• How To Maximize Health Benefits Provided by LONGEVINEX®

    March 10, 2013: by longevinex.com

    Low-Dose Is The Key To Achieving “Hormesis” Effect That Activates Internal Antioxidant Defenses

    The dose of natural molecules provided in Longevinex® has been carefully determined to achieve optimal biological effect. Excessive dose of Longevinex® or other molecules in the diet or food supplements similar to those provided in Longevinex® (bioflavonoids and polyphenols- list provided below) may be counterproductive and dull or negate the optimal health benefits that Longevinex® is designed to achieve.

    How Longevinex works

    In 1954 Denham Harman, a researcher at the University of Nebraska, first proposed the free radical theory of aging1 – that unpaired electrons from oxygen humans breathe produces a destructive species of oxygen (a free radical) that damages tissues and organs and over time leads to aging.

    Since then biologists have also learned that nitrogen gas, which comprises ~78% of breathable air, also produces its own species of free (unbound) radicals. Maybe 3-5 percent of the air humans breathe becomes potentially destructive free radicals.

    Dr. Harman’s discovery eventually led to many millions of people taking antioxidant supplements, but except for eliminating true deficiencies of essential antioxidants like vitamin C and vitamin E, antioxidant supplementation has yielded marginal health benefits2 or gains in longevity. In fact, there is concern that excessive amounts of some antioxidants may yield diminishing returns.3

    What is obvious is that most centenarians (those humans who live 100 years or more) achieve longevity without taking dietary supplements. In fact, long-living elders living in Okinawa use fewer antioxidant supplements than elders in the USA but live longer.4 So the amount of protective antioxidants centenarians consume from the diet is relatively small, yet somehow effective.

    Many health seekers may be surprised to learn that a so-called healthy diet is not responsible for super-longevity among centenarians. For example, increased servings of fruit and vegetables and whole grains do not significantly reduce the risk for heart attacks.5 The public health impetus to indiscriminately eat more fruits and vegetables, while desirable, does not beget longevity per se.

    Internally-produced antioxidants

    Centenarians exhibit higher circulating levels of antioxidants than in other aged subjects. Some of those antioxidants however are created internally rather than acquired from the diet. These are endogenous enzymatic antioxidants such as glutathione (glu-ta-thy-on), catalase and superoxide dismutase (SOD), and they are far more promising in prolonging the healthspan and lifespan of humans than any store-bought antioxidant.

    What can be confusing is that some centenarians exhibit low levels of inflammation and therefore do not trigger activation of more of these internal antioxidants. Low levels of enzymatic antioxidants are found in a state of health, and high activity levels with inflammation, infection or malignancy. For example, SOD activity has actually been found to be lower in centenarians.>6 When internal enzymatic antioxidant activity is high, this means the body is under duress. They are activated on an as-needed basis.

    What centenarians could have in common around the globe is that they may be subject to a variety of mild biological stressors, such as low-dose terrestrial radiation, high-altitude shortage of oxygen, or limited availability of food (mild food deprivation such as occurred in Okinawa), or molecular mimics of biological stress such as red wine, that switch on internal antioxidant defenses and presumably produce long life.

    The biological phenomenon, where mild biological stress increases internal antioxidant defense, is known as hormesis.

    Genetic mechanism behind hormesis revealed

    In the modern era, we are being fooled by the fact humans are living healthier (though over-reliant upon medications), but the maximal lifespan remains unchanged.7 Yes, there are more centenarians, but not super-centenarians living beyond 120 years. However, there is growing scientific evidence to show that mild biological stress (hormesis) may be responsible for this current upswing in human lifespan.

    Even low-dose medications such as Deprenyl (a forgotten anti-aging drug introduced in the 1990’s, now prescribed to treat Parkinson’s disease), which can be mildly toxic, could produce healthier longer-living humans.8 Deprenyl does so via activation of a gene transcription factor (a binder to DNA that controls the flow of genetic information) called Nrf2 that increases activity of two internal antioxidants SOD and catalase. This means a precise genetic mechanism for super-longevity is now known.

