As many Longevinex® users already know, we have taken special measures to protect the active form of resveratrol (trans resveratrol) from exposure to light and oxygen by microencapsulation (enfolding it within plant starches and dextrins) so as to prevent it from turning into its degraded (cis resveratrol) form. However, exposure to another environmental agent was not anticipated – political heat.

As I write, landmark reports in journals showing how well resveratrol and Longevinex® limit damage to the heart in the event of a heart attack, to the point of turning an otherwise mortal attack into a survivable event, are being expunged from the scientific record, retracted in the wake of a scientific witch hunt against a researcher who dared to cooperate with a dietary supplement company.

Despite on-the-record testimony from various resveratrol researchers that the allegedly falsified activities have no bearing on the conclusions drawn from these experiments, the university where these experiments were conducted continues to contact journal editors, demanding they withdraw these papers from publication. So now we get a clear picture of the ultimate objective – to eradicate resveratrol research from the scientific record. Some of this research involved Longevinex®.

So allow me to show you a sample of the images that were published in one typical example of the questioned papers.

Damage following a heart attack

Below you see photographic images providing direct observable evidence of the protective properties of Longevinex®. You can also see a bar chart which quantifies the area of heart tissue that was damaged. White areas represent scarred tissue. The animal heart not provided with Longevinex® sustained about 37% damage whereas the Longevinex-treated heart exhibits about 18% damaged muscle tissue. The difference is considerable. The area of damage is reduced by more than half. This is critically important since heart muscle cells are not rapidly replaced following a heart attack. These heart photos have not been questioned by university reviewers. This makes Longevinex® the first and only branded resveratrol pill to demonstrate this unique protective action in animal hearts. Neither aspirin or statin drugs have been shown to protect the heart like resveratrol-based nutriceuticals do.

Western blot tests

Below are the western-blot images which indicate the amount of protein produced by two survival genes (sirtuin1 and sirtuin3). You can see ink blots of different intensity. These blots are what university reviewers have deemed to be scientific fraud because they were enhanced using Photoshop or other software.

However, cast your eyes upon the accompanying bar charts which quantify the amount of gene-derived protein. This hard-number data has not been altered and is not in question. The bar charts provide accurate quantifiable data on how well Longevinex® activated these survival genes following an experimentally-induced heart attack in laboratory mice.

Western Blot Analysis Of Gene Protein Making

The accuracy of the ink blots, which were altered for the purpose of visualization and duplication in science journals, have been called into question by reviewers. However, the hard numerical data derived from these western blot tests has not been altered. The results of western blot testing would not have altered the conclusion of this study. See here.

Virtually all western-blot images are enhanced for reproduction and visualization purposes in scientific journals because it is a requirement of the journals not the researchers. This fact has not come to light in the recent allegations. The western blot tests in question, published in 12 journals and 26 published reports, were performed by many individuals in different research institutes and none were performed by the accused researcher. We have learned that all of the allegations are based upon analysis of the published images, not original western blot images which the university confiscated, of which some were destroyed, eliminating the possibility of an adequate defense by the accused researcher.

So why have inconsequential images reproduced in science journals gained such worldwide attention? Is it because resveratrol-based nutriceuticals would be the first proven technology that would significantly reduce the risk of mortal heart attacks altogether? There are hundreds of billions of dollars of pharmaceutical and health insurance dollars riding on the answer to that question.

An accompanying report (RESVERATROL IS HAVING A HEART ATTACK) shows that modern cardiology has not embarked upon one human clinical study to show whether resveratrol works even though its heart-protective properties have been well documented for over a decade. Cardiologists are demanding more evidence but are dragging their feet to produce it. Even an Ivy League researcher lamented that there has not been one human study on this most promising molecule in cardiology.

Only about 1/10^th of one-percent of American adults over age 50, the at-risk group for mortal heart attacks, take resveratrol pills, not enough to mount a difference in coronary artery disease mortality rate in the population at large.

Furthermore, many consumers are using mega-dose resveratrol pills which can actually worsen damage caused by a heart attack. Others are taking trace amounts provided in economical brands of resveratrol pills that will be unlikely to produce any protection. Please read our accompanying report.

Bill Sardi
Managing partner
Resveratrol Partners LLC
dba LONGEVINEX®

Experimentally-induced heart attack in laboratory mice produced scarred heart on left (white areas) while Longevinex®-treated mice exhibit less scarring as measured in the bar charts presented above the heart images.

To view the entire research paper click here >>

Don’t let those Western Blot images fool you

Western blot tests are ink blots that indicate the intensity of protein-making by a gene.  While some investigators have called into question the western blot images used in studies like this (shown here) which are often photographically enhanced for  reproduction purposes in science journals, please refer to the bar chart for the accurate numerical comparison of gene activation after a heart attack (I-R = ischemia-  reperfusion, meaning after oxygenated blood has been resupplied to the heart).

Increasingly, up to 3-months following an experimentally induced heart attack in laboratory mice, the bar chart unequivocally shows the Sirtuin1 survival gene is activated over time in rodent hearts by Longevinex® following a heart attack.

To view the entire research paper click here >>

The Superior Biological Action Of Longevinex® Demonstrated By A Test More Advanced Than Western Blot Analysis – MicroRNA.

MicroRNA analysis was conducted at the Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, Maryland, United States of America.

To examine the full paper click here >>

Las Vegas, NV (Jan 11, 2012) – Bill Sardi, managing partner for Longevinex®, a resveratrol-based dietary supplement, says the product his company makes has passed independent scientific scrutiny in human studies conducted both in the USA and overseas and that the animal-lab researcher at the University of Connecticut who has conducted studies involving Longevinex® and whose work has now come under scientific scrutiny, has no business relationship with Longevinex®.

Sardi says, to his knowledge, criticism of Dr. Dipak Das’ work at the University of Connecticut primarily involves irregularities in a test called the western blot analysis which would not alter the findings that Longevinex® has been proven to reduce the area of scar tissue following a heart attack in excised rodent hearts.

Actual photographs showing the amount of scarring following a heart attack provide incontrovertible evidence that both resveratrol and Longevinex® protect the rodent heart prior to a heart attack by activating protective molecules such as nitric oxide, adenosine and heme oxygenase prior to a heart attack, says Sardi.

“None of the allegations that I have briefly read in newspapers negate the pioneering work of Dr. Das, who first showed that resveratrol can turn a mortal heart attack in animals into a non-mortal event,” says Sardi. The implications of this discovery are profound given that aspirin has just recently been found to be ineffective in reducing the risk of a mortal heart attack in humans, adds Sardi.

The proposed health benefits involving Longevinex® have been corroborated by independent studies conducted by National Institutes of Health researchers as well as researchers in other centers in the USA and overseas, says Sardi. Links to these reports are provided herein. As early as 2008 resveratrol researchers confirmed that Longevinex® activates 9-fold more genes than plain reseveratrol in rodent hearts.

Sardi says his company has received reports that patients whose coronary arteries were 99% blocked by plaque experienced no chest pain or damage to their heart, evidence that Longevinex® was cardio-protecting the heart. Sardi says his company has received a report from a cardiologist that an 89-year old man taking Longevinex®, who was judged to be too frail to undergo invasive heart surgery and who had a completely blocked coronary artery, experienced no heart damage and circulation was restored over time on its own.

Normally the heart releases protective antioxidants following a heart attack, when blood circulation is restored to a coronary artery that provides the heart with oxygenated blood. But resveratrol, and more so Longevinex®, releases these protective molecules prior to any adverse event, such as a blockage in arteries supplying oxygen to the heart or brain, says Sardi.

“One has to be alerted to the possibility of a witch hunt here,” says Sardi, “since Dr. Das has made landmark contributions to the understanding of resveratrol and how it works. There are billions of dollars of drug sales that are threatened by resveratrol, which not only protects the heart prior to a heart attack, but thins the blood and prevent clots in coronary arteries, inhibits inflammation, controls cholesterol and dilates (widens) blood vessels to maintain normal blood pressure. Resveratrol and Longevinex® threaten to replace many problematic heart drugs that have not been demonstrated to reduce mortal heart attacks,” says Sardi.

Sardi says his company underwrites some of the costs of conducting studies by independent researchers by providing product for analysis and by underwriting some of the costs involved in testing and that his company played no role in the design or outcomes of any of the published studies that have now been called into question. Dr. Das is not a paid consultant to Longevinex® says Sardi.

The news media chose to implicate Longevinex® in the allegations against Dr. Das without first contacting the company for a response, says Sardi. “Longevinex should not be considered guilty by association,” says Sardi.

Dr. Das is attending a scientific conference in India and has not been able to respond to the allegations. ####

When there aren’t enough nucleotides available this can lead to chromosomal instability, shortening of telomeres (end-caps on chromosomes) and defective DNA repair.

Given to astronauts on space missions to boost their immune response and to prematurely-born infants to facilitate growth, supplemental nucleotides are the lettered (A, G, C, T) parts of the coiled DNA ladder (adenine, guanine, cytosine, thymine, uridine).

A recent discovery reveals a shortage of DNA parts can lead to errors in DNA repair and subsequent gene mutations. Living cells are forced to abnormally increase in numbers when there is an insufficient pool of nucleotide spare parts to support normal DNA replication.

Supplemental nucleotides also work in tandem with resveratrol, a red wine molecule that exerts control over c-Myc, a master regulator of many genes that are involved in DNA replication.



Nucleotides on DNA

Additional Information About Nucleotides

Under certain conditions, such as in wound healing (burns, surgery, sunburn, etc) and particularly tissues where cells are slow to die off and be replaced by new cells (heart, brain, eyes), as well as tissues that have fast cell turnover rates (skin, gastric lining), supplemental nucleotides would be considered essential under these conditions.

For example, supplemental nucleotides are known to promote healthy repair of the mucus lining in the digestive tract which has a high demand for nucleotides.

Nucleotides serve to normalize the natural immune response, activating both the first responding white blood cells (neutrophils, largely by adenine), and the late responding natural killer cells and macrophages. Adequacy of adenine, one of the four nucleotides that comprise the DNA ladder, is particularly critical for a normal healthy immune response.

Nucleotides within the mitochondria, the atomic power plants of living cells, are particularly vulnerable to becoming oxidized by free radicals which can induce living cells to lose their ability to replicate (what is called cell senescence).

There is always a pool of spare nucleotides to facilitate DNA repair and cellular renewal. However, a burst of reactive oxygen produced by unpaired electrons, or what is called an oxygen free-radical assault, can reduce the nucleotide spare parts pool needed for cell renewal or wound healing.

Particularly when there is a shortage of the nucleotide guanine due to a free radical attack, living cells can be induced into a senescent state.

Guanine is also a critical nucleotide for maintenance of telomeres, the end-caps of chromosomes.

