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  • Misfolded Proteins Precede Most Chronic Age-Related Maladies; Resveratrol, Vitamin D and Allicin (Garlic) Proposed As Antidotes

    December 11, 2017: by Bill Sardi

    Biologists are re-thinking the origins of disease and aging. A compelling accumulation of data points to protein congestion inside a small organelle called the endoplasmic reticulum in living cells that accelerates aging and disease.

    So let’s take a trip to the E.R. – the endoplasmic reticulum. The E.R. produces proteins and facilitates their passage through a tortuous pathway of tubules. In so doing, proteins must be properly folded to maintain health. Only properly folded proteins are allowed to exit the E.R. Otherwise they are degraded and expelled into the watery cytoplasm of the cell. Medical researchers now believe mis-folded proteins (also known as prions) in the E. R. are at the root of many diseases, particularly diseases of aging.

    The realization that endoplasmic reticulum stress precedes symptoms of disease suggests timely corrective action could delay the onset of disease and aging itself. While modern medicine now lamely attempts to introduce synthetic drugs to put a halt to E.R. stress-related diseases, there are powerful natural remedies available such as the red wine molecule resveratrol, sunshine vitamin D and allicin from garlic that address this problem. These natural remedies can be employed on a daily basis, before diseases of aging begin, or to even reverse existing disease.

    History

    As background information, misfolded proteins in brain cells were first characterized and initially believed to be confined to a prion brain disorder known as Creutzfeldt-Jakob disease, with onset of symptoms later in life (~age 60). Prion diseases are a family of protein misfolding brain disorders that include Alzheimer’s, Parkinson’s, Huntington’s and Lou Gehrig’s disease.

    Living Cell

    While most people have heard that DNA produces proteins called nucleotides that deliver instructions to living cells, fewer people recognize human genes have a dynamic feature — they produce proteins that control body processes in response to environmental conditions (heat, cold, radiation), the diet (calorie restriction) or medicines or even emotions. This process is called epigenetics.

    DNA and the sequence of protein steps called nucleotides on the DNA ladder control inherited factors which represents ~2% of disease whereas epigenetics is the more dominant factor that produces proteins in adaptive response to external factors.

    Gene signals are imparted to 20 amino acids (proteins), a process called translation. The quality control center for these proteins is the endoplasmic reticulum. Otherwise a set of bad instructions would be issued.

    The horror of this protein-folding problem is that the American western processed food diet hastens the onset of these “prion” or protein folding disorders.

    This includes but is not limited to diabetes, heart failure, cancer, glaucoma, macular degeneration, atherosclerosis (hardening of the arteries) and all of the age-related brain disorders (Alzheimer’s disease, Parkinson’s, ALS/ amyotrophic lateral sclerosis).

    The unfolded protein problem in the E.R. is also associated with psychiatric disorders such as depression, schizophrenia, fragmented sleep, even post-traumatic stress disorder.

    The promise of iron and copper chelators

    While little if any of the research involving remedies for diseases that emanate from misfolded proteins is practiced in the clinic yet, there is promise that iron and copper chelators (key-lay-tors) can reduce biological stress within the endoplasmic reticulum. This serves as evidence for the overmineralization theory of aging and both overmineralization and E.R.-related diseases are progressive with advancing age.

    A problem without a solution?

    The therapeutic properties of mineral chelators in the daily practice of medicine have yet to gain traction. But their prospect for E.R. therapy is well substantiated. For example, while an antibiotic (tunicamycin) induces experimental E.R. stress in animal eyes, the use of an iron chelator has been demonstrated to reduce death of light receptor cells at the back of the eyes via reduction of E.R. stress.

    Biological stress in the endoplasmic reticulum provokes the outcropping of new blood vessels that destroy the visual center (macula) of the eyes. The red wine molecule resveratrol, a copper chelator, has been demonstrated to rescue patients with unremitting neovascular macular degeneration.

    Indeed, it’s possible macular degeneration may be the first disease selected for E.R. therapy because this form of sight loss is so incurable and devastating.

    It is not surprising to find, as this report addresses below, that natural molecules such as resveratrol, vitamin D and garlic exhibit mineral controlling properties correct E.R. stress.

