive Benefits of Accelerated Amino Acid Delivery Technologies (Triple-ADT) Expected to Control Alzheimer’s Disease:
Any measure that can prolong independent living and minimize AD morbidity before death translates into profound benefits not only for that person but for their family and the economy as well. Triple-ADT containing Power Amino Acids® (Essential, Semi-Essential, Positive-charged and Satiety amino acids) may be very helpful in preventing or delaying the onset of AD. As such, Triple-ADT products should be capable of “compressing” morbidity in Alzheimer’s Disease for the following five (5) reasons:
1. Triple-ADT Technology may be expected to increase the levels of Transcription Factors like REST Protein (Repressor Element 1-Silencing Transcription Factor)
REST Protein has the following beneficial effects on neurons:
- REST stimulates neuronal growth, protection, survival, differentiation and synaptogenesis
- Lower levels of REST protein correlate with early onset of AD
- Higher levels of REST protein preserve brain function in early AD and correlate with slow progression of AD
- High levels of REST protein in the Cortex and Hippocampus correlate with increases in cognition
- Animal studies show that REST protects neurons from death caused by oxidative stress or beta amyloid, among other threats.
- When REST was disabled in mice the animals began to show signs of AD-like neurodegenerative changes.
Dr. Scheele has studied REST protein and found the following information:
- REST is a large protein, which has a positive-charged C-terminal domain
- REST and P-53 proteins both act as transcription factors and both have positive-charged C-terminal domains that allow for these proteins to access DNA in the cell nucleus.
According to Dr. Scheele’s Theory of Selective Protein Deficiency, Positive-charged proteins disappear before negative-charged proteins in response to a poor nutritious diet, including a diet lacking in Essential and Semi-Essential amino acids, which include positive-charged amino acids that provide satiety. Triple-ADT Products with Essential and Semi-Essential Amino Acids (Power Amino Acids®) including L-Lysine and L-Arginine, work to preserve levels of positive-charged proteins like REST Protein, Brain-Derived Neurotrophic Factor (BDNF) and other positive-charged proteins described below.
Products which exploit Triple-ADT Technologies provide a opportunity to restore positive-charged proteins to the Human Proteome and Metabolome.
2. Triple-ADT Expected to Improve the Processing of Amyloid Precursor Protein
Alzheimer’s disease occurs in the brain as Beta-Amyloid Plaque builds up in the extracellular space of neurons when Amyloid Precursor Protein (APP) is cleaved releasing either Amyloid Beta-40 (normal peptide) or Amyloid Beta-42 (abnormal peptide), which contains two additional hydrophobic amino acid residues. Normal neuronal cells release Amyloid Beta (Ab) peptides in a ratio of 90% Ab40 and 10% Ab42. In contrast, Alzheimer’s patients release Ab peptides in a ratio of 50% Ab40 and 50% Ab42.
Amyloid Plaque leads to neuronal death evidenced by neurofibrillary tangles associated with microtubules and phosphorylated Tau protein.
Amyloid beta peptides (Ab peptides) are released by Gamma Secretase, which acts as an aspartyl protease (pepsin-like) to process APP with the following four subunits, which must be available in stochiometric amounts to function correctly. Two of the subunits (Presenilin and Nicastrin) are negative-charged with pI values between 4.36 and 5.7. Subunit #3 called APH-1A or APH-1B has pI values of 8.23 and 8.42, respectively. Subunit #4 (Pen-2) has a pI value of 9.49. All four subunits are required for activity of gamma secretase.
In the presence of Selective Protein Deficiency in the diet, we may conclude that subunits #3 and #4 will be made in diminished amounts leading to:
- A deficiency of these critical subunits in the gamma secretase tetramer.
- Delays in production and assembly of tetrameric subunits in gamma secretase may allow processing of amyloid beta in cellular compartments with altered pH values changing the point of scission for release of Ab peptides favoring abnormal Ab-42 peptides over normal Ab-40 peptides.
- Note that Ab-42 peptides, containing two extra hydrophobic amino acid residues, can be expected to decrease the solubility of Ab peptides in a manner that fosters aggregation and clumping of extracellular Ab peptides into AD plaque.
- Should misprocessing of Ab occur in this manner the pathological events may be responsive to improved diets supplying critical concentrations of essential and semi-essential amino acids to maintain the assembly of gamma secretase in cellular compartments that promote normal processing of Amyloid Beta favoring normal Ab-40 peptides.