Other studies point to mutations involving cytosine in the DNA ladder as being responsible for aging. There is a progressive decline in a form of cytosine (methyl-cytidine) with advancing age.

Methyl-cytosine is more unstable than cytosine itself and may be more easily damaged by oxidation.

A shortage of essential nutrients, particularly vitamin B12, folic acid, vitamin B6, niacin, vitamin C, vitamin E, iron and zinc, may induce DNA damage that is as damaging to DNA as a strong dose of radiation. But even with adequate nutrients, the body needs a healthy level of nucleotide spare parts to facilitate DNA repair.

While dietary supplements and fortified foods largely provide an adequate supply of folic acid (vitamin B9) which is required for DNA repair, an enzyme called DNA methyl-transferase may oppose the action of folic acid. Natural enzyme inhibitors (resveratrol, quercetin) provided in Longevinex® serve to inhibit methyl-transferase and thus further normalize DNA repair.

Furthermore, Longevinex® provides IP6 phytate extracted from rice bran, which is required for repair of double-strand DNA breaks.

The nucleotides provided in Longevinex® emanate from a natural botanical source and have a proven safety record in humans ranging from infants to hospitalized senior adults.

Supplemental nucleotides represent a marriage of genetics (sequences of nucleotides on the DNA ladder) and epigenetics (protein making of genes) facilitated by resveratrol, quercetin and other ingredients in Longevinex®.

KEY POINTS

• Thepromise of the Sirtuin1 gene as anti-aging target has been disappointing.
• Long-living humans found to have active Sirtuin3 gene.
• Sirtuin1 gene located in cell cytoplasm whereas Sirtuin3 controls antioxidant protection (SOD*) inside mitochondria where cell energy and 90% destructive oxygen free radicals are produced.
• Feverishly-paced research is underway to confirm Sirtuin3 as true anti-aging pill.
• Resveratrol molecule stimulates Sirtuin3 gene; Longevinex® resveratrol matrix activates Sirtuin3 2.95-fold greater than plain resveratrol.

* SOD = superoxide dismutase

Genes they be — a Sirtuin family of seven “silent information regulators” that are guardians of the cell. Sirtuins have been linked with prolonged lifespan in various life forms, starting with yeast cells, fruit flies and roundworms.¹

Sirtuin1 (also referred to as SIRT1) is a survival gene that is switched on when a living organism is deprived of food. Since the lifespan of calorie-restricted laboratory animals nearly doubles, researchers thought, for sure, they had struck biological pay dirt. Researchers thought any molecule that could turn on Sirtuin1 (trigger it to make proteins) could be an anti-aging molecule for humans. In fact, one Harvard genetics professor claimed Sirtuin1 was the “holy grail” of anti-aging² and demonstrated in the laboratory that it could be activated by a red wine molecule called resveratrol.

All this was first announced in Nature magazine in late 2003³, was extolled on the front pages of The New York Times⁴ and The Wall Street Journal⁵, and followed by a laboratory experiment which showed resveratrol prolonged the life of fat-fed mice⁶, and by 2010 a biotech company sold their experimental resveratrol-based drug to a major pharmaceutical company for $720 million.⁷

From promise to disappointment

But that wasn’t quite how it all ended. A later study showed mega-dose resveratrol slightly shortened the lifespan of laboratory rats fed a standard-calorie diet, though it did dramatically improve other measurable health parameters largely by eradicating fatty liver.⁸

Then an MIT professor chimed in and said the pursuit of longevity via Sirtuin1 was a bit more complicated than first thought and that a calorie restricted diet didn’t uniformly up-regulate the Sirtuin1 gene in all organs and tissues.⁹ Dratted science never seems to cooperate just when humanity needed such a pill.

Then more confusion — the initial experiment which showed resveratrol activated Sirtuin1 was flawed. Turns out a fluorescent dye used in gene analysis foiled the experiment as it was found to be the agent that switched on Sirtuin1, not resveratrol.¹⁰ That didn’t negate the incomparable health benefits attributed to resveratrol, but it did negate Sirtuin1 as its primary gene target. Sounds like the pharmaceutical company ought to be asking for its money back. The major pharmaceutical company did announce it was not continuing further research and development of the SRT501 drug. Did the drug company remove SRT501 from its R&D pipeline to make sure it doesn’t compete with today’s disappointing prescription drugs.

Two genes away: Sirtuin3

But a month before the 2003 Nature magazine paper was published about Sirtuin1, researchers in Italy published an overlooked report concerning genetic data from a pool of humans over 100 years of age. These researchers found a relationship exists between longevity and genes located near the 11p15.5 chromosome. Five genes potentially involved in longevity were located and scrutinized. In this chromosomal region lies Sirtuin3, a gene that resides inside the energy power plants inside cells called mitochondria, whereas Sirtuin1 resides in the watery cytoplasm inside living cells.

A significant variation in survivorship was found among those individuals who exhibited a form of Sirtuin3. To date, among all seven Sirtuin genes, it is the only one genetically linked to lifespan in humans.¹¹ But at the time, this discovery was overshadowed by the excitement for Sirtuin1.

Fast forward in time to 2011 – the science pointing to Sirtuin3 as a true anti-aging gene is mounting rapidly. As one research paper described it: “Sirtuin3 has recently stepped out of the shadow of Sirtuin1… mimicking calorie restriction.” Sirtuin3 was found to increase cellular respiration by 80% compared to 30% for Sirtuin1.¹² Sirtuin1 gene’s own pied piper, Harvard researcher David Sinclair, filed for a patent in 2008 claiming activation of Sirtuin3 mimics the metabolic effect of endurance exercise training.¹³ No one noticed.

The whole tenor of anti-aging researchers has changed from the confusion and disappointment experienced with Sirtuin1. Usually reserved scientists are now saying things like “Sirtuin3 may be a central mechanism of aging retardation in mammals,¹⁴“ “Sirtuin3 may have profound implications for aging,¹⁵“ and that “a barrage of recent studies show that Sirtuin3 wards off the vicissitudes of aging.¹⁶“

To further corroborate the link between premature aging and lack of Sirtuin3 proteins, researchers have found that Sirtuin3 activity declines with advancing age.¹⁷

Surprisingly, if the Sirtuin3 gene is removed from laboratory mice, no overt signs of distress are observed. But if these same Sirtuin3-absent mice are subjected to biological or mental stress (food deprivation, excessive radiation, etc.), these stressed mice produce heightened levels of free radicals and decreased levels of cellular energy (ATP – adeno-triphosphate).¹⁸ Sirtuin3 is the antidote to harmful species of oxygen molecules known as free radicals, which are missing a key electron.

Why is Sirtuin3 superior to Sirtuin1?

Why does Sirtuin3 appear to work against aging in a superior manner to Sirtuin1? The answer to this question may lie in the cellular compartment where it is found – the mitochondria. Sirtuin 3, 4 and 5 are found within the hundreds of mitochondrial compartments within living cells, which is where cellular respiration (conversion of oxygen to energy) takes place and where 90% of potentially destructive oxygen free radicals in the body are produced.

Sirtuin3 controls the internal (endogenous) antioxidant response to free radicals in the most critical of places – the mitochondria. It increases the activity of a natural endogenous antioxidant enzyme called superoxide dismutase (SOD) in the mitochondria.

The mitochondria are where 85-95% of oxygen used by cells is consumed to produce cellular energy and where over 90% of the destructive oxygen free radicals (oxidizing agents) are generated. By age 80 only about 4% of mitochondria are actually functioning at full capacity.¹⁹ This fact alone should indicate why Sirtuin3 may have such a profound and promising role as a single gene out of a library of about 25,000 genes. While according to one recent study human aging involves at least 295 genes²⁰, Sirtuin3 appears to single-handedly counter the biological chaos that occurs within the mitochondria.

Think of a living cell with an outer fatty membrane holding in the watery cytoplasm. Within that cell is a nucleus that houses the genetic material – DNA. (See diagram below.) In the watery cytoplasm are hundreds of atomic power plants (mitochondria) that generate cell energy via respiration of oxygen. About 5% of that oxygen turns into potentially harmful oxygen free radicals, what is called oxidation or rusting. It’s like fires are burning in the hundreds of mitochondria in the cell with advancing age which must be extinguished by the manganese form of SOD via control by the Sirtuin3 gene. Put those mitochondrial fires out and cells in the brain, heart, liver, live longer and better withstand biological stress.

These facts do not negate the fact that the proper form of SOD (manganese-SOD) is also activated by resveratrol via the Sirtuin1 gene pathway.²¹ However, Sirtuin1 does not reside in the critical location that Sirtuin3 does.

Here are other known facts about this strategically placed gene:

• Sirtuin3 proteins are found in a broad range of tissues and are consistently increased with biological stress, unlike Sirtuin1.
• Sirtuin3 has been shown to increase cellular energy (ATP).²²
• Sirtuin3 is the master gene that controls the production of SOD in the mitochondria. A deficiency of SOD is associated with many diseases, particularly diseases of aging.²³
• Sirtuin3 is considered a tumor suppressor by virtue of its ability to activate SOD within the mitochondria.²²
• Sirtuin3 proteins are also increased by calorie restriction.²⁴
• An age-related decline in Sirtuin3 has now been associated with heart failure.²⁵
• Sirtuin3 also activates catalase, another endogenous antioxidant enzyme.²⁶
• A large percentage of human tumors show inactivation of Sirtuin3.²⁷
• The precursor for SIRT3-generated SOD is the metallic mineral manganese. With the absence or shortage of manganese, iron may take its place.²⁸
• Unbound iron that can generate destructive free radicals can enter the mitochondria.²⁹
• In mice lacking the Sirtuin3 gene, they rapidly develop a form of breast cancer that has been linked with a low SOD activity levels.³⁰
• Resveratrol, a red wine molecule, has been shown to increase manganese-SOD activity.³¹ Longevinex® is the first branded resveratrol dietary supplement demonstrated to activate Sirtuin3.³² Comparatively, Longevinex® appears to activate Sirtuin3 nearly three-fold greater than plain resveratrol (1.18 to 0.4 arbitrary units).