    Resveratrol, a key molecule in Longevinex®, works superior to Deprenyl as prolonged resveratrol supplementation has been demonstrated to increase enzymatic antioxidants (superoxide dismutase, catalase, glutathione, heme oxygenase) as well as non-enzymatic (vitamin C, vitamin E and beta-carotene) antioxidant levels in animal studies.9

    While hormesis has been described in the medical literature for over 50 years, gerontologists now propose molecules that stimulate Nrf2 may profoundly prolong the human healthspan.

    The dietary habits of many centenarians seem to be extremely rich in plant molecules10 that stimulate Nrf2 that in turn activate internal antioxidants. For example, resveratrol, a red wine molecule, activates Nrf2 and when provided in modest amounts, may produce unusual longevity.

    A recent study claims plant extracts from tea (morin), onion (quercetin), pine bark (taxifolin), as well as extracts from pomegranate, sesame and cinnamon, do not extend the life of laboratory animals, but excessively high doses were employed11, outside the range of hormesis. One wonders if researchers are intentionally ignoring hormesis to drive the public away from what could be a modern miracle.

    Indeed, a vegetable-based diet is considered by some experts to be a form of food and calorie restriction that begets longevity12.

    However, while the consumption of more fruits and vegetables does reduce mortality rates13, it does not necessarily produce super-longevity and unusual healthspan.

    It has now been revealed that the reported longevity on the island of Okinawa in the 1990s was due to the lack of food14, Okinawa being the poorest prefecture in Japan, and the recent improvement in Okinawa’s economy and availability of food has resulted in a rise in heart disease.

    Put hormesis into practice

    The importance of dosage to achieve hormesis cannot be overemphasized. Such a “life force” as hormesis cannot be ignored any longer, especially given the disappointment with prescription medicines.

    It is important to recognize hormesis is a “life force” that promises to make super humans who can think faster and more cogently, who are resistant to pain via production of endorphins, and who are resilient against chronic maladies in a manner that would antiquate most prescription drugs in use today. In fact, after many decades, hormesis is no longer being ignored and has caught the attention of Big Pharma. Pharmaceutical companies now want to profiteer off of hormesis.15

    As researchers explain, “novel types of innovative, mild, repeated stress or stimulation that challenge a biological system in a dose-response manner are likely to have an effect that, properly harnessed, can be used to delay, prevent, or reverse age-related changes in humans.”

    The dose response of hormesis is visualized in the so-called U-shaped or J-shaped risk curve where maximum biological survival is produced at relatively low dose16 and with increased dosage the protective effect vanishes and toxicity becomes worse than if the living organism were not exposed to it at all.

    Only recently has it been recognized that dietary antioxidants may exert the majority of their protective properties via activation of hormesis.17

    In humans, hormesis activates antioxidant mechanisms more powerful than taking a whole bottle of antioxidant vitamin pills. In fact, hormesis may explain why some studies show high-dose antioxidant pills begin to lose their effect compared to low doses.

    If humans can tap into this adaptive response on a regular basis, keeping themselves in survival mode, they would access the most powerful life enhancing mechanism designed into living organisms.

    Another way of describing hormesis is pre-conditioning, that is, turning on defenses in the body prior to an adverse event such as a heart attack or a stroke. It has been known for some time now that if a person experiences a mild blockage in an artery that supplies the heart with oxygenated blood and then experiences a later full-blown blockage of that artery (a heart attack), the damage to that area of the heart will be minimized because the heart turned on its defenses prior to the event. That is what hormesis agents do.

    What surprised biologists is that oxygen free radicals, known to be tissue-damaging agents, “may be necessary to trigger a sequence of events that result in benefits… that produce cellular longevity” within the mitochondrial power plants within living cells. Overzealous use of antioxidants, particularly among healthy individuals, may be counterproductive.18

    Resveratrol and hormesis

    Resveratrol (rez-vair-ah-troll), known as a red wine molecule, is the best studied molecule known to induce hormesis and the only such small molecule where some dosage data is available.

    Researchers say many effects induced by resveratrol are dependent on dose and that opposite effects occur at low and high doses, being indicative of a hormetic dose response.”

    Then disappointment came in 2008 when researchers reported that mega-dose resveratrol did not extend lifespan in laboratory mice on a normal calorie diet. Yet these same researchers were also talking about resveratrol as a hormesis agent (low-dose plant-based hormetic agent).