    Not just cellular morbidity but cell mortality too

    Endoplasmic reticulum stress not only produces cellular dysfunction but ultimately leads to the demise of living cells. Chronic stress in the E.R. can result in a logjam of unfolded proteins that can induce cell death. This would be of considerable concern in organs like the brain, eyes and heart as brain cells, photoreceptor cells and heart muscle cells do not readily renew themselves.

    E.R. stress and aging

    Given that the problem of unfolded proteins in the E.R. is age related, combined with the fact people in developed countries are living longer, broadens the number of adults who are candidates to develop E.R.-related pathology. Arthritis, respiratory diseases and bowel inflammation are among the many maladies associated with E.R. dysfunction.

    While the unfolded protein problem in the E.R. may be an immutable feature of advancing age, it is not beyond therapeutic remedy.

    The unfolded protein response in the E.R. of living cells is induced by a decline in molecules that serve to chaperone proteins as they traverse the endoplasmic reticulum. Molecular chaperones facilitate proper protein folding.

    Proteins and protein fragments may accumulate in the E.R. in insoluble forms to produce plaque within the liver, brain, arteries and elsewhere. E.R. dysfunction is a hallmark of aging itself.

    So it is not a surprise to learn that E.R. stress is mitigated by activation of the Sirtuin1 survival gene, a gene heralded as a controller of aging.

    When do proteins begin to misfold in the E.R.? The answer to that question is long before symptoms of age-related disease becomes apparent. In animals, protein misfolding is observed in early adulthood long before behavioral or physiological changes occur.

    Some people have suffered chronic endoplasmic reticulum stress since birth but death of irreplaceable cells occurs only later in life.

    Insomnia is commonly experienced as adults age. Sleeping hours appear to be the critical time period for proteins to be properly folded and cleared from the E.R. Less than 6 hours of sleep induces E.R. distress.

    Sleep deprivation does not induce E.R. stress in young laboratory animals as it does among old animals. This suggests E.R. stress is at the root of the aging process.

    Biologists have demonstrated that the provision of a vitamin delays the start of protein misfolding from day 4 to day 12 in the 21-day lifespan of the roundworm. If this experiment is applicable to humans, intervention prior to loss of function can be initiated to delay aging.

    Aging brain cells are characterized by misfolding of proteins within the E.R. Activation of the Sirtuin1 survival gene, which can be accomplished with resveratrol, corrects this problem.

    Mild biological stress improves E.R. function

    If proteins don’t fold properly and clear the endoplasmic reticulum, a cellular death (apoptotic) signal can be induced. Irreplaceable cells in the brain, eyes and heart may die off prematurely.

    The body puts up a defense when the endoplasmic reticulum is initially stressed by activation of a gene transcription factor called Nrf2. The Nrf2 protein activates internal enzymatic antioxidants (glutathione, catalase, superoxide dismutase- SOD) in the E.R. as a counterbalance.

    As the accompanying chart below shows, molecules that induce mild biological stress improve protein folding mechanisms in the endoplasmic reticulum.

    Chart: Protein Folding

    Conquering E.R. stress in the diabesity era

    An interesting finding is that endoplasmic reticulum stress plays a central role in the development of leptin resistance. Leptin is a satiation hormone that signals a person to stop eating. In some people, that stop-eating signal is blocked and they lose control and overeat. In experimental studies the provision of what are called molecular chaperones reverse leptin resistance. This means correction of E.R. stress may help quell the diabesity epidemic that grips countries that consume western diets.

    E.R. stress and diabetes

    It is interesting to note that the injection of deformed proteins into healthy laboratory mice induces symptoms of diabetes. While protein misfolding in the E.R. is increasingly recognized as a correctable problem in diabetes, modern medicine intends to introduce expensive problematic drugs to restore E.R. function rather than use off-the-shelf natural remedies.

    Misfolded proteins in the E.R. are associated with the loss of insulin-secreting beta cells in the pancreas. Beta cell loss in both Type I and Type II diabetes involves endoplasmic reticulum dysregulation. Sleep deprivation worsens the problem.

    Resveratrol: best documented E.R. therapy

    Resveratrol research continues to astound. Public adoption of resveratrol pills falls behind the crying need to delay or avert E.R. stress disorders.

    Resveratrol is solely a copper chelator (binder). It is not surprising to learn that the anti-aging molecule resveratrol stabilizes proteins in living cells via its ability to reduce copper-induced oxidation. Therefore, resveratrol normalizes protein folding and degradation and inhibits conversion of cells into a senescent (non-reproductive) state.