• Quercetin³³, ferulic acid³⁴ and IP6³⁵ (derived from rice bran), provided in the Longevinex® formula, are also known to be protective antioxidants in the mitochondria.
• Sirtuin3 is known to reverse the age-related conversion in the generation of cellular energy from oxygen burning during youth to sugar burning in the latter years of life. Sirtuin3 also helps to maintain normal levels of oxygen in the mitochondria necessary to inhibit activation of the hypoxia inducing factor gene (HIF1). Tumor cells grow in a hypoxic (oxygen-starved) environment. The activation of Sirtuin3 reverses the Warburg effect in breast cancer cells growing in lab dishes. Two-time Nobel Prize winner Otto Warburg was the first to describe the phenomenon in the 1930s, where tumor cells convert from using oxygen to utilizing sugar to survive.³⁶

Sirtuin3 and hearing loss

An intriguing animal study was conducted among mice that have been bred for hearing loss. If these animals are given a calorie restricted diet, despite their genetic predisposition to develop hearing loss, this sparse calorie diet completely prevented this occurrence. However, if the Sirtuin3 gene is removed from these animals and then they are given a limited calorie diet, the protection against hearing loss is completely negated.³⁷

Corroboration of the beneficial effects of Longevinex® in humans have been received by researchers who have documented that older males experience hearing improvement as measured by audiological examination.³⁸

What now?

Researchers are working feverishly on Sirtuin3 gene research. Will unfolding research result in a re-run of what occurred in 2003 with all the public fascination spawned by widespread news media coverage that surrounded resveratrol as a Sirtuin1 gene activator? Will the news media continue to ignore the stellar performance of the Longevinex® nutriceutical, which has many times now outperformed the $720 million SRT501 resveratrol drug?^39,40,41,42 Will the National Institute on Aging launch a study to confirm whether resveratrol or a resveratrol-based matrix actually prolongs the life of laboratory animals? Stay tuned.

More than just SOD

While manganese-SOD may be a primary protector of the mitochondria, it only converts troublesome destructive oxygen molecules called free radicals into hydrogen peroxide (H₂O₂), which itself is potentially destructive. Another internally-produced antioxidant enzyme, catalase, must convert hydrogen peroxide (H₂O₂) into harmless water (H₂O). The process is O₂ (reactive oxygen) -> H₂O₂ (hydrogen peroxide) + catalase -> = H₂O (water).

Now if you read up on catalase, you would think it was the key antioxidant that produces longevity. In fact, in 2005 Science magazine published a report entitled “The Anti-Aging Sweepstakes: Catalase Runs for the ROSes” (ROS = reactive oxygen species).⁴³

And there is strikingly convincing evidence for catalase as a key anti-aging antioxidant. For example, among mice bred to over-produce catalase, median lifespan was maximally increased by 5.0 to 5.5 months (these lab animals only live 2.0-2.5 years, so this is a 16-24% jump that in human terms would be equivalent to another 15-20 years of healthy living).⁴⁴ Understand, that is five times greater predicted life extension than what can be achieved by elimination of cancer and heart disease in these animals. In mice bred to over-produce catalase, all of the age-related changes in heart function were significantly reduced.⁴⁵

Catalase probably deserves as much or more attention if for nothing else than one molecule of catalase can break 40 million molecules of hydrogen peroxide every second, turning it to harmless water.
Also consider that while other antioxidants play a role in the mitochondria, they are often not able to deal with the large amount of oxidation (reactive oxygen species) and the mitochondria often lack sufficient catalase activity.⁴⁶ With -38% chemically-induced reduction of catalase, normal cells display accelerated aging. The mitochondria become dysfunctional.⁴⁷

When the human catalase gene is inserted in laboratory mice, they live longer, which is even more of an enticement to jump to the conclusion that catalase is THE longevity molecule.⁴⁸

The unheralded endogenous antioxidants

While consumers hear of the many protective properties of dietary and supplemental antioxidants such as vitamin C, vitamin E, coenzyme Q10 and others, three primary enzymatic antioxidants (catalase, superoxide dismutase and glutathione peroxidase) produced in living cells are overlooked.

Indeed, both selenium and vitamin E, the precursors for glutathione peroxidase, are required to protect mitochondria from damage by hydrogen peroxide.⁴⁹

When researchers conducted a study to measure free radical production in the brains of different vertebrate animals, they found that SOD, catalase, glutathione peroxidase, the three major internally-produced antioxidants, along with vitamin C, correlated with maximum longevity. Low levels of free radical production and low antioxidant concentrations are a central finding in long-lived animals.⁵⁰

Contrary data

However, there is contrary data that confounds a clear oxidant-antioxidant explanation of aging. High levels of oxidative damage in mitochondrial DNA do not decrease longevity in mice.⁵¹ Contrary to other experiments, when researchers intentionally induced overproduction of SOD, catalase, or combinations of the two, it didn’t result in extended lifespan of mice.⁵² In another mouse study, life-long reduction of MnSOD activity led to increased levels of oxidative damage to DNA and increased cancer incidence but did not appear to affect aging.⁵³

Yet with all the praise for catalase, some researchers say the majority of studies using antioxidant strategies “do not support a clear role for mitochondrial oxidative stress or a vicious cycle of oxidative damage in the determination of lifespan in mice and furthermore do not support the free radical theory of aging.”⁵⁴

In mice, the provision of increasing amounts of supplemental coenzyme Q10, a widely promoted antioxidant supplement, did not raise SOD, catalase or glutathione peroxidase antioxidant levels in the mitochondria and had no effect upon mortality.⁵⁵

Of course, there is nothing better than human studies to test the antioxidant theory of aging. So recently researchers at the US Dept of Agriculture Human Nutrition Research Center on Aging at Tufts University enrolled 46 moderately overweight volunteers, age 20-42 years, and were given diets of differing reduced calorie load. Only glutathione peroxidase levels increased over a 6-month period of caloric restriction. No other antioxidants such as SOD or catalase were altered in blood plasma.⁵⁶

Still, while scientific controversy reigns, researchers at the Division of Geriatrics, University of California at Los Angeles believe we are on the cusp of a breakthrough in the pursuit of human longevity and state that “the advancement of mitochondrially-targeted small-molecule antioxidants suggests the prospect of swift translation to human use.”⁵⁷

King resveratrol

Certainly, resveratrol rises to the top of a list of candidates as anti-aging molecules, with good reason. Examine these studies:In a lab dish, at very low concentration, resveratrol increases activity of the three major antioxidant enzymes, SOD, catalase and glutathione peroxidase, in cells obtained from the human retina.⁵⁸ This occurs without provision of the nutrients (copper, zinc, manganese, vitamin E, selenium) necessary to produce these antioxidants.

It has been clearly demonstrated that resveratrol activates all three key antioxidant enzymes (glutathione, SOD and catalase) in arteries.⁵⁹

Does resveratrol always shine in the laboratory? Well, in one experiment, at very low concentration, resveratrol had no effect upon key antioxidant enzymes such as catalase, glutathione peroxidase or copper-zinc variety of SOD in the lab dish. But, as researchers described it in their own words: “resveratrol dramatically and progressively induced mitochondrial manganese-SOD activity.” Two weeks into their experiment resveratrol increased manganese-SOD protein levels by 6-fold and Mn-SOD activity levels by 14-fold!⁶⁰

Test tube studies however are not real live environments. So researchers put resveratrol to the test in mice, in what are called in vivo experiments. The lab mice were fed a standard calorie diet, a high-fat diet and were also fed via an osmotic pump to ensure the feeding was the same between animals. Unsurprisingly, resveratrol increased manganese-SOD protein-making by 140% and its activity by 75%.⁶¹

Is aging too large for biology to get its hands around it?

When one considers all of the factors that come into play in aging it would appear to be a daunting challenge to develop an anti-aging substance that would address all of the genes and biological processes involved, ranging from inflammation and oxidation to DNA breaks and enzyme control. But then again, there is resveratrol. Just examine how researchers explain the breadth of resveratrol’s biological influence:

Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Resveratrol, a polyphenol, has been shown to mediate its effects through modulation of many different pathways. This molecule has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g; NFkappaB, STAT3, HIF-1alpha, beta-catenin and PPAR-gamma), suppress the expression of antiapoptotic gene products (e.g; Bcl-2, Bcl-X(L), XIAP and survivin), inhibit protein kinases (e.g; src, PI3K, JNK, and AKT), induce antioxidant enzymes (e,g; catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS, and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D, and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol’s prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.”⁶²

What causes age-related increase in mitochondrial oxidation?

A question arises. If oxidation within the mitochondria increases with advancing age, and the mitochondria cease to function optimally in advanced age, what causes the progressive deterioration within the mitochondria? Genes do not run the show, they only respond to environmental cues within living cells.

This author maintains the accumulation of minerals, namely copper, iron and calcium, is what controls the rate of aging. Indeed, a recent report clearly describes how potentially destructive metals like copper, iron, even chromium and cobalt, produce metal-induced free radicals such as superoxide and the dreaded hydroxyl radical which then overwhelm antioxidant systems and damage DNA.⁶³

Copper is the more powerful oxidant and it is of interest to note that while all metallic metals can induce potentially destructive free radicals, copper has been demonstrated to “overwhelm antioxidant defenses” (catalase, glutathione, SOD) more so than iron and other metallic minerals.⁶⁴ As copper levels rise in the blood plasma, the risk for heart disease rises also.⁶⁵ That cannot be said for iron. And resveratrol is “by far, the most potent chelator of copper.”⁶⁶

It is interesting to note that females live longer than males in many species, including humans. And the mitochondria from females produce significantly less hydrogen peroxide than those from males and have higher levels of mitochondrial reduced glutathione, manganese superoxide dismutase, and glutathione peroxidase than males. Oxidative damage to mitochondrial DNA is also fourfold higher in males than in females. Researchers indicate “these differences may be explained by estrogens. Surgical removal of estrogen-producing ovaries abolishes the gender differences between males and females and estrogen replacement rescues the ovariectomy effect. The challenge for the future is to find molecules that have the beneficial effects of estradiol, but without its feminizing effects. Phytoestrogens or phytoestrogen-related molecules may be good candidates to meet this challenge.”⁶⁷Resveratrol is a safe phytoestrogen.

Sorting it all out

What are we learning here? The messages to take home are large and many for longevinarians.

1. Sirtuin3 is probably primary among the family of seven Sirtuin genes, and may be a sole genetic marker for longevity, but it doesn’t work alone and obviously works within networks of survival/longevity genes and overlapping antioxidant systems.
2. Antioxidant enzymes, that is, those internally (endogenously)-produced antioxidants may take precedence over externally provided antioxidants as provided in the diet (examples: vitamin C, vitamin E), but do require nutrient precursors, such as selenium + vitamin E = glutathione peroxidase; manganese-SOD = manganese; catalase = zinc, copper, manganese.
3. Not only is Sirtuin3 involved, but it works in tandem with Sirtuin4 and Sirtuin1 and both influence another gene, FOXO1, to “translocate” from the watery cytoplasm to the nucleus of the cell. What signal triggers this is yet unknown. Additionally, Sirtuin6 is newly recognized as a required gene in double-strand DNA repair.⁶⁸
4. Then again, with all that has been learned up to this point, even low-grade superoxide radical challenge induces an adaptive state and triggers defenses in the body, which is beneficial (so-called hormetic action where a low-grade toxin is protective and high-grade toxin produces cell and possibly total organism death).