    Resveratrol, a grape skin and red wine-derived polyphenolic molecules, exhibits hormetic action delivering numerous health benefits at lower doses while being detrimental at higher doses.

    Some researchers recognize that human clinical trials need to be based on the clear understanding of hormetic health benefits of resveratrol.19 But there are a number of planned human studies that intend to use mega-dose resveratrol20 that will surely produce a null or negative outcome.

    Of considerable interest is a unique commercial brand of resveratrol (Longevinex®) that protects the heart at an even lower dose (100 mg resveratrol) and continues to protect the heart even at high doses that typically destroy 100% of animal hearts tested with plain resveratrol. In other words, there is no toxicity at very high dose. This is the first time in biology an L-shaped toxicity curve has been exhibited.21 This makes Longevinex® the safest of all resveratrol supplements.

    Stem cells, resveratrol and Nrf2

    One of the most fascinating discoveries in recent times has been the possibility of injecting regenerative stem cells (unspecialized cells) into damaged tissues to make them like new again. However, stem cells are internally produced where inflammation or wound healing occurs, but they cannot easily survive an environment of destructive free radicals. It is instruction to learn that stem cells may not need to be harvested and re-injected into damaged tissues. Resveratrol has been demonstrated to activate internal stem cells via Nrf2. Therefore, resveratrol-based products could be used to regenerate damaged tissues internally.22To achieve this, proper dosage needs to be ascertained.

    Estimating dosage range to achieve hormesis

    In the 1990s the red wine-drinking French exhibited a mortality rate for coronary artery disease that was 266% lower than North America23 (90 versus 240 per 100,000 adults). This was despite a diet that has more cholesterol and fats than a typical western diet. This phenomenon became known as “The French Paradox.24

    More exacting studies found that the consumption of 3-to-5 (5-oz) glasses of dark, aged red wine produced the lowest heart disease mortality rate.25 Given that dark, aged red wine provides about 60 milligrams of wine solids known as polyphenols (resveratrol, quercetin, catechin, kaempferol, malvidin, gallic acid, ferulic acid), that amount of red wine provided ~180-to-300 milligrams of these antioxidant molecules.

    Using that dosage range as a model, Longevinex® was initially formulated to provide a similar dosage (265 milligrams) and array of polyphenolic/metal-chelating (key-lay-ting) molecules as found in 3-to-5 glasses of red wine, without the alcohol. The idea was to create a molecular mimic of a calorie restricted diet. The array of molecules in Longevinex® is intended to produce synergistic (more than additive) effects. Combinations of polyphenols have been demonstrated to exert greater biological activity.

    Indeed, when low-dose Longevinex® was put to the test in a short-term laboratory study, it activated 9-fold more longevity genes26 (1711) compared to plain resveratrol (225) or a limited-calorie diet (198), while employing a dose of resveratrol 17-320 times lower than prior animal studies. Furthermore, a long-term limited calorie diet modifies 831 genes whereas Longevinex® switched 677 of these 831 in the same direction (switched on or off) as a calorie-restricted diet.

    This data suggests longevity seekers would need to take resveratrol over a period of many years to achieve the same biological effect that Longevinex® produced over a matter of weeks. Longevinex® is still the closest proven molecular mimic to a food-deprivation diet.

    Furthermore, low-dose Longevinex® was demonstrated to reduce damage (area of scarring) in animal hearts that were intentionally subjected to a heart attack (blockage of circulation) far better than plain resveratrol using a dosage of resveratrol (100 mg human equivalent) far lower than plain resveratrol (175-350 mg).27 Essentially Longevinex® turned a mortal heart attack into a non-mortal event, something that has not been demonstrated with aspirin or statin drugs.

    Rise in mental focus and alertness

    One of the common reports received from users of Longevinex® is that of marked improvement in mental focus, alertness and memory. The underlying mechanisms for this are just now being understood. Resveratrol has a natural anti-depressant effect via inhibition of an enzyme known as monoamine oxidase (MAO).28

    There are MAO-inhibiting drugs used to treat mood problems. Resveratrol also produces a significant increase in brain chemicals such as serotonin (natural anti-depressant) and adrenaline (an adrenal stimulant). Mental acuity is then sharpened.

