Now researchers in China address bioavailability by showing resveratrol and resveratrol bound to glucuronate bind to albumin, deters oxidation (hardening) of cholesterol, inflammation and growth of tumor cells.  In other words, its metabolite forms are com parable in biological action to resveratrol.  Argument over: resveratrol exerts biological activity as a free unbound molecule and when bound to detoxification molecules.  ©2013 Bill Sardi, Resveratrol News.com

Chembiochem 2013 May 23. doi: 10.1002/cbic.201300080. [Epub ahead of print]

Influence of Glucuronidation and Reduction Modifications of Resveratrol on its Biological Activities.

Source

State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000 (China).

Abstract

Resveratrol (3,5,4′-trihydroxystilbene, RES), a star among dietary polyphenols, shows a wide range of biological activities, but it is rapidly and extensively metabolized into its glucuronide and sulfate conjugates as well as to the corresponding reduced products. This begs the question of whether the metabolites of RES contribute to its in vivo biological activity. To explore this possibility, we synthesized its glucuronidation (3-GR and 4′-GR) and reduction (DHR) metabolites, and evaluated the effect of these structure modifications on biological activities, including binding ability with human serum albumin (HSA), antioxidant activity in homogeneous solutions and heterogeneous media, anti-inflammatory activity, and cytotoxicity against various cancer cell lines. We found that 1) 4′-GR, DHR and RES show nearly equal binding to HSA, mainly through hydrogen bonding, whereas 3-GR adopts a quite different orientation mode upon binding, thereby resulting in reduced ability; 2) 3-GR shows comparable (even equal) ability to RES in FRAP- and AAPH-induced DNA strand breakage assays; DHR, 3-GR, and 4′-GR exhibit anti-hemolysis activity comparable to that of RES; additionally, 3-GR and DHR retain some degree activity of the parent molecule in DPPH^. -scavenging and cupric ion-initiated oxidation of LDL assays, respectively; 3) compared to RES, 4′-GR displays equipotent ability in the inhibition of COX-2, and DHR presents comparable activity in inhibiting NO production and growth of SMMC-7721 cells. Relative to RES, its glucuronidation and reduction metabolites showed equal, comparable, or some degree of activity in the above assays, depending on the specific compound and test model, which probably supports their roles in contributing to the in vivo biological activities of the parent molecule.

Copyright © 2013 WILEY-VCH Verlag GmbH &

One of Hollywood’s goddesses, and undeniably one of the most beautiful women in the world, Angelina Jolie has announced she underwent double mastectomy surgery in February of this year.  Knowing that what Hollywood stars do the public copies — expect a parade of double mastectomies to follow.

Similarly in 2005 when Australian pop singer Kylie Minogue announced she was undergoing cancer treatment, hundreds of thousands of women scheduled screenings, an unexpected outcome that was dubbed “the Kylie effect.”

CNN News anchor Zoraida Sambolin has also jumped on the bandwagon and announced she is undergoing a double mastectomy.

Of course, this is a bonanza for physicians and breast cancer clinics, but are women any healthier and will they survive longer?  That is not likely.  Nor are precious health care dollars being spent wisely.

The news story

In a news story, Angelina Jolie, age 37, is said to have a mutation in her BRCA1 gene that gave her an 87% of developing breast cancer and a 50% chance of developing ovarian cancer in her lifetime.   Surgical removal of both of her breasts is said to reduce her risk for breast cancer to 5%.

The news report says “the brave star hopes that she can encourage other women to be informed and consider their options.”   Bottom line, Jolie is going to become the poster girl for what is likely to become an epidemic of unnecessary screening and treatment.

Apparently actress Jolie appears to have elected to undergo surgery based solely on the results of genetic screening that showed she carries a mutated form of the BRCA-1 gene.  News reports did not say she had any solid tumor in either breast.

Only an estimated 5-10% of American women have a faulty (mutated) BRCA-1 gene.

The unthinkable: breast removal without cancer

What we have here is a previously unthinkable situation.  In private consultation with a surgeon (who certainly is not an unbiased party), a frightened woman can elect to undergo removal of her breasts even though she has no detectable cancer at all, just a BRCA gene mutation.  Surgeons are all too happy to calm a woman’s fears and lop off her breasts before there is any sign of disease whatsoever.

Women whose close family members have succumbed to breast or ovarian cancer are the easiest to talk into lopping off their breasts.  One study shows women whose mothers succumbed to ovarian cancer, like Angelina Jolie, are 7.9 times more likely to opt for surgical removal of their breasts and ovaries than women without a family history.

Risk for gene mutation increases with mammography

What is not disclosed now is that frightened women who have a family history of breast cancer, thanks to the misdirected encouragement of these celebrities, may unwittingly increase their risk to develop BRCA gene mutations in their zeal to get screened.  Here’s how.

Ironically, radiation emitted from x-ray mammography is documented to induce the very mutations in BRCA-1 and 2 genes that are associated with progression of the disease.   Researchers suggest mammography x-rays may not be the method of choice to detect breast cancer among women carrying the BRCA gene mutation.  Now a sinister trick would be to subject women to x-ray mammography just prior to genetic testing, and fresh mutations in their BRCA-a DNA would be detected.  Don’t think some enterprising breast clinic hasn’t thought of this.

Should women with a tumor in one breast undergo double mastectomy?

Most women with a detected lump in a single breast are not likely to face the same situation as Angelina Jolie.  That is because most will not carry a mutated form of the BRCA-1 gene.

Among women who have one breast removed and retain the other breast, there is a 0.4% risk of dying within 5 years and a 6.8% risk of dying within 20 years from first diagnosis.  So women should not necessarily follow Angelina Jolie’s footsteps.