There is even another unheralded antioxidant enzyme, peroxiredoxin (Prx) that detoxifies hydrogen peroxide in the mitochondria and is linked to longevity. So we can’t pin all of our hopes on one gene or a single antioxidant.

5. Resveratrol, and more so Longevinex®, activates intracellular antioxidants within the mitochondria, without provision of their nutrient precursors (copper, manganese, zinc, selenium, vitamin E).

Follow-up questions and answers:

Question: the form of SOD (superoxide dismutase) antioxidant within the mitochondria is produced from manganese. Is adding manganese to the diet an anti-aging strategy?

Reply: Here is what the manganese-SOD molecule looks like:

SOD is formed from three precursors – copper, zinc and manganese. Manganese-SOD constitutes approximately 10-15% of the total SOD activity in most tissues.

Manganese SOD appears to be a more powerful antioxidant than the copper or zinc-SODs under biologically stressed conditions.⁶⁹

SOD activity is increased in response to biological stress. A frank deficiency of manganese and reduced manganese-SOD activity has been demonstrated to be deleterious to the heart. Provision of supplemental manganese has been shown to be therapeutic.⁷⁰ However, the heart-protective properties of manganese were only demonstrated in manganese-deficient animals compared to manganese-sufficient animals.⁷¹

Higher intake of manganese from the diet, but not necessarily supplements, is associated with lower risk for brain disease.⁷² Inorganically-bound manganese in drinking water is potentially more troublesome than bound forms of manganese in the diet.⁷³ In animals, chronic exposure to manganese and other heavy metals in drinking water was counterproductive and actually decreased SOD activity over the long term.⁷⁴

Supplemental manganese has drawn cause for concern in multivitamins.⁷⁵ The estimated safe daily intake for manganese is 2-5 mg per day, however dosage range for side effects begins at just 4.2 mg/day for a 70-kilogram/160-lb individual. So the potentially problematic dose falls within the so-called safe range.⁷⁶

A high intake of manganese when accompanied with iron is also of concern in relation to age-related brain disease.⁷⁷ With advancing age, metallic metals accumulate in living tissues. The accumulation of manganese may be deleterious.⁷⁸

The Western diet appears to generally provide sufficient amounts of manganese.⁷⁹

Provision of oral SOD itself without biological stress may sometimes be problematic. Manganese is a heavy metal that is only needed in minute amounts to produce SOD. Excessive activation of manganese-SOD, while anticipated to be increased under biological stress, may not be beneficial when constantly increased when biological stress is low or absent.⁸⁰

Question: what about taking oral SOD itself?

Reply: SOD is a antioxidant enzyme that is rapidly degraded by gastric acids when ingested orally. Even enteric coated tablets do not adequately protect SOD and SOD supplements are said to produce no pharmacologic activity when taken orally. Oral SOD was found to ineffectively raise SOD levels in laboratory mice.⁸¹ However, this is a dated study and only used low (less than 1mg) doses.

Oral SOD may be of some value when administered directly into tissues. The provision of oral SOD directly into the gut reduced oxidative stress in animals with colitis. A 910-mg equivalent human dose (13 mg/kilogram for a 70 kilogram/160-lb human) was employed.⁸²

Various brands of oral SOD are sold in retail shops. The bioavailability of oral SOD is not equivalent to what is employed in the research laboratory where injectable SOD is often used. Oral SOD is poorly bioavailable unless special encapsulation methods are employed.⁸³ Manganese-SOD has a high molecular weight of around 81,000 Daltons and would be expected to be poorly absorbed.⁸⁴ For comparison, the molecular weight of readily absorbed vitamin C is 176 Daltons. Low molecular weight SOD has been successfully employed in animal studies, but was administered intravenously.⁸⁵ The trick is to activate SOD in the mitochondria, not to assume that oral SOD makes its way to remote tissues beyond the digestive tract.

References

To access abstract, click on PubMed (National Library of Medicine) master identification number (PMID) at end of citation.