Products which exploit Triple-ADT technologies therefore may be expected to improve nutritional health allowing for all four Secretase subunits to bind together optimally to favor the release of normal Ab-40 peptides over abnormal Ab-42 peptides.
3. Brain-Derived Neurotrophic Factor (BDNF) Signals Hunger & Satiety and Stimulates Neuronal Growth
Brain-Derived Neurotrophic Factor (BDNF) is a paracrine hormone secreted into the blood circulation of the Hypothalamus in the vicinity of the Appetite Center (Arcuate Nucleus). This small peptide has 247 amino acids with a pI of 9.01. High levels of BDNF in the hypothalamus signal satiety and low levels signal hyperphagia, enormous hunger and appetite leading to voracious eating in experimental mice. Within this short peptide there are 35 Lysine and Arginine residues (positive-charged amino acids) and 29 Aspartate and Glutamate residues (negative-charged amino acids).
BDNF has also been shown to stimulate neuronal growth, protection, differentiation and synaptogenesis, which suggests that BDNF supports brain health and combats dementia syndromes like Alzheimer’s Disease. Like REST protein, BDNF appears to be Exhibit A for a positive-charged “Nutrient Sensor” that functions to signal hunger and satiety in an organism while simultaneously providing trophic factors which optimize normal brain health.
With an isoelectric point of 9.01, BDNF is one of the most positive charged proteins in the brain. Hence the synthesis of BDNF should be stimulated with Power Amino Acids found in Triple-ADT Products.
4. Telomere Health, Aging and Chronic Degenerative Disease
The Subject of the 2009 Nobel Prize awarded to Elizabeth Blackburn, Carol Greider and Jack Szostak was the discovery of Telomeres, stretches of DNA that cap the ends of chromosomes. Aging appears to shorten telomeres as a function of cumulative rounds of cell division. Science has linked short telomeres with chronic degenerative disease, including (i) heart disease, (ii) diabetes and (iii) cancer.
Telomerase is an enzyme that has the capacity to lengthen telomeres and reverse the metabolic dysfunctions observed with telomere shortening. All three protein subunits of Telomerase are positive-charged proteins. The Reverse Transcriptase called TERT has a pI of 10.54. The DKC1 subunit, which is responsible for an Aging Syndrome, has a pI of 9.46 and TEP, the Telomerase Associated Protein, has a pI of 8.26. It appears likely that all three of the protein subunits, described above, act as Nutrient Sensors, monitoring the nutrient content of dietary amino acids that enter the body.
Dyskeratosis Congenita 1 is a congenital syndrome related to the DKC1 subunit that shows premature aging with hair loss and/or greying, dental loss, osteoporosis, aplastic anemia, nail dystrophy, oral leukoplakia, abnormal skin pigmentation and liver and pulmonary fibrosis.
Given the high Isoelectric points of Telomerase subunits, these proteins may be expected to respond to Power Amino Acids® found in Triple-ADT Products.
5. Type-2 Diabetes and FOXO1 Regulation Throughout the Body
Triple-ADT products can be expected to correct the abnormality in insulin signaling in the AD brain as AD has been described as Type-3 Diabetes.
Type-2 Diabetes throughout the body and Type-3 Diabetes in the Brain are associated with elevated blood sugar levels, Insulin resistance and Leptin resistance. Recently, there has emerged the concept of “3 Ds,” which calls attention to the association of (i) Diabetes, (ii) Depression and (iii) Dementia.
FOXO1 is a regulator of gene expression in the nucleus of cells where it serves to decrease adipogenesis leading to a “lean” phenotype. Sirtuin-2, a Class 3 NAD-dependent deacetylase, deacetylates FOXO1, which allows it to remain in the nucleus where Lysine residues interact with chromosomal DNA.
When FOXO1 is acetylated on its Lysine residues it shuttles from the cell nucleus to the cell cytoplasm. In the cytoplasm it is phosphorylated on serine-253 in the presence of insulin. These modification steps trap FOXO1 in the cytoplasm where it stimulates adipogenesis and fat deposition leads to an “obese” phenotype.
There are a number of FOXO1 homologs distributed throughout the body. FOXO1 homolog 2 isoforms are all positive charged proteins, including class 1 isoforms which show pI values of 7.7, class 2 isoforms which show pI values of 7.79, class 4 isoforms which show pI values of 8.48, Class 5 isoforms which show pI values of 8.99 and Class 6 isoforms which show pI values of 8.48.
