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  • Will Resveratrol Pills Produce A Longer Life? There May Be A Partial Answer

    March 12, 2016: by Bill Sardi

    Resveratrol pills are posed as a molecular mimic of a limited calorie diet.  Short of a ten-decades long study it may be difficult to produce conclusive evidence that resveratrol pills promote the same lifespan-healthspan doubling effect of a calorie-restricted diet in laboratory animals. Such a study would be impractical as well as exceedingly expensive.

    Longevity seekers must rely upon animal studies or markers of human aging to measure whether an intervention like daily resveratrol (rez-vair-ah-trol) consumption would be worthwhile

    Will resveratrol pills significantly extend the healthspan and lifespan of humans? There may now be a partial answer to that question, though it takes reading some round-about science.

    The lost vitamin: C

    Many generations ago humans lost their ability to internally produce vitamin C (also known as ascorbic acid or ascorbate).  A mutation in a gene that produces an enzyme (gulonolactone oxidase) in the liver resulted in humans, unlike most other animals, having to completely rely upon dietary sources of vitamin C to maintain health and avert scurvy, a state of frank vitamin C depletion.

    The result of this gene mutation is that humans live shorter, less healthy lives.

    Biochemist Irwin Stone educates us about the life prolonging properties of vitamin C in his treatise entitled Homo Sapiens Ascorbicus published decades ago. [Medical Hypotheses 1979]

    According to Stone, mammals that make their own vitamin C live 8-10 times beyond their age of physical maturity. Mammals without this ability have a difficult time reaching 3-4 times. Humans physically mature (growth stops) around age 18 years and live about 70-80 years today, or about 3.88-4.44 times beyond maturation.  If this gene mutation could be corrected this would translate into humans living 144-180 years.

    Modern humans do have the option to supplement their diet with oral vitamin C.  But that won’t completely make up for the endogenous on-demand synthesis of vitamin C.  In animals that do synthesize vitamin C internally, many thousands of milligrams of ascorbate are produced per day, more with physical or emotional stress, elevated blood sugar, infections, etc.  Consumption of thousands of milligrams of vitamin C every day is probably beyond practicality for most people.

    A mouse makes about 275 milligrams of vitamin C per day per kilogram (2.2 lbs.) of body weight. If a mouse weighed 154 pounds, about the weight of a human, this would amount to about 19,250 milligrams of vitamin C per day. A 160-pound goat produces about 13,000 milligrams per day, and more under stress. A dog or cat will produce about 40 milligrams of vitamin C per kilogram of body weight per day, or the equivalent of 2800 mgs per day if these animals were about the same size as humans. Using animals as a rule of thumb, humans may benefit from consumption of anywhere from 2,000-20,000 milligrams per day.

    There is considerable evidence that higher vitamin C intake from the diet or food supplements prolong the life of humans. [Knowledge of Health 2002]

    Supplemental vitamin C as replacement

    It is instructive to read of an experiment conducted with genetically altered mice that also lack the enzyme required for endogenous vitamin C production.  Even though these mice given supplemental vitamin C had a lifespan similar to mice that have an intact gene to produce the gulonolactone oxidase enzyme required to synthesize vitamin C, their metabolic profile differed.

    Vitamin C deficiency accelerates aging and shortens longevity in laboratory animals. [Journal of the Pharmaceutical Society of Japan 2010]

    Mice that are genetically bred so they do not produce vitamin C in their liver (their gulonolactone oxidase enzyme is non-functional) develop symptoms of scurvy when they are not fed vitamin C.  The fortification of their chow or drinking water with vitamin C restores these mice to normal lifespan.

    Surprisingly, outside of habitual vitamin C consumption there may be newly published evidence that resveratrol may make up for this universal gene mutation in humans.  The lifespan of gene mutated mice with low dose vitamin C was extended to 8.5 months whereas 40-times that amount increased median lifespan to 23 months, almost a trebling effect.  [Aging Feb 2016]  But we are talking about taking fifty 1000-mg vitamin C pills a day to replicate that effect in humans.  But there is more to learn.

    Enter SMP-30: an anti-aging protein

    Another molecule required for endogenous vitamin C production is Senescence Marker Protein-30 (SMP-30), also known as regucalcin.

    Most animals produce vitamin C internally via a pathway that includes SMP-30.  SMP-30 helps to limit accumulation of fats in the liver and decreased tolerance of glucose (sugar).

    SMP-30 is described as “the penultimate step in the pathway to synthesize vitamin C.”  Among mice genetically altered to produce no SMP-30, vitamin C restores a normal phenotype (genetic composite). [Biomolecular Concepts 2011]

    There are generally copious amount of SMP-30 in the liver of young adult humans.  SMP-30 decreases with advancing age.  SMP-30 (also known as regucalcin) is primarily found in the liver and kidneys but also in lesser amounts in other organs.

    SMP-30 was identified as a marker of aging over a decade ago.