1. Milne JC, Denu JM, The Sirtuin family: therapeutic targets to treat diseases of aging. Curr Opin Chem Biol. 2008 Feb;12(1):11-7. PMID:18282481
2. The Associated Press, Big doses of red wine could promote long life, 11/1/2006
   http://www.msnbc.msn.com/id/15511128/ns/health-health_care/t/big-doses-red-wine-could-promote-long-life/
3. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003 Sep 11; 425(6954):191-6. PMID: 12939617
4. Nicholas Wade, New Hints Seen That Red Wine May Slow Aging. The New York Times, June 4, 2008 http://www.nytimes.com/2008/06/04/health/research/04aging.html
5. David Stipp, Researchers seek key to anti-aging in calorie cutback. The Wall Street Journal Tuesday, October 31, 2006 http://www.post-gazette.com/pg/06304/734200-114.stm
6. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-42. PMID: 17086191
7. GlaxoSmithKline to acquire Sirtris Pharmaceuticals, a world leader in ‘Sirtuin’ research and development. Tuesday 22 April 2008
   http://www.gsk.com/media/pressreleases/2008/2008_us_pressrelease_10038.htm
8. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 2008 Aug;8(2):157-68. PMID: 18599363
9. Chen D, Bruno J, Easlon E, Lin SJ, Cheng HL, Alt FW, Guarente L. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev. 2008 Jul 1;22(13):1753-7. PMID: 18550784
10. Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman EA, Caldwell SD, Napper A, Curtis R, DiStefano PS, Fields S, Bedalov A, Kennedy BK. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem. 2005 Apr 29;280(17):17038-45. PMID: 15684413
11. Rose G, Dato S, Altomare K, Bellizzi D, Garasto S, Greco V, Passarino G, Feraco E, Mari V, Barbi C, BonaFe M, Franceschi C, Tan Q, Boiko S, Yashin AI, De Benedictis G. Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly. Exp Gerontol. 2003 Oct;38(10):1065-70. PMID: 14580859
12. Dransfeld CL, Alborzinia H, Wölfl S, Mahlknecht U. SIRT3 SNPs validation in 640 individuals, functional analyses and new insights into SIRT3 stability. Int J Oncol. 2010 Apr;36(4):955-60. PMID: 20198340
13. USPTO: Patent application title: USE OF COMPOUNDS ACTIVATING SIRT-3 FOR MIMICKING EXERCISE Inventors: David A. Sinclair (Chestnut Hill, MA, US) Juan Carmona (Belton, TX, US) Assignees: President and Fellows of Harvard College
    IPC8 Class: AA61K317088FI USPC Class: 514 44 R
    Publication date: 04/07/2011 Patent application number: 20110082189 http://www.faqs.org/patents/app/20110082189
14. Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, Tanokura M, Denu JM, Prolla TA. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell. 2010 Nov 24;143(5):802-12. PMID: 21094524
15. Bell EL, Guarente L, The SirT3 Divining Rod Points to Oxidative Stress. Mol Cell. 2011 Jun 10;42(5):561-8. PMID: 21658599
16. Liu Y, Zhang D, Chen D, SIRT3: Striking at the heart of aging. Aging (Albany NY). 2011 Jan;3(1):1-2. PMID: 21094524
17. Lanza IR, Short DK, Short KR, Raghavakaimal S, Basu R. Joyner MJ, McConnell JP, Nair KS, Endurance exercise as a countermeasure for aging. Diabetes.2008 Nov;57(11):2933-42. PMID: 21248372
18. Schumacker PT. A tumor suppressor SIRTainty. Cancer Cell. 2010 Jan 19;17(1):5-6. Review. PMID: 20129243
19. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell. 2005 Feb 25;120(4):483-95. PMID: 15734681
20. Harries LW, Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing. Aging Cell June 13, 2011 PMID: 21668623
21. Tanno M, Kuno A, Yano T, Miura T, Hisahara S, Ishikawa S, Shimamoto K, Horio Y, Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure. J Biol Chem 285 (11): 8375-82, 2010. PMID: 20089851
22. Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, Deng CX, Finkel T. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14447-52. PMID: 18794531
23. Chen Y, Zhang J, Lin Y, Lei Q, Guan KL, Zhao S, Xiong Y, Tumor suppressor SIRT3 deacetylase and activates manganese superoxide dismutase to scavenge ROS. EMBO Reports 12(6): 534-41, 2011. PMID: 21566644
24. Hallows WC, Yu W, Smith BC, Devries MK, Ellinger JJ, Someya S, Shortreed MR, Prolla T, Markley JL, Smith LM, Zhao S, Guan KL, Denu JM. Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol Cell. 2011 Jan 21;41(2):139-49. PMID: 21255725
25. Sadoshima J Sirt3 targets mPTP and prevents aging in the heart. Aging (Albany NY). 2011 Jan;3(1):12-3. PMID: 21248376
26. Schumacker PT, A tumor suppressor SIRTainty. Cancer Cell. 2010 Jan 19;17(1):5-6. PMID: 20129243
27. Finley LW, Carracedo A. Lee J, et al, SIRT3 opposes reprogramming of cancer cell metabolism through HIF1a destabilization. Cancer Cell 19: 416-28, 2011. PMID: 21397863
28. Naranuntarat A, Jensen LT, Pazicni S, Penner-Hahn JE, Culotta VC. The interaction of mitochondrial iron with manganese superoxide dismutase. J Biol Chem. 2009 Aug 21;284(34):22633-40. PMID: 19561359
29. Breuer W, Shvartsman M, Cabantchik ZI, Intracellular labile iron. Int J Biochem Cell Biol. 2008;40(3):350-4. PMID: 17451993
30. Hursting SD, Lavigne JA, Berrigan D, Perkins SN , Barrett JC. Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Annual Review of Medicine 54: 131-52, 2003. PMID: 12525670
31. Valdecantos MP, Pérez-Matute P, Quintero P, Martínez JA, Vitamin C, resveratrol and lipoic acid actions on isolated rat liver mitochondria: all antioxidants but different. Redox Rep. 2010;15(5):207-16. PMID: 21062536
32. Mukherjee S, Ray D, Lekli I, Bak I, Tosaki A, Das DK. Effects of Longevinex (modified resveratrol) on cardioprotection and its mechanisms of action. Can J Physiol Pharmacol. 2010 Nov;88(11):1017-25. PMID: 21076489
33. Potenza L, Calcabrini C, De Bellis R, Mancini U, Cucchiarini L, Dachà M. Effect of quercetin on oxidative nuclear and mitochondrial DNA damage. Biofactors. 2008;33(1):33-48. PMID: 19276535
34. Lin YH, Zhang JJ, Chen WW. Protective effect of sodium ferulate on damage of the rat liver mitochondria induced by oxygen free radicals. Yao Xue Xue Bao. 1994;29(3):171-5. PMID: 8079647
35. Panduri V, Weitzman SA, Chandel NS, Kamp DW, Mitochondrial-derived free radicals mediate asbestos-induced alveolar epithelial cell apoptosis. Am J Physiol Lung Cell Mol Physiol. 2004 Jun;286(6):L1220-7. PMID: 14766669
36. Bell EL, Guarente L, The SirT3 divining rod points to oxidative stress. Molecular Cell 42: 561-68, 2011. PMID: 21658599
37. Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, Kim J, Yancopoulos G, Valenzuela D, Murphy A, et al, Mallalian Sir2 homolog regulates global mitochondrial lysine acetylation. Mol Cell Biol 27, 8807-8814, 2007. PMID: 17923681
38. Data received from Stuart Richer OD, PhD, Director, Ocular Preventive Medicine- Eye Clinic, James A Lovell Federal Health Care Center, North Chicago, Illinois.
39. Juhasz B, Mukherjee S, Das DK, Hormetic response of resveratrol against cardioprotection. Exp Clin Cardiol. 2010 Winter;15(4):e134-8. PMID: 21264071
40. Juhasz B, Das DK, Kertesz A, Juhasz A, Gesztelyi R, Varga B, Reduction of blood cholesterol and ischemic injury in the hypercholesteromic rabbits with modified resveratrol, longevinex. Mol Cell Biochem. 2011 Feb;348(1-2):199-203. PMID: 21052791
41. Mukherjee S, Ray D, Lekli I, Bak I, Tosaki A, Das DK, Effects of Longevinex (modified resveratrol) on cardioprotection and its mechanisms of action. Can J Physiol Pharmacol. 2010 Nov;88(11):1017-25. PMID: 21076489
42. Mukhopadhyay P, Mukherjee S, Ahsan K, Bagchi A, Pacher P, Das DK. Restoration of altered microRNA expression in the ischemic heart with resveratrol. PLoS One. 2010 Dec 23;5(12):e15705. PMID: 21203465
43. Miller RA, Biomedicine. The anti-aging sweepstakes: catalase runs for the ROSes. Science. 2005 Jun 24;308(5730):1875-6. PMID: 15976292
44. Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS.Extension of murine life span by overexpression of catalase targeted to mitochondria.Science. 2005 Jun 24;308(5730):1909-11. PMID: 15879174
45. Dai DF, Santana LF, Vermulst M, Tomazela DM, Emond MJ, MacCoss MJ, Gollahon K, Martin GM, Loeb LA, Ladiges WC, Rabinovitch PS.Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation. 2009 Jun 2;119(21):2789-97. PMID: 19451351
46. Bai J, Cederbaum AI. Mitochondrial catalase and oxidative injury. Biol Signals Recept. 2001 May-Aug;10(3-4):189-99.PMID: 11351128
47. Koepke JI, Wood CS, Terlecky LJ, Walton PA, Terlecky SR. Progeric effects of catalase inactivation in human cells. Toxicol Appl Pharmacol. 2008 Oct 1;232(1):99-108. PMID: 18634817
48. Enns LC, Wiley JC, Ladiges WC. Clinical relevance of transgenic mouse models for aging research. Crit Rev Eukaryot Gene Expr. 2008;18(1):81-91. PMID: 18197787
49. Combs GF Jr, Noguchi T, Scott ML. Mechanisms of action of selenium and vitamin E in protection of biological membranes. Fed Proc. 1975 Oct;34(11):2090-5.
    PMID: 1100438
50. Barja G, Cadenas S, Rojas C, López-Torres M, Pérez-Campo R. A decrease of free radical production near critical targets as a cause of maximum longevity in animals. Comp Biochem Physiol Biochem Mol Biol. 1994 Aug;108(4):501-12. PMID: 7953069
51. Sanz A, Stefanatos RK. The mitochondrial free radical theory of aging: a critical view. Curr Aging Sci. 2008 Mar;1(1):10-21. PMID: 20021368
52. Pérez VI, Van Remmen H, Bokov A, Epstein CJ, Vijg J, Richardson A. The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell.2009 Feb;8(1):73-5. PMID: 19077044
53. Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ, Huang TT, Nelson J, Strong R, Richardson A. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics. 2003 Dec 16;16(1):29-37.
    PMID: 14679299
54. Jang YC, Remmen VH. The mitochondrial theory of aging: insight from transgenic and knockout mouse models. Exp Gerontol. 2009 Apr;44(4):256-60. PMID: 19171187
55. Sohal RS, Kamzalov S, Sumien N, Ferguson M, Rebrin I, Heinrich KR, Forster MJ.
    Effect of coenzyme Q10 intake on endogenous coenzyme Q content, mitochondrial electron transport chain, antioxidative defenses, and life span of mice. Free Radic Biol Med. 2006 Feb 1;40(3):480-7. PMID: 16443163
56. Meydani M, Das S, Band M, Epstein S, Roberts S. The Effect of Caloric Restriction and Glycemic Load on Measures of Oxidative Stress and Antioxidants in Humans: Results from the CALERIE Trial of Human Caloric Restriction. J Nutr Health Aging. 2011;15(6):456-60. PMID: 21623467
57. Wanagat J, Dai DF, Rabinovitch P.Mitochondrial oxidative stress and mammalian healthspan. Mech Ageing Dev. 2010 Jul-Aug;131(7-8):527-35. PMID: 20566356
58. Pintea A, Rugină D, Pop R, Bunea A, Socaciu C, Diehl HA. Antioxidant Effect of Trans-Resveratrol in Cultured Human Retinal Pigment Epithelial Cells. J Ocul Pharmacol Ther. 2011 Jun 11. PMID: 21663493
59. Li H, Förstermann U. Resveratrol: a multifunctional compound improving endothelial function. Editorial to: “Resveratrol supplementation gender independently improves endothelial reactivity and suppresses superoxide production in healthy rats” by S. Soylemez et al. Cardiovasc Drugs Ther. 2009 Dec;23(6):425-9. PMID: 19937102
60. Robb EL, Page MM, Wiens BE, Stuart JA. Molecular mechanisms of oxidative stress resistance induced by resveratrol: Specific and progressive induction of MnSOD. Biochem Biophys Res Commun. 2008 Mar 7;367(2):406-12. PMID: 18167310
61. Robb EL, Winkelmolen L, Visanji N, Brotchie J, Stuart JA. Dietary resveratrol administration increases MnSOD expression and activity in mouse brain. Biochem Biophys Res Commun. 2008 Jul 18;372(1):254-9. PMID: 18486604
62. Harikumar KB, Aggarwal BB. Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle. 2008 Apr 15;7(8):1020-35. PMID: 18414053
63. Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology. 2011 May 10;283(2-3):65-87. PMID: 21414382
64. Fahmy B, Cormier SA. Copper oxide nanoparticles induce oxidative stress and cytotoxicity in airway epithelial cells. Toxicol In Vitro. 2009 Oct;23(7):1365-71.
    PMID: 19699289
65. Ford ES. Serum copper concentration and coronary heart disease among US adults. Am J Epidemiol. 2000 Jun 15;151(12):1182-8. PMID: 10905530
66. Belguendouz L, Fremont L, Linard A. Resveratrol inhibits metal ion-dependent and independent peroxidation of porcine low-density lipoproteins. Biochem Pharmacol. 1997 May 9;53(9):1347-55. PMID: 9214696
67. Viña J, Sastre J, Pallardó F, Borrás C. Mitochondrial theory of aging: importance to explain why females live longer than males. Antioxid Redox Signal. 2003 Oct;5(5):549-56. PMID: 14580309
68. Mao Z, Hine C, Tian X, Van Meter M, Au M, Vaidya A, Seluanov A, Gorbunova V.SIRT6 promotes DNA repair under stress by activating PARP1. Science. 2011 Jun 17;332(6036):1443-6. PMID: 21680843
69. Tsunoda R, Okumura K, Ishizaka H, Matsunaga T, Tabuchi T, Tayama S, Yasue H, Enhancement of myocardial reactive hyperemia with manganese-superoxide dismutase: role of endothelium-derived nitric oxide. Cardiovasc Res. 1996 Apr;31(4):537-45. PMID: 8689645
70. Malecki EA, Greger JL, Manganese protects against heart mitochondrial lipid peroxidation in rats fed high levels of polyunsaturated fatty acids. J Nutr. 1996 Jan;126(1):27-33. PMID: 8558311
71. Pucheu S, Coudray C, Tresallet N, Favier A, de Leiris J, Effect of dietary antioxidant trace element supply on cardiac tolerance to ischemia-reperfusion in the rat. J Mol Cell Cardiol. 1995 Oct;27(10):2303-14. PMID: 8576945
72. Miyake Y, Tanaka K, Fukushima W, Sasaki S, Kiyohara C, Tsuboi Y, Yamada T, Oeda T, Miki , Kawamura N, Sakae N, Fukuyama H, Hirota Y, Nagai M; Fukuoka Kinki Parkinson’s Disease Study Group. Dietary intake of metals and risk of Parkinson’s disease: A case-control study in Japan.J Neurol Sci. 2011 Jul 15;306(1-2):98-102. PMID: 21497832
73. Bouchard MF, Sauvé S, Barbeau B, Legrand M, Brodeur MÈ, Bouffard T, Limoges E, Bellinger DC, Mergler D, Intellectual impairment in school-age children exposed to manganese from drinking water. Environ Health Perspect. 2011 Jan;119(1):138-43. PMID: 20855239
74. Jadhav SH, Sarkar SN, Aggarwal M, Tripathi HC, Induction of oxidative stress in erythrocytes of male rats subchronically exposed to a mixture of eight metals found as groundwater contaminants in different parts of India. Arch Environ Contam Toxicol. 2007 Jan;52(1):145-51. PMID: 17031751
75. Catherine A Mulholland and Diane J Benford, What is known about the safety of multivitamin-multimineral supplements for the generally healthy population? Theoretical basis for harm.Am J Clin Nut, Vol. 85, No. 1, 318S-322S, January 2007 PMID: 17209218
76. Greger JL, Dietary standards for manganese: overlap between nutritional and toxicological studies. J Nutr. 1998 Feb;128(2 Suppl):368S-371S. PMID: 9478027
77. Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD, Checkoway H, Parkinson’s disease risks associated with dietary iron, manganese, and other nutrient intakes. Neurology. 2003 Jun 10;60(11):1761-6. PMID: 12796527
78. The Manganese Health Research Program, Brief Background on the Health Effects of Manganese, http://www.manganese-health.org/about_us/healtheffects
79. Greger JL, Nutrition versus toxicology of manganese in humans: evaluation of potential biomarkers. Neurotoxicology. 1999 Apr-Jun;20(2-3):205-12. PMID: 10385884
80. Bödör C, Matolcsy A, Bernáth M, Elevated expression of Cu, Zn-SOD and Mn-SOD mRNA in inflamed dental pulp tissue. Int Endod J. 2007 Feb;40(2):128-32. PMID: 17229118
81. Zidenberg-Cherr S, et al. Dietary superoxide dismutase does not affect tissue levels. Am J Clin Nutrit 1983;37:5. PMID: 6849282
82. Seguí J, Gironella M, Sans M, Granell S, Gil F, Gimeno M, Coronel P, Piqué JM, Panés J. Superoxide dismutase ameliorates TNBS-induced colitis by reducing oxidative stress, adhesion molecule expression, and leukocyte recruitment into the inflamed intestine. J Leukoc Biol. 2004 Sep;76(3):537-44 PMID: 15197232
83. Regnault C, Soursac M, Roch-Arveiller M, Postaire E, Hazebroucq G, Pharmacokinetics of superoxide dismutase in rats after oral administration. Biopharm Drug Dispos. 1996 Mar;17(2):165-74. PMID: 8907723
84. Sugiura M, Adachi T, Inoue H, Ito Y, Hirano K, Purification and properties of two superoxide dismutases from human placenta. J Pharmacobiodyn. 1981 Apr;4(4):235-44.
    PMID: 7264869
85. Lawrence de Garavilla, Timothy Chermak, Heather L. Valentine, and
    Robert C. Hanson, Novel Low-Molecular-Weight Superoxide Dismutase Mimic
    Deferoxamine-Manganese Improves Survival Following Hemorrhagic and
    Endotoxic Shock. Drug Development Research 25: 139-148 (1992)
    http://onlinelibrary.wiley.com/doi/10.1002/ddr.430250206/abstract