    The problem of too much

    It has also been learned that molecules like resveratrol are antioxidants at low-dose but promote oxidation (and cell death) at high dose concentration. This pro-oxidant action would be desirable when attempting to kill off bacteria, viruses or malignant cells. However, this pro-oxidant state is more appropriately employed under a doctor’s supervision. For healthy adults, the more practical objective is to activate hormesis (internal antioxidants) via Nrf2 with low-dose molecules.

    Over-doing it

    At some point, the promise of increased healthspan and lifespan via hormesis vanishes with excessive consumption. A potential problem is that health seekers may consume many of the same class of molecules that trigger hormesis29 in the form of dietary supplements which can then result in over-dosage and negate any hormetic action altogether. How many supplement users take curcumin, green tea extract (EGCG), or extracts from grape seed, rosemary (carnosic or rosmarinic acid), broccoli (sulforaphane), milk thistle (silibin), cinnamon, vanilla, acai berry, pomegranate (ellagic acid), apple peel (quercetin), in addition to resveratrol? It is not uncommon to find many health seekers taking many of these molecules as food supplements.

    Excessively high doses of resveratrol and similar molecules (polyphenols, flavonoids) may inhibit an enzyme that keeps a lid on the stimulant action of adrenaline (epinephrine).30

    It is important to emphasize that natural molecules like those provided in Longevinex® do not increase adrenal stress hormones, life’s stressful events do, but once abnormally high stress hormones levels are produced, excessive consumption of polyphenols may negate the body’s ability to handle that stress.

    In so doing, high-doses of these natural molecules may lead to undesirable symptoms31 of anxiety, feeling of panic, headaches (migraines), heart palpitations and nausea.

    To achieve hormesis (optimal healthspan and lifespan) the total of these molecules from dietary supplements should range from ~175 milligrams to 350 milligrams.

    It is important to emphasize the dosage range to achieve hormesis was derived from what was added (supplemented) to the typical human diet by wine or supplements. Total consumption of polyphenols and flavonoids, diet plus supplements, would be much higher.

    The competitive commercial war to produce dietary supplements that offer stronger and stronger doses of polyphenols and flavonoids may be counterproductive. For example, there are 1000 milligram mega-dose resveratrol pills that are promoted to consumers with the idea of “get more for your money.” That would be doubling the amount of polyphenols in the diet in a single pill.

    Natural foods and molecules that may increase stress hormones when consumed in excess

    Quercetin Apple peel, onions, blueberry, chocolate Strong
    Hesperetin Lime, orange, lemon Strong
    Vanilla Chocolate, ice cream Strong
    Naringin Grapefruit Strong
    Nobiletin Orange Strong
    Tangeretin Orange Strong
    Red wine extract (no alcohol) Red wine Strong
    Catechin Cocoa, chocolate, red wine
    Epigallocatechin gallate Tea, peacans Strong
    Theaflavin Black tea Strong
    Cyanidin Black currant, cherries, olives Strong
    Salicylic acid Fennel, cranberry, cinnamon Modest
    Resveratrol Wine, grapes Modest
    Chlorogenic & caffeic acid Coffee Modest
    Extracts of alcohol spirits Alcohol spirits Brandy, gin, whiskey, sherry

    One study shows the intake of polyphenols in beverages alone, such as those listed above, amount to about 180 milligrams per person per day (in Spain).32 Yet another report says the intake of polyphenolic molecules from the diet could be as much as 1 gram (1000 milligrams) per day.33

    The precise polyphenol content of foods and beverages can be accessed online at Polyphenol-Explorer.34 A briefer online tool can be accessed here.35

    Longevinex® provides 265 milligrams of polyphenolic molecules (resveratrol, quercetin, ferulic acid, rice bran phytate) and leaves room for consumption of 1-2 glasses of dark red wine (60-120 mg polyphenols) or from other food sources to achieve an intake level roughly equivalent to consumption of 3-to-5 glasses of red wine.