A bulletin just issued by The American Society of Breast Surgeons says women with diagnosed breast cancer in one cancerous breast that choose to undergo surgical removal of their healthy breast face unnecessary complications.  This physician group says there is no strong evidence that suggests the removal of the second breast has a survival benefit.  That advice applies to women without the BRCA-1 gene mutation.

Just when breast screening was going out of vogue

The groundswell of women who are now likely to race to breast clinics for screening, science is pointing to fewer, not more, screening.  A report published in the journal Breast Cancer Research asks: “Is the tide turning against breast screening?”  The report says screening for detected cancers are unlikely to be cases that were “caught early” and more likely represent women who will receive harmful, unnecessary treatment.

Consumer Reports says: “The medical and public-health community has systematically exaggerated the benefits of screening for years and downplayed the harms.  Their report quotes a leading physician to say in 2008 there were an estimated 70,000 women 40 and older who were found to have small, non-aggressive tumors that were treated even though “they probably wouldn’t be life-threatening.”

Lifetime risk for a woman developing breast cancer is ~10%.  This in itself says 9 of 10 women screened for the disease will not benefit from screening and may be mistakenly diagnosed with cancer they don’t have.

About BRCA genes

What is known is that BRCA-1 and BRCA-2 are cancer suppressor genes. A mutation in these genes can spell trouble for women over their lifetime.  Yet, death from breast cancer is not inevitable as it is admitted lifestyle choices reduce the risk considerably.  This suggests these genes are repairable.

It is well known that certain small molecules can aid in DNA repair.  One of the most promising molecules is resveratrol, known as a red wine molecule.

For example, resveratrol has been shown to target BRCA-1 and BRCA-2 genes and activate them to control breast cancer cell growth in a lab dish.  Reduced activity of the BRCA-1 gene accompanies breast cancer.  In a lab dish, resveratrol activated (increased gene expression) of the BRCA-1 gene human breast cancer cells.

Resveratrol facilitates BRCA gene DNA repair

Resveratrol contributes to the stability of the genome (library of genes) via repair of double-strand DNA breaks.  DNA double-strand DNA breaks, the most severe type of mutation, if unrepaired cause ovarian tissues to age prematurely.

Living cells go through renewal cycles as old cells die and new ones replace them.  Slowing the cell renewal cycle enhances DNA repair and, for example, slow or prevent the susceptibility of healthy ovarian tissues to progress into cancerous tissue.   Low-dose resveratrol slows the cell renewal cycle (S-phase), thus facilitating DNA repair.

Breast cancers emanating from mutated BRCA-1 and BRCA-2 genes over-activate the hypoxia inducing-1 (HIF-1) gene.  Hypoxia is a state where cancer cells no longer rely upon oxygen for cell energy and produce sugar.  Resveratrol down-regulates the HIF-1 gene.

Resveratrol curbs estrogen

It is also well known that elevated estrogen levels are associated with BRCA gene mutations. Resveratrol has been identified as a natural molecule that serves as a safe replacement for estrogen and is a candidate for prevention of breast cancer.

Furthermore, resveratrol has also been shown to inhibit the movement and spread of cancer (metastasis) in advanced stages of breast cancer.

Resveratrol is considered a superior molecule in preventing the initiating step that turns healthy cells into cancer cells.

Asking physicians about resveratrol

Physicians are not likely to know much about resveratrol in regard breast cancer and any advice to take resveratrol pills would fall outside the existing standard of care for this disease.  However, most women would not be taking resveratrol as treatment but rather prevention.

Asking doctors about resveratrol pills is likely to be met with disfavor.  However, given there is no proven or available breast cancer preventive agent available today, women may want to ask this question: “what harm could come from it?”

Because resveratrol is a natural molecule that is widely available dietary supplement it is not likely to undergo the drug approval process.  If any brand of resveratrol pill would undergo successful testing that it prevents breast cancer it would be forced, by definition, into being a high-priced drug by the Food & Drug Administration.  Even if clinical trials were started soon it would take years to prove resveratrol prevents BRCA-1 mutations that promote breast cancer.  There is no financial incentive for pharmaceutical companies or physicians to submit resveratrol for clinical testing as a breast cancer preventive.

All what you have read here about resveratrol has been published for some time now but not one human clinical trial has been launched for breast cancer prevention.  Modern medicine may be intentionally overlooking the most promising anti-cancer weapon ever conceived.

Women can elect to take resveratrol pills on their own

No brand of resveratrol pill can make any claim it cures, treats or prevents any disease.  But consumers can read and learn about resveratrol and elect to take resveratrol on their own, despite the lack of studies that validate a specific brand.

It is important to recognize most brands of resveratrol pills have been found to be biologically inactive and it would be important to choose a brand that stabilizes resveratrol, as it is a molecule that is vulnerable to degradation once exposed to light, heat or oxygen, as well as a brand that has undergone safe and successful use in animals and humans.  Low dose resveratrol is considered superior to high dose resveratrol.

Based upon the best available evidence today, resveratrol pills are unproven, but certainly not disproven, and are probably the most promising preventive measure against breast cancer that exists, BRCA-1 gene mutations included.  ©2013 Bill Sardi, ResveratrolNews.com and KnowledgeOfHealth.com

The anticipation builds for anti-cancer drugs that target a broad array of genes that combat various types of cancer in different organs rather than a different drug for each cancer by their anatomical origin.  Instead of anti-cancer drugs for each organ, such as lung, prostate, breast and colon, geneticists now say new drugs in development may address many forms of cancer.

The first examples of this new thinking are studies published in the New England Journal of Medicine showing uterine cancer and leukemia have similar genetic fingerprints and could be treated by the same drug.  A large effort to this end is being commandeered at the Cancer Genome Atlas website.