Copyright 2011- Bill Sardi

This review of breakthroughs in anti-aging technologies will focus on the past year’s published scientific reports as well as developments outside science. This report is intentionally written to provide outspoken opinion and critical analysis of efforts to prolong human life since the public and scientific researchers themselves are often misdirected in their pursuit of longevity.
Having written an annual report on the state of anti-aging advances for the past 5 years, I can say that that this field of scientific investigation becomes more perplexing with events outside the laboratory sometimes dominating over true scientific advancement.

When executives at a pharmaceutical company began to sell a widely promoted longevity drug (resveratrol) as a look-alike dietary supplement via a non-profit side venture, eyebrows were raised and the parent company in Britain quickly stopped distribution of these pills, declaring the dry-powder nutriceutical version sold online by the Healthy Lifespan Institute wasn’t the same as the liquid drug version (SRT501). Overseas executives then promptly declared there would be no further development of a drug the world was holding its breath for. The company would pursue other patentable molecules for the treatment of disease, not to conquer aging. Those other patentable molecules appear to have fizzled also.

Frankly, with this action Big Pharma abandoned an effort which, if successful, would have put itself out of business. Conquer aging and there is little need for a myriad of pills to treat every age-related disease. Did Big Pharma pay $720 million just to get this pill off the market? It appears so. Yet the thought of this never seemed to dawn on anyone.
A great way to extort the drug companies is to develop a pill that would prolong human life and force them to buy you out for hundreds of millions of dollars to keep it off the market.

Did the world’s only credible effort to bring an anti-aging pill to fruition get thrown out the window with the abandonment of SRT501? Keep reading.

The bigger question was whether anyone was left to carry the torch for an anti-aging pill? It appears the baton has been passed to nutriceutical manufacturers. At the writing of this report there were 510 published resveratrol studies listed by the National Library of Medicine in 2010, with over 95% involving research-grade resveratrol (preserved in a frozen and sealed vial), which is not equivalent to what is being sold in retail stores in dosage, purity, or proven effectiveness. Only a few studies of branded resveratrol supplements have been published. Among over 290 brands of resveratrol pills on the market, only one company, Longevinex®, has sponsored ten ground-breaking studies with the remaining 290 brands producing just 3 studies, two of which failed to produce a positive outcome.

Not the first time

A report I wrote earlier this year revealed this isn’t the first time biologists and commercial interests have chosen to back away from the development of a pill that could result in humans living longer than ever imagined. The discovery in the 1970s that genes can be switched on and off by small molecules which could produce an anti-aging pill was summarily swept under the rug when the life insurance industry realized people would delay their purchase of policies if they were to live significantly longer.

With population control efforts in full swing (birth control pills) at the time, Time magazine tipped its hand by saying “we have birth control but not age control” Covert population control was the hidden agenda. The elites of the world chose to forego further research on an anti-aging pill even though they had discovered a small natural molecule, likened to resveratrol, that switched genes in the animal lab in the 1970s.

Darwinian biology must be cast aside

Gene testing was in the news this year. Yet it was disingenuous for testing companies and the news media not to reveal these tests only address the 2-percent of disease that is inheritable via gene mutations.

A vestige in biology that needs to be shed is Darwinian biology. Biologists are clinging to an outdated model that has already been disproved. The reason why this is important is because the Darwinian or gene mutation model of biology is hindering progress in understanding what causes humans to age.

In 1995, the late Richard C Strohman, then emeritus professor of molecular and cell biology at the University of California, Berkeley, wrote of the impossibility of Darwinian biology in explaining human aging and disease. Strohman noted that disease tends to be geographic rather inherited, and as people travel or migrate, diseases change, which suggests the diet and environment influence genes more so than inheritance. The genetic answer to chronic age-related disease, which predominates in long-living populations, is encoded in the epigenome involved in receiving signals from environmental factors such as food, food deprivation, solar radiation and temperature. A single mutation does not predict disease because there are duplicate genes. Nature has back-up systems. If one gene is mutated, a duplicate gene would often function in its place.

The discovery of epigenetics – the realization that the protein-making machinery of genes could be switched on and off (expressed or silenced, as geneticists say it) – revolutionized the modern understanding of man’s biological fate, but it wasn’t a welcome discovery. Darwinian biology prevailed and the mistaken idea that the sequencing of human genes was cast in stone by our forefathers left humanity to accept its fate. The prevailing dogma was that humans would live long or short lives dependent upon the inheritance of genes from their fathers and mothers. Changes in the sequence of nucleotides on the DNA ladder were forever. This mistaken idea was corrected in the January 18, 2010 edition of Time Magazine, with a cover story that was titled: “Why your DNA isn’t your destiny.” The public was, for the first time, being briefed on the science of epigenetics.

Even still today biologists themselves continue to plug in the archaic Darwinian model into an epigenetic world and the public has Darwinian fate indelibly etched into their memory. This is in spite of the fact that Darwin himself, on two successive 2-month visits to the Galapagos Islands in the mid-1800s, could not have observed changes in the shape of bird beaks emanating from gene mutations over such a short period of time, since these mutations take many generations to occur. It is obvious what Darwin saw was epigenetic adaptation and variation.

Biologists are still struggling to integrate epigenetics (gene switching) with genomics (gene mutations). They do concede that “progress in evolutionary genetics of aging has largely stalled.” Biology is talking out of two sides of its mouth. On one hand, it is widely documented that variations (polymorphisms) in human genes account for very little of the variance in lifespan. Yet that is often not the public face biologists put forward when they speak about human aging.

Twin studies show that longevity in humans is only moderately inheritable> “with a genetic component of 25-32%.” Aging researchers know there are striking differences between identical (monozygotic) twins whose DNA sequencing is the same.

There is also evidence that epigenetics can over-ride the effects of gene mutations, something that is not even considered.

In 1947 researchers demonstrated that vitamin A altered the expression of genes in mice who typically exhibit thick wrinkled skin and loss of hair coat due to having two copies of a gene for a single trait (known as a homozygous trait). The provision of vitamin A reversed these changes, producing less wrinkled skin. This was an early example of epigenetics overriding an inherited trait. Research like this was obviously overlooked in favor of the ideathat inherited genetic traits were permanent.

Some researchers say they know that “the biological reasons for ageing are no longer an unsolved problem in biology.” They recognize that the discovery of single-gene mutations can extend the lifespan of animals only in the laboratory. For example, several mice strains with defective growth hormone pathways experience an extended lifespan.

It is now recognized that “epigenetics is at the epicenter of modern medicine.” True, what is at the core of understanding human aging IS epigenetics. Yet while epigenetics continues to intrigue, genes only take commands from the environment – temperature, radiation, stress, food or lack of food. Researchers now claim “nutrition has a strong impact upon epigenetic processes and, therefore, holds promise in having important roles in regulating longevity and aging.”

The main point here is that aging researchers are talking about natural molecules, not man-made drugs. This makes perfect sense since nutrients are consumed in the daily diet and favorably or unfavorably switch genes. And it is something specifically within food — namely minerals — that largely control aging genes.

The demise of Sirtuin

The year 2010 was also the year of the demise of the Sirtuin1 gene. Once declared the “holy grail of aging” by a Harvard professor on the front page of The New York Times, geneticists now realize Sirtuin1 can both be up- or down-regulated with advancing age. So it cannot possibly be utilized as a marker of aging. Researchers at MIT, who had previously reported that the Sirtuin1 gene was up-regulated by a calorie-restricted diet, known as an unequivocal intervention that prolongs the life of all living organisms, reported that a limited calorie diet does not consistently up-regulate Sirtuin1 in all tissues and organs.

Furthermore, the now common practice of adding an additional gene to living organisms in the laboratory (what are called transgenic manipulations, such as adding an antioxidant gene), may prove nothing and does not consider there are a large number of genes that are involved in aging. In their own words, biologists now say: “There are single genes that cause premature ageing, but no single genes in humans have been reported so far that significantly increase longevity.” Gene mutations can take away but not necessarily add years to life.

The gene target was too narrow. In hindsight, the pursuit of a single gene target such as Sirtuin 1 appears to be a glaring misdirection on the road to longevity. Aging involves networks of genes, not a single master gene. Furthermore, it is unlikely a single molecule, whether it a drug or nutriceutical be, can control aging. That smudges all the current efforts now underway to develop such an anti-aging drug in the laboratory, since they are all based upon single-molecule approaches.

It is better to study what promotes longevity than what causes humans to age prematurely. It is better to look at the whole rather than the parts. Some time ago researchers reported that a calorie restricted diet, which unarguably prolongs life, activates 832 genes in rodent heart tissue. That should dispel the single gene approach to understand aging. So far, the closest biologists have come to that model is a pill that was found to switch 677 of these 832 genes in the same direction as calorie restriction. Of course, that discovery has been summarily ignored by biologists! The biologists who conducted this experiment won’t even lecture on their own discovery!