The high isoelectric values for FOXO1 homologs suggest that these regulators of gene expression function as Nutrient Sensors capable of inhibiting fat deposition according to the dietary composition of amino acids in the diet, specifically in relationship to the nutrient content of the diet in supplying positive-charged amino acid residues that act as limiting factors in the synthesis of positive-charged proteins.
In this way poorly nourished diets deficient in essential amino acids would diminish the role of FOXO1 to achieve “lean” phenotypes. Conversely, highly nourished diets rich in essential and semi-essential amino acids, including Lysine and Arginine residues, respectively, would enhance the role of FOXO1 to achieve “lean” phenotypes.
Products which exhibit Accelerated Amino Acid Delivery Technologies (Triple-ADT) can be expected to prominently increase the levels of FOX01 proteins throughout the body and brain therefore restoring lean phenotypes to the organism.
Factor4 Shows Beneficial Effects in Nerve Diseases
The following evidence suggests that Factor4 has prominent beneficial effects in Peripheral Neuropathy, Tremor Disorders and Seizure Disorders due to Chronic Traumatic Encephalopathy:
- In a cohort of people treated for obesity and peripheral neuropathy with Factor4 Weight Control® the first symptom to improve, within the first week, is the loss of distal nerve sensation in lower legs and feet. The improvement in distal nerve sensation continues to improve over time. In three subjects who required the use of a cane because of the neurosensory disorder in their distal extremities, they progressed to the point that they no longer needed to rely on a cane.
- In subjects who suffered from obesity and tremor disorders, these symptoms also began to decrease within the first week of treatment with Triple-ADT therapy and the therapeutic improvement continued over time.
- Seizure Disorders have responded in one unique subject:
- One female subject had suffered from chronic traumatic encephalopathy with grand mal seizures occurring approximately every 2 weeks for 43 years. Dilantin and Phenobarbital had no beneficial effects on her seizure disorder over this period of time. Numerous OTC supplements, including vitamins, minerals and micronutrients made her seizure disorder worse.
- Since she started taking Factor4 products, which utilize Triple-ADT technology on March 5, 2016, she remained free from grand mal seizures for over 6 months avoiding what would have been 8 seizures.
- The seizures reappeared but at a lower frequency occurring at intervals of 3 to 5 months rather than every 2 to 3 weeks.
CONCLUSIONS:
- If Triple-ADT technologies can combat seizure disorders due to chronic traumatic encephalopathy and peripheral neuropathies as well as tremor disorders, it has an excellent chance of delaying the onset of Alzheimer’s Disease.
- Hence, we need to study the effects of Triple-ADT in Cognitive Decline Disorders as well as early Alzheimer’s disease.
Approach to Clinical Trials That Examine
The Role of Essential and Semi-Essential Amino Acids
In Delaying the Onset of Alzheimer’s Disease
Rather than conduct clinical trials in advanced or far-advanced Alzheimer’s Disease, it would be prudent to investigate the effects of triple-ADT technologies on preliminary stages of AD. Triple-ADT technologies are not expected to solubilize amyloid plaque or remove phosphorylated Tau Tangles. It is however expected to:
- Minimize the accumulation of Beta-Amyloid Plaque by improving the processing of Amyloid Precursor Protein…and
- Promote the synthesis of BDNF and REST proteins that act to stimulate neuronal growth, protection, survival, differentiation and synaptogenesis
Hence, it appears to be prudent to examine the effects of Triple-ADT technologies on measures of cognitive decline in elderly people. Researchers have developed a battery of 5 memory and cognitive tests that can detect subtle alterations in recall and thinking ability that usually go unnoticed:
- Recalling Words
- Naming Objects
- Nonverbal Reasoning
- Remembering Time and Place
- Drawing Tests involving Copying Complex Figures
Two kinds of clinical tests are envisaged:
- Conducting short-term (3 month tests) on cognitive abilities in individuals who are judged to be compromised
- Conducting long-term (6 to 12 month tests) on cognitive abilities in individuals who are judged to be compromised
Should cognitive abilities improve in compromised individuals, one could tentatively conclude that Triple-ADT technologies have potential in delaying the onset of Alzheimer’s Disease. At this point it might be important to test Triple-ADT technologies in a cohort of individuals judged to suffer from early stages of AD.