    In laboratory mice that have been genetically altered so as not to produce SMP-30 or vitamin C (via missing gulonolactone oxidase enzyme), the generation of  potentially harmful free radicals (superoxide) increases and an unusual amount of lipids (fats) accumulate in the liver of these animals. [Biological & Pharmaceuticals Bulletin 2009]

    Similarly, researchers placed liver cells in a lab dish that were capable of over-producing SMP-30 and this resulted in enhanced efflux (exit) of intracellular calcium and reduced generation of potentially harmful free radicals.  Therefore, these cells  became resistant to injury.  SMP-30 exerts indirect antioxidant activity and thus may protect cells from injury during aging.  [Biological & Pharmaceuticals Bulletin 2009]

    SMP-30 and cell senescence

    Decreases in SMP-30 may contribute to senescence.  The over-production of SMP-30 in animals serves to decrease formation of harmful species of oxygen known as free radicals.  SMP-30 serves as an antioxidant by enhancing the efflux (expulsion) of calcium from living cells, or said in another way, inhibiting the influx and high concentration of calcium in living cells, thus reducing oxidation.  Sick cells exhibit calcium overload.  SMP-30 is known as a calcium binding protein.  [Biological & Pharmaceuticals Bulletin 2009] In fact, SMP-30 was found to be identical to the calcium binding protein called regucalcin.  [Mechanisms Ageing Development 1999]

    SMP-30 protects brain cells from oxidative damage without elevating internal enzymatic antioxidants glutathione, catalase and superoxide dismutase. [Mechanisms Ageing Development 2006]  In other words, it is not serving to activate other internal antioxidants but has intrinsic antioxidant power itself.

    So SMP-30 has an antioxidant effect that appears to overlap that of vitamin C.

    When SMP-30 gene is genetically knocked out of mice they develop scurvy-like symptoms and brittle bones.  [Proceedings National Academy Science 2006]  Similarly, vitamin C deficiency is associated with bone loss (osteoporosis) in aged humans.

    Fatty liver is a prevalent health problem.  Over 90% of obese individuals have a fatty liver condition.  [American Family Physician 2006]  When mice have their SMP-30 gene knocked out, fatty liver often follows.  Decreased SMP-30 levels in the liver and blood samples of humans with fatty liver have been reported.

    Genetically inactivate SMP-30 in laboratory mice and they immediately display symptoms of scurvy. [International Journal Experimental Pathology 2012]  SMP-30 deficient mice have a shortened lifespan. [Biochemical Biophysical Research Communications 2004]

    SMP-30 is primarily produced in the liver and kidneys but is found in lesser amounts in other tissues.   SMP-30 deficient mice have 3.6 fold higher triglycerides.  [Annals New York Academy Science 2004]

    Mice that do not synthesize SMP-30, just like mice who have a non-functioning gulonolactone oxidase gene, are incapable of internally producing vitamin C.  Mice without a functioning SMP-30 gene have ~5% as much vitamin C compared to normal mice. [Geriatric Gerontology International 2014]

    While the impairments and shortened lifespan of genetically altered mice that do not internally produce vitamin C can be reversed with supplemental vitamin C, mice genetically altered so they don’t synthesize SMP-30 exhibit symptoms of scurvy that are not reversed by supplemental vitamin C. [Proceedings National Academy Science 2006]

    SMP-30: Marker of aging

    SMP-30 is considered an important marker of aging.   SMP-30 declines with advancing age but calorie restriction clearly blunts the decline of this protein. [Experimental Gerontology 2004; Antioxidant Redox Signaling 2006]  Recall that resveratrol is considered a molecular mimic of calorie restriction.

    Mice whose SMP-30 gene has been inactivated exhibit early visible accumulation of cellular debris called lipofuscin (pronounced līp-ō-,-ˈfyü-sən) [Geriatric Gerontology International 2010], which is a marker of aging.  [Advances Experimental Medicine Biology 1989]

    Laboratory mice with an inactivated form of SMP-30 have increased blood sugar (glucose) levels compared to mice with functioning SMP-30. [Islets 2010]

    Cell senescence is defined as when cells no longer divide and replace themselves with younger cells and then die off.  Instead, senescent cells no longer replicate themselves in what appears to be an effort to reduce the odds of cancerous growth.  Only recently have biologists recognized that cellular senescence is not benign but rather increases frailty with advancing age and shortens human lifespan.  In animal experiments, selective elimination of senescent cells can extend lifespan by 35%!  [Genetic Engineering & Biotechnology News 2016; Nature Feb 3, 2016]

    Back to resveratrol

    Finally, with all of that said, we get back to resveratrol.  Researchers in Japan have recently reported that resveratrol increases SMP-30 at a far lower dose concentration than metformin, a commonly used anti-diabetic drug.  [Public Library of Science One, Dec 2015]

    In this lab dish study human cells obtained from the inner lining of arteries (vascular endothelial cells) were used.  Resveratrol helped to prevent cells from becoming senescent as induced by high blood sugar (glucose) concentration.  A single exposure to high blood sugar may result in a prolonged senescent effect upon these cells in a phenomenon called “metabolic memory.”  Resveratrol blocked metabolic memory and cell senescence.  The increase in SMP-30 protein is considered a main reason why.

    What can readers take away from this information?

    First, modern humans are genetically flawed and cannot entirely make up for their vitamin C deficient state by consuming vitamin C-rich foods.  Vitamin C dietary supplements are in order.  About 500 milligrams of vitamin C taken periodically throughout waking hours (500 mg every 4 hours, ~2500 mg total) results in maximum blood levels.   However, physical or emotional stress, high blood sugar, smoking, exposure to radiation, toxins, infection, dramatically increase the demand for vitamin C.

    Second, the new piece of information added to this is that supplemental resveratrol may make up for the age-related decline in SMP-30 protein and drift of cells into senescence.

    SMP-30 should be added to the growing list of longevity molecules (Sirtuin1/Sirtuin3 as survival genes and mimics of a calorie restricted diet; Klotho gene by virtue of its ability to inhibit insulin signaling; mTOR inhibitors like rapamycin).

    Resveratrol may act to prolong the human healthspan and lifespan not just by activation of the Sirtuin1 survival gene as initially proposed but also by making up for the universal gene mutation that leaves all of humanity in a perpetual state of vitamin C deficiency.  — ©2016 Bill Sardi,

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