However, the thinking is far too narrow now that geneticists know diseases are integrated via gene networks.  An online map can be viewed showing genes in many diseases overlap one another (note: it takes time to load).

Gone is the idea of using single-gene targeted drugs like Herceptin and Erbitux even though these drugs are still in common use today.  Given knowledge that cancer involves many genes, these gene-targeted drugs, which only prolong life by a few months, should be abandoned.

I responded to The New York Times report of this so-called breakthrough by submitting an online comment that asks: why not activate genes that promote health and prevent disease altogether rather than allowing cancer to get started? In other words, why not promote health rather than treat disease?

Genes are not static in nature.  Yes, if there is an abnormality in the DNA ladder that is called a gene mutation.  Researchers have identified 291 human genes that are mutated in human cancer, though not all of these are involved in a particular type of cancer.  Cancer actually causes gene mutations.

But researchers reveal cancer doesn’t just involve inherited or developed structural gene mutations (breaks in the DNA ladder) but also involves the dynamic protein-making capacity many genes, a process called epigenetics. When genes are making proteins this is called gene expression and when they are not this is called gene silencing.

Based on currently available knowledge, what gene-switching pattern is known to promote health and inhibit cancer?  That would be a gene pattern produced by calorie restriction, know to approximately double the lifespan and healthspan of animals and inhibit or delay cancer by cutting caloric intake in half.

In laboratory mice it is known that a calorie restricted diet practiced over the animal’s lifetime will significantly alter 831 genes.

The epigenetic effect of a limited calorie diet can be molecularly mimicked by consumption of small molecules that influence a broad array of genes.

A short-term study was conducted in 2008 where biologists compared a limited-calorie, a standard calorie diet plus resveratrol, a small molecule commonly found in red wine that is known for its anti-aging and anti-cancer properties and as a molecular mimic of calorie restriction, and a matrix of small molecules commonly found in red wine that included resveratrol as provided in a commercially available nutriceutical (Longevinex®).

In 12-weeks the calorie restriction diet significantly altered 198 genes and resveratrol 225 genes with overlap of many of these genes, partially confirming resveratrol molecularly mimics a limited calorie diet.  However, it would presumably require life-long consumption of resveratrol to molecularly achieve the same effect produced by life-long calorie restriction.

However, the resveratrol-based matrix (Longevinex®) activated 1711 genes and switched 81% of the 831 genes in the same direction as calorie restriction.  To date, this is the closest any array of small molecules has come to mirroring the effects of a limited calorie diet, at least in animals.

Why not go to the doctor to get your health pill rather than your disease treatment pill?  Why wait for disease to occur and then treat it when it could be prevented altogether?  Of course, such a paradigm shift in modern medicine would make cab drivers out of most oncologists.  Don’t anticipate any revolutionary change like this to occur in your lifetime.  — © 2013 Bill Sardi, Knowledge of Health, Inc.

The red wine molecule resveratrol is known to activate the Sirtuin-3 gene.  Longevinex, a branded resveratrol dietary supplement, has been shown to increase Sirtuin-3 gene protein 295% greater than plain resveratrol.  Read the abstract of the report below.

REJUVENATION RESEARCH Volume 16, Number 2, 2013

Rejuvenation of Adult Stem Cells:
Is Age-Associated Dysfunction Epigenetic?

Andrew R. Mendelsohn and James W. Larrick

The dysfunctional changes of aging are generally believed to be irreversible due to the accumulation of molecular and cellular damage within an organism’s somatic cells and tissues. However, the importance of potentially reversible cell signaling and epigenetic changes in causing dysfunction has not been thoroughly investigated. Striking evidence that increased oxidative stress associated with hematopoietic stem cells (HSCs) from aging mice causes dysfunction has been reported. Forced expression of SIRT3, which activates the reactive oxygen species (ROS) scavenger superoxide dismutase 2 (SOD2) by de-acetylation to reduce oxidative stress, functionally reju- venates mouse HSCs. These data, combined with numerous other reports, suggest that ROS act as a signal transducer to play a critical regulatory role in HSCs and at least in some other stem cells. It is likely that ectopic expression of SIRT3 restores homeostasis in gene expression networks sensitive to oxidative stress. This result was surprising because age-associated damage from impaired DNA repair had been thought to be irreversible in old HSCs. The effect of up-regulated SIRT3 in HSCs is one of first examples in which intrinsic cellular aging, not apparently associated with changes in the micro-environment, was reversed. However, the stability of rejuvenation in the absence of continued supplemental SIRT3 expression was not investigated. These data are consistent with a hypothesis that potentially reversible processes, such as aberrant signaling and epigenetic drift, are relevant to cellular aging. If true, rejuvenation of at least some aged cells may be simpler than generally appreciated.

PMID: 23488583

The results of this study may also help explain why telomere length is determined by gender as women have lower iron levels throughout most of life due to menstrual losses and are reported to have longer telomeres and a longer lifespan than males.

This study also points to interventions such as blood-letting and dietary avoidance of iron-rich foods to maintain telomeres and prolong human lifespan.

Other studies point to women who use multivitamins having longer telomeres than women who don’t take multivitamins.

Given that elevated iron levels, below true clinical iron overload, is associated with greater morbidity and mortality and shortened telomeres suggests iron may not just affect a minority of iron-overloaded adults but actually be a more pervasive influence over human lifespan.

The current recommendation for daily iron intake from the diet and supplements was established to prevent anemia with no consideration of excessive iron’s effect on telomeres.

This newly published study correlates with the over-mineralization theory of aging as postulated by this author.  — © Bill Sardi, ResveratrolNews.com

American Journal Hematology2013 Mar 20. doi: 10.1002/ajh.23438. [Epub ahead of print]

Telomere length and elevated iron: The influence of phenotype and HFE genotype.