An early study in 2003 pointed to resveratrol, a red wine molecule, as a primary stimulator of Sirtuin1. But subsequent studies showed Sirtuin1 was stimulated by a fluorescent dye used in the gene analysis test. Furthermore, this past year researchers reported the perplexing fact that manipulations that either increase or decrease Sirtuin1 activity are both associated with a beneficial effect in animal models of ageing-associated disorders. So how can Sirtuin1 be used as a marker of anything? Yet idiotic nutriceutical companies continue to trumpet their products as Sirtuin1 activators. It’s a public charade with the blind leading the blind.

Many theories, but what causes aging?

For those who truly pursue longevity it is best not to fall into the trap of listening to everything that biologists say since their rhetoric often runs in circles. The field of anti-aging research often appears to take two steps forward followed by three steps back.

Ask any researcher who studies ageing this question: “What causes humans to age?”

He or she is likely to answer there are more than 300 theories of aging. Despite other researchers who claim the mysteries of aging have been solved, the prevailing consensus is that there is no consensus, that “the mysteries that control human lifespan are yet to be unraveled.” Theories abound, the antioxidant theory, the hormone theory, telomere theory, wear-and-tear theory. Yet all of these fall under the umbrella of the over-mineralization theory of aging, to be explained in more detail below.

A biologist recently asked these questions, but had no answers for them.

Why do we age? When do we start aging? What is the aging marker?  Is there a limit to how old we can grow?

Allow me to fill in the blanks to answer these questions:

Humans age because we begin to over-mineralize once full childhood growth is achieved for males and once menopause and baby-making is completed for females. During the growing years humans are having birthdays but not aging. There is no cellular evidence of aging during the growth years, such as accumulation of cellular debris (lipofuscin). Lipofuscin is the earliest sign of aging. Theoretically, there would be no limit to the length of human life if over-mineralization can be slowed, reversed or avoided.

The over-mineralization theory of aging explains:

Why females outlive males. Females control iron and copper via monthly menstrual flow while males begin accumulation 1 excess milligram of iron per day of life after full childhood growth is achieved. By age 40 males have four times as much calcium and twice as much iron as an equally-aged female and have double the risk for diabetes, cancer and heart disease.

The over-mineralization theory of aging:

• Explains why aging, as evidenced by the appearance of cellular debris, begins with the cessation of childhood growth. Iron, copper and calcium accumulate within cells resulting in dysfunction of cell cleansing mechanisms (lysosomes). The accumulation of cellular debris (lipofuscin) generates free radicals and induces gene mutations and switches genes.
• Explains why vegetarians may tend to live a bit longer than carnivores. Vegetarians consume less iron.
• Explains why the rate of aging accelerates in mid-life. Iron accumulates progressively in midlife.
• Explains why there is a leveling off of the rate of aging in late life. A steady-state of iron is reached in late life, evidenced by a leveling off of iron storage (ferritin).

For references to the above statements readers may wish to refer to the free online report entitled The Over-mineralization Theory of Aging, located here.

In further support of the over-mineralization theory of aging, it is interesting to note that hemoglobin, which is an iron-carrying molecule, generally decreases as men age. One study of 3507 men found hemoglobin levels below 14 grams per deciliter of blood in 14.8% of men age 71-75 years versus 53.6% in those aged 86 years and older. However, in this group of 3507 men, 47 developed Parkinson’s disease over a period of nearly a decade and their hemoglobin rose significantly. An increased hemoglobin level in late life is associated with the onset of Parkinson’s disease.

Eugene Weinberg, a noted authority on iron and health, says cells accumulate iron as they age. The iron content of some cells in the human body increases by as much as ten fold as they age. In aging rats, a 23% increase in iron content of gastrocnemius muscle increases oxidative damage by 85%.

In a human study of 10,714 US adults, 2.3% had high iron transferrin saturation levels and in the subsequent 22 years of their lives their rate of death rose more rapidly compared to others with lower iron transferrin levels (transferrin is the iron transport protein made in the liver).

In another study of 9229 people age 35-70 years who were followed for 12 years, individuals with both elevated iron and high dietary iron intake died more rapidly than with just one of the raised factors.

Aging is accompanied by the accumulation of cellular debris called lipofuscin within cells. Lipofuscin is toxic to cells because it can incorporate metals such as copper and iron, resulting in cell death. Such increasing toxicity is extensive in aging cells.

It is becoming apparent that “life was designed to exist at the very interface of iron toxicity and iron sufficiency.”

All proposed anti-aging pills control minerals

A hidden fact is that all the current technologies being explored to prolong the human lifespan control iron. In fact, iron switches genes. In an animal study, the provision of iron in the diet increased theproduction of an iron-controlling peptide (hepcidin) by 6.25 fold. Iron regulates various genes including those involved in progressive aging.

Let’s examine the link between iron and anti-aging strategies:

• In monkeys, a calorie-restricted diet has been found to decrease iron accumulation in the brain and preserve motor function. Calorie-restriction limits iron-induced cell damage.
• The provision of lipoic acid and carnitine has been proposed as an anti-aging strategy by noted biologist Bruce Ames. In fact, Bruce Ames was probably the first to propose a scientifically valid anti-aging pill by combining these two nutrients into a dietary supplement. It is not surprising to learn these two antioxidants reduce iron-induced oxidation.
• Metformin, a commonly prescribed anti-diabetic drug, is posed as an anti-aging pill. Yet it often goes unsaid that metformin reduces body stores of iron, and this may be its main mechanism for prolonging life.
• Metformin also restores ovulations in patients with premature menopause associated with polycystic ovary syndrome. Ovulation would resume monthly loss of iron and copper and reinstate the advantage females have over males in controlling accumulation of metals.
• The mTOR inhibiting drug rapamycin (Sirolimus) is now widely talked about as the next anti-aging pill. Again, it is no surprise to find that iron deficiency down-regulates mTOR (mammalian target of rapamycin). Also, iron chelating drugs inhibit mTOR. In fact, iron deficiency anemia is a known adverse effect of rapamycin (sirolimus) therapy.
• The first calorie restriction mimetic, proposed over a dozen years ago, was 2-deoxyglucose (2DG), a non-metabolizable form of glucose. 2DG has been found to reduce impairment of glucose and neurotransmitters induced by the provision of iron in rodents.
• The amino acid taurine was first proposed as an anti-aging pill when it was found that it was among the top five dietary factors associated with lower mortality in Japanese adults. Taurine reduces oxidative stress in the brain by virtue of its ability to inhibit metal-induced oxidation that degrades dopamine, an important brain chemical. Taurine also reduces oxidation in heart tissues induced by the provision of iron.
• One of the reasons why the antioxidant theory of aging has not been confirmed in a large number of studies is that not all antioxidants control unbound iron, copper and other heavy metals

You’re out of your telomeres

2010 was also a year of great interest in telomeres, which may be another misdirection in quest for an anti-aging pill. Telomeres are end caps on chromosomes. Telomeres shorten with advancing age.

The association between telomere length and mortality is poor.However, the telomere story is so captivating that it has a life of its own. Attempts to develop telomere-elongating treatments may be misdirected but are also popular.

Researchers say, although telomere length is implicated in cellular aging, evidence that telomere length is a biomarker of aging in humans is equivocal rather than conclusive.

Another drawback of telomere biology is that telomere length is often averaged. But it is the shortest, not the average length of telomeres that are potentially deleterious. Furthermore, it is still unknown whether telomere length may result in increased lifespan on one hand and higher risk for tumors on the other.

Telomere length is also controlled in part by iron. One study shows individuals who took iron supplements had shorter telomeres compared to non-supplement users.

In another study, those subjects with shorter telomeres and less healthy lifestyles had a significantly increased risk of the presence of coronary artery calcification. Overmineralization of tissues again appears to be involved if not causal in telomere shortening.

FYI: Resveratrol also inhibits telomerase, the enzyme that breaks down telomeres. So does IP6 from rice bran. 16979586

Forget telomeres, repair DNA breaks

Probably what longevity seekers ought to pursue are molecular approaches to thwart double-strand DNA breaks rather than telomere lengtheners.

Researchers propose that double-strand DNA breaks, being the most toxic and difficult to repair, result in accelerated aging Biologists indicate DNA double-strand breaks are the most dangerous of DNA lesions. They may lead to massive loss of genetic information and cell death. Inexact DNA repair may lead to premature aging.

Mice that are genetically engineered so their Ku80 protein is deleted are found to prematurely age. Ku80 protein is required for DNA repair. Mean telomere length appears to decrease with increasing longevity, although not significantly, while levels of Ku80 protein, which is required for repair of double-strand DNA breaks, varies dramatically in species of animals and Ku80 levels strongly correlated with longevity.

It is interesting to note that among centenarians, fibroblasts, cells that make connective tissue, were found to be less vulnerable to hydrogen-peroxide generated damage. The integrity of DNA appears to be greater among centenarians.

Intracellular iron (iron that resides within cells) is a prominent source of oxidative stress within cells that leads to double-strand DNA breaks.

In the year 2000 it was discovered that an iron-chelating (key-lay-ting) inositol hexaphosphate (IP6), a dietary molecule commonly provided in bran, is necessary for the repair of double-strand DNA breaks. Such a discovery should have alerted researchers on aging to the importance of this molecule.

Small molecules called flavonoids, especially those found in red apple peel and red onion (quercetin), and in citrus peel (diosmin), red grapes and green tea leaves (catechin), which are the best known, bind to iron and protect against DNA damage.

MicroRNA and aging

Many longevity seekers were drawn into efforts to prolong life via resveratrol pills, telomere lengtheners, stem cell activators, by the advent of epigenetic medicine. Epigenetics refers to protein-making by genes (switching genes on, or what is called gene expression, or switching genes off, what is called gene silencing) that are not changes in the sequences on the DNA ladder, which are referred to as gene mutations.

The initial epigenetic mechanisms described were small molecules that can pass through cell walls and enter genetic machinery, either by adding methyl groups or influencing wrapping of strings of DNA around structures called histone bodies.

However, in the past decade a greater understanding of epigenetics has led researchers to now recognize that microRNA are the “guiding hands of the genome.” MicroRNA are small snippets of messenger RNA that exit the cell nucleus and mesh with longer strands of messenger RNA. As microRNA mesh with messenger RNA, they shut off that segment of RNA that is assembling proteins, thus switching off genes. Longevity seekers should stay alert for studies involving microRNA and aging. The activation of microRNA change with advancing age and can act as both pro- and anti-longevity regulators.

The first microRNA analysis of a commercially available resveratrol pill was recently published. The results were quite astounding. Resveratrol, and even more so a combination of other small molecules with resveratrol (Longevinex®), was able to restore a near-normal microRNA profile to rodent heart tissue if treated prior to a heart attack. Longevinex® exerted a far greater influence over microRNA than plain resveratrol. Longevinex® exceeded the effect of resveratrol in 15 of the top 25 miRNAs that were measured.