    In laboratory animals resveratrol alleviated insulin resistance (inability of cells to utilize insulin to convert sugar into energy) via its ability to calm E.R. stress.

    A toxic agent in cigarette smoke blocks the production of nitric-oxide gas within arteries that in turn facilitates arterial dilatation (widening) and the control of blood pressure. Resveratrol blocks this effect via production of a mild amount of stress within the E.R.

    Vitamin D and E.R. protein misfolding

    It has been shown that vitamin D deficiency in lab animals increases E.R. stress that accelerates hardening of the arteries and high blood pressure.

    The prevalence of vitamin D deficiency is almost twice that for non-diabetics and doubles the risk for cardiovascular disease compared to vitamin D adequate subjects. The provision of supplemental vitamin to diabetics is described as a “natural endoplasmic reticulum stress reliever” that induces a type of white blood cell (macrophage) that is “anti-atherogenic.”

    Vitamin D + resveratrol synergistically restore protein folding

    In a novel human study, a combination of vitamin D, omega-3 fish oil and resveratrol normalized the unfolded protein problem in the E.R. and helped some patients maintain mental acuity during 3 years of supplementation.

    E.R. stress is a critical factor in Alzheimer’s disease. An antibiotic drug (tunicamycin) induced E.R. stress in brain cells, a problem completely reversed by the combination of vitamin D plus resveratrol. Researchers conclude vitamin D + resveratrol may “be an effective maneuver in the treatment of Alzheimer’s disease in human subjects.”

    Heart failure, often experienced as an enlarged heart, can be experimentally (chemically) induced. In one lab dish experiment enlarged heart muscle cells were effectively treated with resveratrol, which suppressed enlargement and cell death by inhibition of E.R. stress.

    When resveratrol is instilled into diabetic rodents, resveratrol restores function to heart muscle cells by reduction of E.R. stress and therefore reduces occurrence of heart muscle cell death that would otherwise result in heart failure.

    Pro-oxidant mega-dose resveratrol and the E.R.

    Pro-oxidant mega-dose resveratrol can induce E.R. stress sufficient to induce programmed cell death (apoptosis), which may be beneficial in the treatment of cancer.

    Resveratrol via its ability to alleviate E.R. stress has produced only modest improvements in fatty liver compared to a calorie-restricted diet in lab animals. However the use of pro-oxidant mega-dose resveratrol in laboratory animals (equivalent to 14,000 milligrams resveratrol in a 160-lb human) precludes it from producing optimal health benefits.

    Resveratrol has a profound effect upon the E.R. in cancer cells. When extremely high concentrations of resveratrol are achieved, calcium is released from the endoplasmic reticulum to selectively kill cancer cells but not healthy cells. (This would require a doctor’s supervision.)

    Similarly, when high concentrations of resveratrol are achieved in cancer cells also instilled with saturated fat, this combination induces the death of cancer cells via extreme E.R. stress.

    Among 1726 molecule screened for their ability to induce E.R. stress to selectively kill cancer cells, resveratrol and its liver metabolite piceatannol were the most potent.

    Modern medicine’s approach

    Metformin, an anti-diabetic drug also known for its anti-aging effects, has been shown to help clear unfolded proteins from the E.R. and as problematic as it is (induces vitamin B12 and magnesium deficiency), would be modern medicine’s best drug entry into the clinical treatment of E.R. stress.

    E.R. stress and age-related eye disease

    When an experimental antibiotic (tunicamycin) that is known to induce E.R. stress is injected into animal eyes, the electrical impulses in the eyes in response to light stimulus is impaired. The co-administration of the antibiotic plus an iron-chelating drug reduces the loss of light sensitivity. Iron chelators may be appropriate for eye diseases that involve E.R. stress.

    Allicin and the E.R.

    Allicin, the active principal molecule in fresh-crushed garlic cloves and buffered (alkalinized) garlic tablets (Garlinex) reduces E.R. stress. When an E.R. toxin (tunicamycin) was administered to laboratory animals they exhibited significant impairment of cognition (thinking). The co-administration of allicin reduced E.R. stress-related mental deficits.

    The evidence is compelling. Endoplasmic reticulum therapy can begin early, before initiation of disease or the aging process itself. Economical natural remedies abound and await use by an informed public. ©2017 Bill Sardi, ResveratrolNews.com

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