Source

Department of Family Medicine, Medical University of South Carolina.

Abstract

Elevated body iron stores are associated with morbidity and mortality due to oxidative stress. Hereditary hemochromatosis, a common condition caused by HFE gene mutations, can lead to excess iron storage and disease but clinical penetrance of HFE gene mutations is low and many people with elevated iron stores lack HFE mutations. We analyzed data from the Hemochromatosis and Iron Overload Screening (HEIRS) Study to assess the relationship between HFE genotype (individuals with either homozygous or compound heterozygous status for C282Y and/or H63D HFE mutations were defined as genotype positive, or G+), elevated iron phenotype (individuals exceeding gender-specific transferrin saturation and serum ferritin threshold levels were considered phenotype positive, or P+), and leukocyte telomere length, a marker of biological aging and cumulative oxidative stress. In unadjusted analyses in comparison to individuals who were G-P-, G+P- were not significantly different (OR 0.74; 95% CI 0.26-2.04), while the G+P+ (OR 2.03; 95% CI 1.15-3.56), and G-P+ (OR 2.24; 95% CI 1.5-3.29) had increased risk of short telomeres (<=25^th percentile) rather than long telomeres (>=75^th percentile). In analyses adjusting for age, gender and race/ethnicity, the effect of individuals with elevated iron phenotypes having short telomeres persisted with G+P+ individuals (OR 1.94; 95% CI 1.02-3.72), and G-P+ individuals (OR 2.17; 95% CI 1.39-3.39) being significantly different from the G-P- group. In conclusion, elevated iron phenotype, but not HFE genotype, was associated with shortened telomeres. Further studies will be needed to determine if telomere length provides a marker for morbidities specifically associated with iron overload. Am. J. Hematology., 2013. © 2013 Wiley Periodicals, Inc.

Certainly the world has been waiting for resveratrol to live up to its promise as a molecular mimic of a limited calorie diet.  In the animal laboratory, 40-50% reduction of calorie intake among warm-blood mammals about doubles their healthy lifespan.  Could this happen for humans?  The science has been mixed so far.  Sardi says he knows why.

For one thing you can’t take healthy people and anticipate their pre-disease numbers to improve appreciably.  Often the measures modern medicine uses are not linked to improved outcomes or longer life.  For example, cholesterol is one measure of health that has never been shown to parallel mortality rates, says Sardi.

You have to measure true markers of aging, such as iron storage (ferritin), accumulation of cellular debris (lipofuscin), mitochondrial function, red blood cell width and labile iron, none which were measured in the recent study says Sardi.

He says another problem is that mega-dose resveratrol works in a contrary manner to elevate stress hormones, worsen pre-disease states and negate the full benefit achieved when a mild biological stress agent activates internal antioxidants via a phenomenon known as hormesis.   Sardi says mega-dose resveratrol runs contrary to what has been learned from wine drinking and laboratory studies.

This negative study, published in the journal DIABETES, cites a similar study where far less resveratrol (150 mg) used in this study (500 mg) was employed among a similar group of subjects over the same time period with successful results.  Numerous studies point to lower doses mimicking a calorie restricted diet, not mega-dose resveratrol, says Sardi.  “One would think researchers are intentionally trying to put the scientific kibosh on resveratrol,” he says.

The biggest oversight in evaluating these studies is that it takes a lifetime for a calorie-restricted diet to fully activate a vast number of longevity genes.  This was conclusively shown in a study with calorie restricted mice.

In the short-term (12 weeks), calorie-restricted diet activated 198 genes, but over the animal’s lifetime this diet activated 831 genes and took full effect.

In that same experiment, relatively low-dose resveratrol (equal to 100 milligrams in a 160-lb human) activated just 225 genes in the short-term.   If this experiment translates to humans, it would take life-long resveratrol supplementation to fully activate all of the longevity genes activated by a long-term limited calorie diet.

But remarkably, when a matrix of small natural molecules (Longevinex®) was combined with resveratrol, 1711 genes were activated over the short-term — double that of life-long calorie restriction and 7-times that of short-term resveratrol.

More precisely, the combination of natural molecules (Longevinex®) switched 677 of 831 (81.4%) longevity genes in the same direction as a calorie-restricted diet.  This is the closest mimic to a limited calorie diet ever demonstrated.

Longevity seekers may have to adhere to life-long use of resveratrol to achieve the same effect as calorie restriction, something that Longevinex® exceeded in just a few weeks.  If this is true, most resveratrol pill users are wasting their money.

www.longevinex.com

Some of the specific objectives are to improve resveratrol’s antioxidant activity, improve its anti-inflammatory properties, elevate its anti-viral activity, produce higher blood serum concentrations and greater stability, and increase its cancer cell-killing effect, etc.  Patents are being filed on improved resveratrol-like molecules.

But at the same time is Big Pharma attempting to disparage and subjugate resveratrol as a third-class molecule?

Recently researchers in Italy analyzed 14 off-the-shelf resveratrol dietary supplements.  Their published study comes to some questionable conclusions.  The primary findings of the study were:

Pharmaceutical-grade resveratrol (pure 100% trans resveratrol produced synthetically rather than extracted from a botanical source) “outperformed most competitors in both radical scavenging and antioxidant efficacy.”

But in some analyses, natural resveratrol was actually superior to synthetic resveratrol (“resveratrol analogs may have important antioxidative activity, but the one with the higher IC50 — measure of antioxidant activity – was presented by the natural compound.”

Resveratrol’s designation as a near-miraculous molecule is not derived from its antioxidant properties (it is in fact a weak antioxidant) but its ability to activate a broad number of genes.

The Food & Drug Administration has, in the past, said it would classify pure synthetically made molecules as “drugs” and botanical sources of lessor purity as “dietary supplements.”