This slow, methodical approach, following cognitive abilities over time in individuals with varying stages of compromised cognition might provide useful information on methods to delay the onset of Alzheimer’s Disease and other dementia Syndromes as well (Parkinson’s Disease, Lewey-Body Dementia, Fronto-temporal Dementia, Alcohol-Related Dementia)
It is especially important to conduct these clinical studies as part of FDA Clinical Trials in order to obtain FDA Approval.
THEORY OF SELECTIVE PROTEIN DEFICIENCY
In 2015 Dr. Scheele published his theory on Selective Protein Deficiency Syndromes on the internet at www.SelectiveProteinDeficiency.com. Components of the theory are presented as follows:
- Breakthrough Science
- Food Chain Signals
- Biology of Chronic Degenerative Disease & Aging
- Nutrient Sensor Hypothesis
- Primer on Amino Acids: Essential, Semi-Essential & Non-Essential Amino Acids
- Historical Commentary
- Factor4 Health Story
- Factor4 Breakthrough
- Bibliography
- Slide Presentations
IMPROVE WORLD HEALTH: A 501C3 ORGANIZATION
In order to raise funding for further research and Clinical Trials, Dr. Scheele started a 501c3 Non-Profit Organization called Improve World Health in La Jolla, CA. Components of this organization are described as follows:
- Summary Home Page
- Mission Statement
- Vision Statement
- Strategy Statement
- Operating Plan
DARWIN: BUILDING A BETTER DATABASE ON PROTEIN SEQUENCES
Over the past 5 years Drs. Shin-Ichi Fukuoka and Scheele have analyzed numerous proteins that appear to be vulnerable to Selective Protein Deficiencies related to Chronic Degenerative Diseases. The results of these investigations are summarized in “The Biology of Chronic Degenerative Disease” published on www.SelectiveProteinDeficiency.com. The fruits of this research show great promise in understanding the pathogenesis of these divergent diseases. For example, in one case we could correlate the movement of FOX01 into the nucleus, where a positive-charged domain associated with the regulatory protein confers the LEAN phenotype, and the movement of FOX01 into the cytoplasm, where a negative-charged domain allows phosphorylation that correlates with the FAT phenotype. From these studies we could correlate DNA binding to positive-charged domains that contain the Nuclear Localization Sequence.
These Structure-Function correlation studies were so successful in providing explanations for metabolic disease, we have designed a method called DARWIN to analyze all of the existing protein structures in Biology.
The Darwin Database will identify, for the first time, in detail, all of the positive-charged proteins and protein domains throughout the Body, the Peripheral Nervous System and the Brain. It will do this by providing novel color-coding technologies capable of identifying strings of positive-charged and negative-charged peptides throughout the Human Proteome of 23,000 proteins.
Positive-charged domains identify proteins that are subject to Glycation Disease fostered by sugar-rich diets containing increased amounts of Glucose and Fructose. Glycation Disease and Advanced Glycation End-Products appear to be a major cause of pathological changes in Metabolic Pathways which occur as a result of poor nutrition in today’s society.
The identification of positive-charged proteins and subunits will provide critical information in understanding the relationship of diet to Alzheimer’s Disease:
- Positive-charged proteins and domains appear to be the first structures to become eliminated due to a poorly nourished diet
- Positive-charged proteins and protein domains suggest that these structures are localized to the nuclei of cells, whereby they exert regulatory functions on gene expression related to dietary factors that may be called Nutrient Sensors.
- Positive-charged proteins and protein domains also appear to be the main targets of high levels of glucose and fructose that result in Glycation Diseases that destroy the functions of regulatory proteins as a function of diets rich in sugar, high-fructose corn syrup and carbohydrates
- Factor4 Products work to prevent and treat these dietary diseases by facilitating the synthesis and regeneration of positive-charged proteins despite the presence of poor nutritious diets.
The methods by which Triple-ADT products accelerate the regeneration of Positive-Charged Proteins by providing Power Amino Acids® (Essential, Satiety and Positive-charged amino acids) in formulations that Accelerate Amino Acid Delivery to organs and tissues throughout the body have been described in detail in three issued patents:
- US Patent No. 7,982,066 B2 issued on 7-19-11 (Utility Patent)
- US Patent No. 8,362,297 B2 issued on 1-29-13 (Composition Patent)
- US Patent No. 8,779,189 B2 (Power Amino Acids® in capsules)
BOARD OF ADVISORS
We intend to attract leaders in the field of Brain Research to join our Board of Advisors:
Suggested advisers:
- Bruce McEwen, PHD, Professor of Brain Sciences at the Rockefeller University
- Eric Reiman, M.D. Executive Director of the Banner Alzheimer’s Institute in Phoenix, AZ
- Others?