    To learn more about hormesis, access the online report entitled: “Is Humanity Passing Up The Greatest ‘Life Force’ Ever Discovered?” located at: http://www.resveratrolnews.com/is-humanity-passing-up-the-greatest-life-force-ever-discovered/443/

    Important take-home lessons

    • Hormesis is the most powerful health force known and is paradoxically triggered by mild biological stress or toxins that activate internal antioxidants.
    • Typically consumers know hormesis has been achieved when they experience elevated mood, improved mental clarity and alertness, memory enhancement, greater physical stamina and greater tolerance to pain.
    • While hormesis can be activated by intermittent exposure to low-dose radiation, high-altitude mild oxygen deprivation or food deprivation (but not starvation), a narrow dosage range of natural molecules can mimic these mild biological stressors, as exemplified by red wine or red-wine resveratrol pills. A pill (Longevinex®) that provides an array of natural molecules including resveratrol in a measured amount has been demonstrated to exhibit hormesis without the typical toxicity at high doses. Longevinex® provides a reliable and proven way for humans to employ hormesis on a daily basis.
    • Over-consumption of polyphenols (flavonoids) may dull or negate hormesis, over-producing stress (adrenal) hormones that can induce symptoms.
    • Polyphenols are universally found in many beverages, foods and spices and consumption would be difficult to measure because the diet differs from day to day. However, the amount and array of polyphenols added to the diet from beverages (wine) and dietary supplements appear to control hormesis. Longevinex® has been designed to provide polyphenols in a mid-hormesis dose (100 mg resveratrol/265 mg) leaving room for consumption of wine or other modest-dose polyphenols.
    • The over-consumption of polyphenols in dietary supplements (examples: curcumin from turmeric, grape seed, green tea extracts, milk thistle, quercetin, cinnamon, acai berry, bilberry, elderberry, many others), as well as from beverages like coffee, tea and wine, may be counterproductive and negate hormesis. Check your supplement regimen, particularly if you experience heart palpitations, skin rash, anxiety, headache, nauseas, hunger, weakened immunity or insomnia.

    Whether humanity makes a course correction to embrace the powerful health and longevity properties of hormesis is to be determined. It has been over 50 years since hormesis was first described in scientific journals. In this modern world there may be a need to commercialize hormesis to build awareness and allow insurance plans to pay for associated costs of delivery. Regardless of the foot-dragging by modern medicine, health and longevity seekers can learn about hormesis and put it into practice without prescription and without waiting for researchers and physicians to catch up with existing science.