To help prove an alleged superiority of synthetic resveratrol over botanical extractions, researchers tested 14 brands of resveratrol supplements for their ability to inhibit the growth of cancer cells (leukemia cells) in a lab dish.

• These researchers report that synthetic “pure resveratrol,” due to a “different substantial concentration” was found to be superior to botanically-based resveratrol in a lab dish.
• These same researchers reported the absence of any synergistic effect by adding other similar molecules to resveratrol.

This latter finding stands alone in the medical literature.  There are multiple examples of how resveratrol combined with other small molecules (polyphenols) work remarkably better (more than an additive effect).

Examine the following evidence for yourself.

• Resveratrol was found to work synergistically in a matrix of other red wine molecules.
• Resveratrol combined with tea molecules synergistically suppress skin cancer cell growth, breast cancer and growth of colon cancer cells.
• Resveratrol combined with other polyphenols and vitamin D worked synergistically to inhibit weight gain and improve bone strength.

One commercially available multi-ingredient resveratrol dietary supplement has already been demonstrated to:

1. Unlike plain (pure) resveratrol, exhibit no toxic cell-killing effect at high-dose concentration.
2. Restore near-normal gene activity patterns following a heart attack and prevent damage to heart muscle tissue in a superior manner to research-grade resveratrol, as measured by microRNA analysis.
3. Abolished the first sign of blood vessel disease (inability of blood vessels to dilate or widen) twice that of research-grade resveratrol.
4. Inhibit invasive new blood vessels that destroy the visual center of the eye (macula) when other FDA-approved drugs failed.  – Copyright 2013 Resveratrol ews.com

Bill Gifford, writing online for the New Republic, asks “Where’s My Red Wine Pill?” in the wake of confusing headlines which recently said the quest for an anti-aging pill is back on track now that a Harvard scientist has re-confirmed resveratrol (rez-vair-a-trol) targets the Sirtuin-1 survival gene and that a 150-year lifespan may soon be common.

The confusion emanates from the many incongruent facts that surround this scientific re-discovery, the most prominent being the European drug company that purchased a developmental red wine pill company located near Boston is now shutting its U.S.-based operation down — an announcement that followed the gene-target breakthrough by just a few days.

Of course, connecting the dots may be difficult for some, but not for all, especially those longevity seekers who have been following this pharmacological shell game for some time now.

Just exactly which shell is the anti-aging pill under?

That’s not to say that resveratrol isn’t living up to its promised expectation as a longevity pill.  A Harvard professor just said it is.  But the public is being asked to buy into the idea that the goal of achieving long sought-after super-longevity will have to be accomplished by some synthetic molecule that doesn’t molecularly resemble resveratrol.

Furthermore, to achieve what is being demonstrated in the laboratory and now among humans with resveratrol-like drugs would require a dose of resveratrol that is found in 100-glasses of red wine, said David Sinclair PhD at Harvard Medical School and co-founder of Sirtris Pharmaceuticals.  Dr. Sinclair intimated humanity will have to wait for its powerful drug-version of resveratrol to achieve super-longevity.

But wait, a 5-ounce glass of dark, aged red wine provides ~1-milligram of resveratrol and there are plenty of 100 mg resveratrol pills available in health food shops these days.  So should humanity hold its breath for Sirtris’ “new chemical entities” that are supposed to mimic resveratrol?

Learn before you buy

Before you stop reading and head off to buy a bottle of these vino pills, you might want to know not just any red wine pill will do.  A recent published study found only three of fourteen brands of commercially available resveratrol pills to be biologically active.  So the dietary supplement industry has its own shell game going.

The difference between what laboratory scientists use — research-grade resveratrol (that is preserved and stored in an airtight, opaque vial that is stored at minus-20 degrees Centigrade), and available dietary supplements, may be the fragility of resveratrol.  It is a molecule that is degraded into a different form when exposed to ultraviolet light as well as by heat and oxygen.  Very few companies make any effort to stabilize resveratrol before it is tableted or encapsulated.

Even if its active form, trans resveratrol, is preserved during manufacturing, it may not be active months later when it is consumed.

Back to the shell game

What laboratory scientists and clinical researchers have been doing is over-dosing animals and human subjects on resveratrol in what appears to be an intentional effort to produce null or negative results.  Large doses of resveratrol may actually increase damage to the heart after a heart attack, but similar large doses are now being planned for a large human study which may preclude any benefit and could doom the future of resveratrol.  Only a specially formulated brand of resveratrol avoids this cardio-toxic effect at high dose.

Resveratrol works, as Bill Gifford points out in his New Republic article, but only in the dosage range of 3-to-5 glasses per day, producing an unparalleled reduction in coronary artery disease mortality to 90 per 100,000 in the red wine-drinking French versus 200-240 per 100,000 in North America.

Another recent experiment shows resveratrol activates different gene pathways depending upon dose and that the Sirtuin-1 pathway is generally better activated by lower-dose resveratrol.  This is borne out by another recent paper citing low-dose but not high-dose resveratrol as being effective for diabetes among humans.

While 3-to-5 glasses of red wine would only provide 3-to-5 milligrams of resveratrol, that much wine would provide 180 to 300 milligrams of total polyphenols, the molecules believed to be responsible for its health benefits.  (There are 60 milligrams of polyphenols like resveratrol, quercetin, catechin, ferulic acid, in a glass of red wine.)  So the total milligram-dose of these molecules, not just resveratrol alone, is believed to produce its anti-aging effect.

That was demonstrated in a laboratory mouse study in 2008 when it was shown that a life-prolonging calorie-restricted diet activated 198 longevity genes, resveratrol 225 genes but resveratrol combined with other molecules 1711 genes, the latter being a commercially-available dietary supplement.