REFERENCES:
- Scheele, G. (1975) Two dimensional gel analysis of soluble proteins – Characterization of guinea pig exocrine pancreatic proteins. J. Biol. Chem. 250: 5375-85
- Schick, J., Beil-Moeller, H., Kern, H.F. and Scheele, G.A. (1982) Differential rates of synthesis of individual pancreatic enzymes during prolonged in vivo stimulation, In Mechanisms of Intestinal adaptation (Robinson, JWL, Dowling, RH, Riecken, EO, eds.), MTP Press, pp 511-514.
- Schick, J., Kern, H. and Scheele, G. (1984) Hormonal stimulation in the exocrine pancreas results in coordinate and anticoordinate regulation of protein synthesis, J. Cell Biol. 99: 1559-64.
- Schick, J., Verspohl, R., Kern, H. and Scheele, G. (1984) Two distinct genetic patterns of response in the exocrine pancreas to inverse changes in protein and carbohydrate in the diet, Am. J. Physiol. 248: G611-616.
- Scheele, G. (1986) Regulation of gene expression in the exocrine pancreas, In The Exocrine Pancreas: Biology, Pathobiology and Diseases (V.L. Go, J.D. Gardner, F.P., Brooks, E. Lebenthal, E.P. DiMagno, G.A. Scheele, eds.) Raven Press. New York, NY, pp 55-67.
- Scheele, G.A. (2011) The Obesity Cure, Published by Bookmasters and Atlas Books, Ashland, OH.
- Scheele, G.A. (2015) https://SelectiveProteinDeficiency.com
- Scheele, G.A. (2015) www.ImproveWorldHealth.org
GEORGE A. SCHEELE, M.D.
Dr. Scheele is a world-renowned physician, inventor, author and two-time Nobel Associate, who has pioneered in understanding the critical role of amino acids in regulating metabolic health and body weight. He introduced Factor4 Weight Control® in 2007 with essential, semi-essential & non-essential amino acids to treat the metabolic defects that lead to overweight disorders and obesity. In 2016 his interests turned to AD.
As a graduate of Princeton University and Johns Hopkins Medical School he served as one of the initial “Ironmen” on the Osler Medical Service. Dr. Scheele served as Professors of Medicine on the faculties of The Rockefeller University, Yale University School of Medicine and Harvard Medical School. Dr. Scheele invented new concepts and techniques which “cracked the code” in understanding how Power Amino Acids® and Accelerated Amino Acid Delivery Technologies (Triple-ADT) correct the deficiencies in amino acids, positive-charged proteins, and metabolic pathways that normalize body weight and restore metabolic health.
A pioneer in the development of the fields of Cell Biology and Molecular Biology and their impact on understanding chronic human diseases, he participated in work that won two Nobel Prizes in Medicine awarded to George Palade in 1974 and Gunter Blobel in 1999.
As a leader in Nutritional Science and Medical Research with 40 years of innovative scientific research and 10 years of breathtaking achievements in the fields of obesity and metabolic disease, Dr. Scheele’s passion has always been to “Improve World Health”. After moving to La Jolla in 1998, he has utilized his vast experience to develop superior health-care products for individuals living in today’s fast-paced world.
Dr. Scheele is currently the Founder, President, and CEO of NovaLife, Inc. a San-Diego based biotech company that has pioneered in the development of innovative health-care products for people who suffer from Chronic Degenerative Diseases, like Obesity, Diabetes, Lipid disorders, Cardiovascular disease, Autoimmune Disorders, Alzheimer’s Disease and Premature Aging.
Dr. Scheele is also the President of a 501c3 Non-Profit Organization called “Improve World Health” in La Jolla, California. The focus of IWH is on methods to prevent and treat Chronic Degenerative Diseases associated with the Metabolic Syndrome. These diseases include Obesity, Type-2 Diabetes, Lipid Disorders, Cardiovascular Disease, Autoimmune Diseases, Alzheimer’s Disease and Premature Aging.