    © 2013 Resveratrol Partners LLC, dba Longevinex®


    1. Harman D, Origin and evolution of the free radical theory of aging:  a brief personal history, 1954–2009. Biogerontology Dec; 10 (6): 773-81.
    2. Ozkanlar S, et al, Antioxidant vitamins in atherosclerosis–animal experiments and clinical studies.  Advances Clinical Experimental Medicine 2012 Jan-Feb; 21 (1): 115-23.
    3. Thomas DR, Vitamins in aging, health and longevity. Clinical Intervention in Aging 2006; 1 (1): 81-91.
    4. Dodge HH, Comparisons of plasma/serum micronutrients between Okinawan and Oregonian elders: a pilot study. Journal Gerontology A Biological Science & Medical Sciences. 2010 Oct; 65 (10): 1060-67.
    5. Rautiainen S, Total antioxidant capacity from diet and risk of myocardial infarction: a prospective cohort of women. American Journal Medicine 2012 Oct; 125 (10): 974-80.
    6. Anderson HR, Low activity of superoxide dismutase and high activity of glutathione reductase in erythrocytes from centenarians.  Age Ageing 1998 Sep; 27 (5): 643-48.
    7. Calabrese V, Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity. Molecular Aspects of Medicine 2011 Aug; 32 (4-6: 279-304.
    8. Kitani K, The necessity of having a proper dose of (-)deprenyl (D) to prolong the life spans of rats explains discrepancies among different studies in the past. Annals NY Academy Science 2006 May; 1067: 375-82.
    9. Sengottuvelan M, Resveratrol ameliorates DNA damage, prooxidant and antioxidant imbalance in 1,2-dimethylhydrazine induced rat colon carcinogenesis. Chemical Biological Interaction 2009 Oct 7; 181 (2) 193-201.
    10. Davinelli S, Extending healthy ageing: nutrient sensitive pathway and centenarian population. Immunity & Aging, 2012 Apr 9; 9.
    11. Spindler S, Influence on longevity of blueberry, cinnamon, green and black tea, pomegranate, sesame, curcumin, morin, Pycnogenol, quercetin and taxifolin fed isocalorically to long-lived, outcrossed mice. Rejuvenation Research 2013 Feb. 24.
    12. Ginter E, Vegetarian diets, chronic diseases and longevity. Bratislava Medical Journal 2008; 109 (10): 463-66.
    13. Rissanen TH, Low intake of fruits, berries and vegetables is associated with excess mortality in men: the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. Journal Nutrition 2003 Jan; 133 (1); 199-204.
    14. Miyagi S, Longevity and diet in Okinawa, Japan: the past, present and future. Asia Pacific Journal Public Health 2003; 15 Supplement: S3-9.
    15. Maynard KI, Hormesis pervasiveness and its potential implications for pharmaceutical research and development. Dose Response 2011; 9(3):377-86.
    16. Lorimier AA, Alcohol, wine, and health. The American Journal of Surgery 2000; 180 (5): 357-61.
    17. Calabrese V, Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity. Biochim Biophys Acta 2012 May; 1822(5):753-83.
    18. Tapia, PC, Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: “Mitohormesis” for health and vitality. Medical Hypotheses 2006; 66(4):832-43.
    19. Das, DK, Commentary on ‘resveratrol commonly displays hormesis: occurrence and biomedical significance’ by Calabrese et al. Human Experimental Toxicology 2010 Dec; 29(12):1016-7.
    20. Resveratrol for Alzheimer’s disease, National Institutes of Health, Clinical Trials.
    21. Juhasz B, Hormetic response of resveratrol against cardioprotection. Experimental Clinical Cardiology 2010 Winter; 15 (4): e134-38.
    22. Gurusamy N, Red wine antioxidant resveratrol-modified cardiac stem cells regenerate infarcted myocardium. Journal Cellular Molecular Medicine 2010 Sep; 14(9):2235-9.
    23. Renaud S, Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 1992 Jun 20; 339: 1523-26.
    24. Renaud S, The French paradox: dietary factors and cigarette smoking-related health risks. Annals New York Academy Science 1993 May 28; 686: 299-309.
    25. Groenbaek M, Alcohol, type of alcohol, and all-cause and coronary heart disease mortality. Annals New York Academy Science 2002 May; 957: 16-20.
    26. Barger JL, Short-term consumption of a resveratrol-containing nutraceutical mixture mimics gene expression of long-term caloric restriction in mouse heart. Experimental Gerontology 2008 Sep; 43 (9): 859-66.
    27. Mukherjee S, Effects of Longevinex (modified resveratrol) on cardioprotection and its mechanisms of action. Canadian Journal Physiology Pharmacology 2010 Nov; 88 (11): 1017-25.
    28. Yanez M, Inhibitory effects of cis- and trans-resveratrol on noradrenaline and 5-hydroxytryptamine uptake and on monoamine oxidase activity. Biochem Biophys Research Communications 2006 June 2; 344 (2): 688-95.
    29. Kelsey NA, Nutraceutical antioxidants as novel neuroprotective agents. Molecules 2010 Nov 3; 15 (11): 7792-814.
    30. Coughtrie M, Interactions between dietary chemicals and human sulfotransferases-molecular mechanisms and clinical significance. Drug Metabolism & Disposition 2001 Apr;29 (4 Part 2):522-8.
    31. What does an excess of norepinephrine cause? http://www.ehow.com/facts_5647343_excess-norepinephrine-cause_.html
    32. Hervert-Hernandez D, Contribution of beverages to the intake of polyphenols and antioxidant capacity in obese women from rural Mexico. Public Health Nutrition 2012 Jan; 15(1):6-12.
    33. Scalbert A, Polyphenols: antioxidants and beyond. American Journal Clinical Nutrition January 2005; 81 (1):215S-217S.
    34. http://www.phenol-explorer.eu/foods
    35. http://ajcn.nutrition.org/content/79/5/727/T1.expansion.html

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