That resveratrol pill (trade name Longevinex®) switched 677 (81.5%) of 831 longevity genes in the same direction (on or off) as a calorie restricted diet, making it the closest molecular mimic to a food deprivation diet to date.  And it takes life-long adherence to a calorie-restricted diet to activate 831 longevity genes, something that Longevinex® exceeded by 9-fold in the human equivalent of a month.

This suggests the full effect of plain resveratrol pills would be achieved only after life-long use.  Strangely, the researchers who made this exciting discovery have never lectured about it and never mentioned it when they were interviewed on a 60-Minutes TV report in 2009, but ironically are reported to take this pill personally.

David Sinclair focuses his research on a single gene pathway, Sirtuin-1, but aging in humans is controlled by ~295 genes.  The idea of focusing on a single gene pathway may be a narrow way of looking at aging genetically.  Resveratrol is mischaracterized as a “dirty gene” that targets many genes when that is one of its unique advantages.  In fact, single gene-targeted drugs have been criticized as being too simplistic and have been met with disappointment.

Does Big Pharma have the resolve to make resveratrol a reality?

Preservation of resveratrol is one issue that may spoil its promise as an anti-aging pill, and dosage is another.  But the Harvard professor himself winks at his audience when he says (as quoted in Mr. Gifford’s report): “We know the science is real; the problem now is to push it over the goal line. If they don’t end up as drugs in our lifetime, it’s not the fault of scientists, and more of a business decision.”

Does Big Pharma really intend to bring this mega-pill to market? Did Sirtris Pharmaceuticals parent company penalize this breakthrough by yanking it from its geographical roots?

Dr. Sinclair seems to be bravely standing up to his employer when he is quoted to say: “”I’m advising [GSK] and my advice would be to continue being optimistic about clinical trials. That’s where the next big discovery will come from.”

Isn’t Dr. Sinclair tacitly saying Big Pharma may only be pretending it wants to bring this cure-all to market?  Did Big Pharma buy up Sirtris to take resveratrol pills off the market?  According to Dr. Sinclair, a resveratrol-like drug would address maybe 20 different age-related diseases in one pill.  Can we expect Big Pharma to put itself out of business?

Modern medicine’s latest answer to the problem posed by multiple medications (known as polypharmacy) is to combine many problematic drugs into one pill. But imagine the side effects and cost?  Drugs address symptom relief, not the cause of age-related diseases as do resveratrol and polyphenols.

Yet a larger question is how long can humanity go on over-drugging seniors in the latter years of their lives and bankrupting health insurance pools as well?  Wouldn’t a pill that slows down the rate of aging address all the age-related diseases and spare health plans from inevitable insolvency?

Recall that executives at Sirtris Pharmaceuticals actually made a dietary supplement version of its SRT501 resveratrol pill and began selling it online, but its parent company Glaxo-Smith-Kline, forbade this.  Wasn’t that an implied admission a resveratrol dietary supplement could be equivalent to Sirtris’ resveratrol drug?  What kind of shell game is Big Pharma playing on humanity?

Is resveratrol bioavailable?

Gifford goes on to question the bioavailability of resveratrol, saying most of it ends up in your bladder as expensive urine and mistakenly concludes that results in humans are “only modestly positive and far from overwhelming.”

While many resveratrol researchers continue to maintain resveratrol can’t possibly work because the liver intercepts it and attaches it to detoxification molecules, rendering it too large a combination molecule to pass through cell walls and enter genetic machinery within living cells, it is producing spectacular results in the human eye where it must pass through the liver and then the blood/ocular barrier to produce changes in gene activity.

One brand of resveratrol has, in early small group use, managed to remarkably restore lost vision to aged eyes when medications were ineffective, abolishes the first sign of arterial disease (loss of flow-mediated dilatation or widening of arteries upon physical exertion or mental stress) about twice as well as plain resveratrol, turned experimental mortal heart attacks in laboratory animals into non-mortal events and protected millions more heart muscle cells from damage than plain resveratrol (a similar human study would be unethical), and may, due to its demonstrated ability to inhibit new abnormal blood vessels, be a potent anti-cancer weapon.  So humanity may be closer than it is being told to a bona fide anti-aging pill.

A Ft. Lee, New Jersey preventive cardiologist, who recommends Longevinex® to all of his patients, reports a Medicare reviewer noted that none of his first-time heart attack patients have experienced a second event and none of his high-risk patients have experienced a first-time heart attack.

Researcher David Sinclair wrote his first paper on resveratrol and the French Paradox in late 2003.  It’s almost 10 years since that paper was published.  David Sinclair didn’t wait for all the science to be sorted out before he began taking resveratrol pills.  But he was forbidden by his university to reveal the brand of resveratrol pill (Longevinex®) he chose to use.

In summary, we’ve got a journalist asking “Dude, where’s my red wine (anti-aging) pill?;” researchers obfuscating its discovery by employing potentially problematic doses; an array of resveratrol dietary supplements (427 brands in all says the Natural Medicine’s Comprehensive Database) that are offered in a wide dosage range and are of specious quality, and leading researchers who aren’t waiting for the science to be sorted out to begin taking red wine pills themselves but aren’t forthcoming about the brand of resveratrol pill they personally use.

Bill Sardi is managing partner for Longevinex® located in Las Vegas, Nevada.

http://www.newrepublic.com/article/112706

Dude, Where’s My Red Wine Pill?

BY BILL GIFFORD

IF EVER THERE WAS A DRUG TAILOR-MADE FOR OVERWEIGHT AMERICANS, THIS SEEMED TO BE IT

It’s been a confusing couple of weeks for lovers of red wine and longevity. On March 8, Science published a paper demonstrating the mechanism by which certain molecules activate a family of proteins called sirtuins, which are thought to be responsible for some of the benefits of caloric restriction. (Those would include improved metabolism, resistance to cancer, and possibly increased longevity.)

Then, last Tuesday, GlaxoSmithKline suddenly announced that it was shutting down its Sirtris division, the Boston-based company that was actually supposed to be making the “red wine pills,” and which GSK had bought for $720 million just five years ago. Wait, what? Since one of those molecules was resveratrol, a compound found in red wine, headline writers across the globe freaked out. “ ‘Red Wine Pill’ Like Drinking 100 Glasses a Day Could Cure Major Diseases,” blared Fox News. Even Pravda weighed in, with “Red Wine Pill Could Extend Human Life Expectancy to 150 Years.”

The announcement marked a new, confusing phase in the long red-wine-pill saga, which kicked off with a front-page story in the New York Times on November 2, 2006. As the Times reported, Harvard researchers led by David Sinclair had found that resveratrol extended the lifespans of obese laboratory mice; that is, the mice pigged out on high-fat food, but their health did not seem to suffer. Thanks to the resveratrol, they lived just as long as normal mice. If anything, they did better: In videos, the chubby, resveratrol-treated mice jogged away happily on treadmills.

If ever there was a drug tailor-made for overweight Americans, this seemed to be it. Six months later, Sirtris—the company Sinclair cofounded to develop resveratrol-based drugs—had its IPO. Eleven months after that, in April 2008, GSK bought Sirtris outright for $720 million, or nearly double its stock-market valuation. Five years later, contra the headlines, there are still no red-wine longevity pills on the horizon. What happened?

Resveratrol itself is amazing stuff. It’s produced in the skins of grapes, late in their maturation, as a kind of natural antifungal agent. In 2003, Sinclair had discovered that it seemed to activate a longevity-promoting gene in yeast called SIR2. Similar genes are present in nearly all animals, including humans; in mammals, they’re called sirtuins, and they appear to be activated by caloric restriction. Resveratrol seemed to offer an easier, starvation-free route to sirtuin activation, and Sinclair and others then found that the stuff had similar effects on nematode worms, mice, and even fish. In a 2008 study, Sinclair even found that resveratrol helped turn normal mice into super-athletes with extraordinary endurance. (Paging Lance Armstrong…)

Beyond that, resveratrol also seemed to combat certain kinds of cancers, and it is a powerful antioxidant. It also has strong cardioprotective effects, and was thought to be responsible for the “French paradox,” the mysterious French ability to remain (relatively) healthy despite pigging out on Camembert and confit de canard. And it has been shown to fight diabetes, inflammation, and even neurological disorders.

As a pharmaceutical, though, resveratrol has issues. Sinclair calls it “a dirty drug,” meaning it has too many targets in the cell. But that may be moot, because it seems to have extremely low “bioavailability” in humans. (Translation: Most of it exits via your bladder.) That doesn’t stop people from spending $30 million a year on resveratrol supplements, including Sinclair himself (as he told the Times in 2006). But relatively few human studies have been done on resveratrol, and the results are modestly positive, but far from overwhelming, particularly in healthy adults.

Finally, and fatally, as a natural compound, resveratrol itself cannot be patented and sold by a pharmaceutical company. It was Sirtris’s job to try to make new, improved, and potentially profitable versions of resveratrol, as well as entirely new compounds that would target the sirtuins. The company launched several clinical trials of possible sirtuin-activating drugs. But then, one by one, those trials were halted, at least two of them due to unexpected side effects. That leaves only one Sirtris compound, SRT2104, still under active study, for psoriasis and ulcerative colitis.

In the labs, as well, the sirtuin theory of aging was taking heavy fire. In 2011, another group published a paper in Nature that challenged Sinclair’s research directly: His results, it was claimed, were an artifact of the way he did his experiments. The Science paper, published earlier this month, was Sinclair’s triumphant rebuttal, outlining in precise detail how resveratrol and friends actually work on the sirtuin pathway. Just four days later, GSK pulled the plug. A GSK spokeswoman says the company will continue to work on sirtuin activators, but says that aside from SRT2104, there are none in the pipeline. Also, she adds, “they don’t have anything to do with red wine.”

Says Sinclair, who is still a scientific adviser to GSK: “We know the science is real; the problem now is to push it over the goal line. If they don’t end up as drugs in our lifetime, it’s not the fault of scientists, and more of a business decision.”

Which is too bad, but at least red wine itself is still good for you. And until that longevity pill comes along, it’s all we’ve got. Just be sure you use a proper dose: In at least two major studies of wine and health, the greatest benefits were seen in people who consumed between three and five glasses of the red stuff.  Per day.

Bill Sardi talks about his first encounter in 2003 with a Harvard professor who claimed to have discovered a red wine molecule that activates a key gene also activated by a limited-calorie diet which doubles the lifespan of laboratory animals.  That’s where the story begins, but not where it ends.  Listen here:

For answers to further questions or to order Longevinex, please call 1 866 405-4000 or visit www.longevinex.com

[Antagonizing effect of resveratrol on the lipid peroxidative damage induced by lead in mice].
Liu F, Xue Z, Zhang N, Wang W, Chen C, Li W.
Wei Sheng Yan Jiu. 2012 Nov;41(6):920-4. Chinese.

Natural polyphenols may ameliorate damage induced by copper overload.
Arnal N, Tacconi de Alaniz MJ, Marra CA.
Food Chem Toxicol. 2012 Feb;50(2):415-22. doi: 10.1016/j.fct.2011.10.037. Epub 2011 Oct 19.
PMID: 22036966 [PubMed - indexed for MEDLINE]

TOBACCO

Resveratrol attenuated smokeless tobacco-induced vascular and metabolic complications in ovariectomized rats.
Majumdar AS, Joshi PA, Giri PR.
Menopause. 2013 Feb 25. [Epub ahead of print]

HORMONE DISRUPTORS

Induced growth of BG-1 ovarian cancer cells by 17β-estradiol or various endocrine disrupting chemicals was reversed by resveratrol via downregulation of cell cycle progression.
Kang NH, Hwang KA, Kim TH, Hyun SH, Jeung EB, Choi KC.
Mol Med Rep. 2012 Jul;6(1):151-6. doi: 10.3892/mmr.2012.887. Epub 2012 Apr 23.

DIOXIN

Attenuation of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity by resveratrol: a comparative study with different routes of administration.
Ishida T, Takeda T, Koga T, Yahata M, Ike A, Kuramoto C, Taketoh J, Hashiguchi I, Akamine A, Ishii Y, Yamada H.
Biol Pharm Bull. 2009 May;32(5):876-81

HERBICIDES

Resveratrol inhibits paraquat-induced oxidative stress and fibrogenic response by activating the nuclear factor erythroid 2-related factor 2 pathway.
He X, Wang L, Szklarz G, Bi Y, Ma Q.
J Pharmacol Exp Ther. 2012 Jul;342(1):81-90. doi: 10.1124/jpet.112.194142. Epub 2012 Apr 4.

CHEMOTHERAPY TOXICITY

Resveratrol protects against acute chemotherapy toxicity induced by doxorubucin in rat erythrocyte and plasma.
Hamlaoui S, Mokni M, Limam N, Carrier A, Limam F, Amri M, Marzouki L, Aouani E.
J Physiol Pharmacol. 2012 Jun;63(3):293-301.
PMID: 22791644 [PubMed - indexed for MEDLINE]

CHEMICAL WARFARE AGENTS

Resveratrol induces catalytic bioscavenger paraoxonase 1 expression and protects against chemical warfare nerve agent toxicity in human cell lines.
Curtin BF, Seetharam KI, Dhoieam P, Gordon RK, Doctor BP, Nambiar MP.
J Cell Biochem. 2008 Apr 1;103(5):1524-35.

AFLATOXIN

The genoprotective activity of resveratrol on aflatoxin B₁-induced DNA damage in human lymphocytes in vitro.
Türkez H, Sisman T.
Toxicol Ind Health. 2012 Jun;28(5):474-80. doi: 10.1177/0748233711414614. Epub 2011 Sep 12.

INTESTINAL PARASITES (H. PYLORI)

Effect of resveratrol on Helicobacter pylori-induced interleukin-8 secretion, reactive oxygen species generation and morphological changes in human gastric epithelial cells.
Zaidi SF, Ahmed K, Yamamoto T, Kondo T, Usmanghani K, Kadowaki M, Sugiyama T.
Biol Pharm Bull. 2009 Nov;32(11):1931-5.

ALCOHOL

Resveratrol alleviates alcoholic fatty liver in mice.
Ajmo JM, Liang X, Rogers CQ, Pennock B, You M.
Am J Physiol Gastrointest Liver Physiol. 2008 Oct;295(4):G833-42. doi: 10.1152/ajpgi.90358.2008. Epub 2008 Aug 28.

HIGH FRUCTOSE CORN SYRUP

High-fructose corn syrup causes vascular dysfunction associated with metabolic disturbance in rats: protective effect of resveratrol.
Akar F, Uludağ O, Aydın A, Aytekin YA, Elbeg S, Tuzcu M, Sahin K.
Food Chem Toxicol. 2012 Jun;50(6):2135-41. doi: 10.1016/j.fct.2012.03.061. Epub 2012 Mar 23

SULFUR MUSTARD GAS

Attenuation of half sulfur mustard gas-induced acute lung injury in rats.
McClintock SD, Hoesel LM, Das SK, Till GO, Neff T, Kunkel RG, Smith MG, Ward PA.
J Appl Toxicol. 2006 Mar-Apr;26(2):126-31.

CARBON TETRACHLORIDE

Resveratrol ameliorates carbon tetrachloride-induced acute liver injury in mice.
Fan G, Tang JJ, Bhadauria M, Nirala SK, Dai F, Zhou B, Li Y, Liu ZL.
Environ Toxicol Pharmacol. 2009 Nov;28(3):350-6. doi: 10.1016/j.etap.2009.05.013. Epub 2009 Jun 11.

NITRATES (NITROSAMINES)

Resveratrol inhibits dimethylnitrosamine-induced hepatic fibrosis in rats.
Lee ES, Shin MO, Yoon S, Moon JO.
Arch Pharm Res. 2010 Jun;33(6):925-32. doi: 10.1007/s12272-010-0616-4. Epub 2010 Jul 6.

ANTIBIOTIC TOXICITY (GENTAMYCIN)

Resveratrol protects auditory hair cells from gentamicin toxicity.
Bonabi S, Caelers A, Monge A, Huber A, Bodmer D.
Ear Nose Throat J. 2008 Oct;87(10):570-3.

RADIATION (X-RAY, GAMMA RAYS)

Resveratrol attenuates radiation damage in Caenorhabditis elegans by preventing oxidative stress.
Ye K, Ji CB, Lu XW, Ni YH, Gao CL, Chen XH, Zhao YP, Gu GX, Guo XR.
J Radiat Res. 2010;51(4):473-9.

ACRYLAMIDE

Resveratrol ameliorates oxidative DNA damage and protects against acrylamide-induced oxidative stress in rats.
Alturfan AA, Tozan-Beceren A, Sehirli AO, Demiralp E, Sener G, Omurtag GZ.
Mol Biol Rep. 2012 Apr;39(4):4589-96. doi: 10.1007/s11033-011-1249-5.