Final notes

How to validate an anti-aging drug in a hurry

How far away is humanity from a confirmed anti-aging pill? Mikhail Blagosklonny of Ordway Research Institute in Albany, New York, says “the discovery of anti-aging drugs is no longer a fantasy.” While validation of an anti-aging pill is said to require a lifetime, he believes an anti-aging pill could be validated in just two years if it were used for one common age-related malady and then monitored to see if it resolved other age-related diseases in the same group of patients. He suggests drugs like rapamycin and/or resveratrol as the most promising.

He goes on to say: “If a drug is effective against one particular disease only, such a drug is not anti-aging. And current drugs are not anti-aging. For example, insulin compensates diabetes. Yet, insulin does not treat cancer. And vice versa chemotherapy may treat cancer but does not treat diabetes. So neither chemotherapy nor insulin is an anti-aging modality. Furthermore, both insulin and chemotherapy may accelerate aging.”

These breakthroughs come none too soon as the International Monetary Fund issued a grim warning that “the Malthusian nightmare is approaching” as nations begin to face the cost of caring for aging populations. In developed nations the future tab for caring for aging societies is 10 times greater than the tab for the current financial crisis that now grips the world. A recent report claims there are 10 million people now alive in Great Britain who will live to 100 years of age, and that’s WITHOUT an anti-aging pill. Most certainly, an anti-aging pill will have to improve the health span and the lifespan of centenarians.

Whatever anti-aging technologies are being developed had better be cheap, not only to consumers but in their development. Predictably, funding for ageing research is being drastically reduced. Karen Duff, a researcher at Columbia University in New York says “we are cutting back on the very research that we need to keep our ageing population healthy.” Today researchers who submit a grant application to the National Institutes on Aging face about an 8% chances of winning funding. This is prior to soon-to-be-implemented austerity measures in healthcare.

It is important for longevity seekers to realize there is a great deal of bamboozling going on in the anti-aging field, and it isn’t solely being distributed by online hucksters, but rather it comes from the scientific community itself.

I have made an attempt to show that efforts to covertly hide the development of an anti-aging pill from the public go back over 35 years. Maybe efforts to hide an anti-aging pill are rooted in population control, but the delay in delivering such a pill is better explained by what is expedient for life insurance and pharmaceutical companies. Recognize just one natural molecule, resveratrol, exerts biological action as an antidepressant, anti-inflammatory, anti-bacterial, anti-viral, anti-fungal, anti-cholesterol, anti-cancer agent. It would replace most drugs in a modern pharmacy.

An anti-aging pill, if they will ever allow one, is years away. You need to make a decision, based upon the best available evidence, as to whether this dream pill is actually within reach today. #### © 2010 Bill Sardi, Not for posting on other websites.

Las Vegas, Nevada (Dec. 29, 2010) – It was Paracelsus, the Renaissance physician (1493-1541 A.D.) who first said “the dose makes the poison.” So, you can drink too much wine, or ingest too much resveratrol, but in an unprecedented study, heart researchers report they couldn’t find a toxic dose for Longevinex®, a resveratrol-based dietary supplement.

Investigators previously reported that six or more glasses of red wine per day actually increase the risk, whereas 3-5 glasses per day optimally reduce risk for cardiac death.  This is the well-known J-shaped risk curve (risk goes down, then up with excessive dose) that has been documented for both red wine and resveratrol.

North Americans who abstain from drinking wine have higher mortality rates for coronary heart disease (~240 per 100,000), making red wine and resveratrol pills tantalizing for those individuals who wish to reduce their risk for a mortal heart attack (~90 per 100,000 for wine drinkers).

The drawback here is that consumption of 3-5 glasses of red wine a day approaches the point of inebriation.  Health seekers who wish to avoid the undesirable effects of alcohol may be led to try resveratrol pills, which if taken in mega-doses, could be potentially toxic to the heart.

Unexpected results

In an animal experiment that surprised researchers, circulation was blocked to excised animal hearts and it was unexpectedly found that Longevinex® exhibited cardio-protection (minimized damage to heart muscle) over a wide dosage range – 100 to 7000 milligrams human equivalent dosage — whereas 1750 mg of plain resveratrol increases damage to the heart and 3500 milligrams stops (“kills”) an excised mouse heart in the laboratory every time.  The study is published in a recent issue of Experimental & Clinical Cardiology and is available for viewing online.

Incredulous researchers, at first puzzled by the results of their animal experiment with mice, continued to increase the human equivalent dosage up to 7000 mg, prolonged the duration of the study up to six months, and even administered Longevinex® to another animal species, rabbits, with the same results.

Resveratrol – antioxidant or pro-oxidant?

In prior animal studies it has been shown that as dosage increases resveratrol shifts from being an antioxidant to a pro-oxidant (promotes oxidation) – it binds to copper at low doses and releases copper at high doses.  Longevinex® exhibited no such toxicity.  This remarkable range of safety for any resveratrol-based product has never been demonstrated before.

Animal studies show plain resveratrol is optimally cardio-protective at human-equivalent dose of 100-175 mg and begins to lose its protective effects in a dose as low as 350 mg.  Published studies confirm that low-dose resveratrol, particularly when combined with other synergistic small molecules from nature as provided in Longevinex®, works better in animal hearts than mega doses.

While this is the first time a resveratrol pill has been demonstrated to exhibit an L-shaped risk curve (risk goes down and stays down at all tested doses),  this does not imply that mega-dose Longevinex® is totally without side effect at all doses, says Bill Sardi, spokesperson for Longevinex®.  Consumers should refer to the product label which describes recommended dosage range and potential side effects with resveratrol pills, Sardi says.

Researchers indicate low-dose resveratrol protects the heart from damage should a heart attack occur, while “plain resveratrol should only be used at lower doses as opposite effects can occur higher doses, resulting in adverse effects on health.”

Longevinex® is the first branded resveratrol product to show true evidence for cardio-protection (i.e. laboratory animals survive an otherwise mortal heart attack)  In another recently published paper Longevinex® was also shown to restore a near-normal gene activation profile to excised animal hearts subjected to an intentional heart attack.

Red wine drinkers in France have a very low rate of cardiovascular mortality.  There are more centenarians per capita in France than any other country.  The idea of creating a red wine pill that mimics the beneficial effects of red wine without side effects has advanced one step closer with Longevinex®.

For more information about Longevinex® go to www.longevinex.com ####

Las Vegas, NV (Dec. 24, 2010) – In the world’s first comparative microRNA analysis of a resveratrol-based nutriceutical, Longevinex®, a low-dose resveratrol-based dietary supplement, exhibited a distinctive gene regulation pattern apart from plain resveratrol and protected the excised animal heart from damage caused by an experimentally-induced heart attack.

Three weeks of oral resveratrol or Longevinex® ingestion prior to an induced heart attack returned microRNA activity close to their pre-event levels.  Among thousands of microRNA’s studied, just six were attributed to exerting the majority of the gene-switching effects measured in the animal heart study — four microRNA optimally regulated by Longevinex® and two optimally by plain resveratrol.

A pre-conditioning effect with resveratrol and Longevinex® had already been demonstrated in prior studies where these small molecules activate antioxidant defenses (nitric oxide, heme oxygenase, adenosine) prior to a heart attack, thus limiting damage in the event of an abrupt halt in the delivery of oxygenated blood to the heart.

This newly published study in the PLoS ONE (Public Library of Science) journal sought to compare and contrast the gene switching pattern for both plain resveratrol and resveratrol in a matrix with other small molecules (Longevinex®) following an induced blockage of circulation in excised animal hearts.

MicroRNA explained

MicroRNA is a mechanism within living cells that switches genes. (For a more complete description of how microRNA works, read here.)  MicroRNA’s are short segments of RNA that turn off gene protein-making machinery (called gene expression) when microRNA meshes with messenger RNA.

First thought to exert a minor influence over the human genome (library of genes), microRNA’s are now more fully recognized as “the genome’s guiding hand” – a fundamental regulator of over 90% of human genes.  MicroRNA appear to exert a stronger influence over the human genome than two other known mechanisms (methylation and histone modification) of gene regulation.  MicroRNAs exceed the biological action of most drugs, which are largely targeted at single genes, while microRNAs regulate complex networks of genes, there is feverish work being done to create drugs that influence microRNA.

Beyond gene switching

Of course, the objective is to produce health benefits, not just switch genes.  Indeed, these small molecules did just that.  Plain resveratrol and Longevinex® both protected heart tissues and reduced the size of a heart attack, as measured by the amount of scar tissue (fibrosis).

Low-dose Longevinex®, providing 100 mg of trans resveratrol, reduced the size of a heart attack (from ~35% without treatment to ~20% scar tissue with treatment) in a superior manner to plain resveratrol (from ~35% to ~24% scar tissue), and reduced death of heart muscle cells (cardiomyocytes) from ~17% without treatment to ~9% with Longevinex® (48% reduction in cell death), compared to a decline from ~17% to ~12% with plain resveratrol (20% reduction in cell death).

While plain resveratrol modestly improved the pumping pressure of the heart (from ~75 to ~90 millimeters of mercury pressure; 20% improvement), Longevinex® doubled heart pumping pressure (from ~70 to ~140 millimeters of mercury pressure; 100% improvement) compared to no treatment at the two–hour point following an experimentally-induced heart attack.

Also at the two-hour point, Longevinex® improved blood flow in the aorta (first blood vessel outside the pumping side of the heart) from ~15 milliliters per minute without treatment to ~26 milliliters per minute (73% improvement), while resveratrol improved blood flow from ~14 milliliters per minute without treatment to ~21 milliliters per minute (50% improvement).

Back to microRNA switching

Upon analysis, it became clear that Longevinex® exerted the greatest influence over the top 25 significantly differentiated microRNA’s in rodent heart tissue.   Longevinex® exceeded the effect of resveratrol in 15 of the 25 microRNA’s.

Comparative analysis of three key microRNA (microRNA 20b, 21, 539) are instructive.

Longevinex® profoundly down-regulated microRNA 20b (-1366-fold) compared to plain resveratrol (-189-fold), a microRNA that exerts control over a gene (hypoxia inducing factor, or HIF-1 alpha) that adapts malignant cells to a low oxygen environment.  MicroRNA 20b also exhibits control over growth factors (such as vascular endothelial growth factor, aka VEGF).  The strong silencing (switching off) of HIF-1 alpha via microRNA 20b would be desirable, for example, to inhibit formation of new blood vessels that feed tumors and which invade the retina at the back of the eyes.

Prior to an induced heart attack, microRNA 21 was tremendously up-regulated (up 391.4-fold) by resveratrol and Longevinex® (up 760.9-fold), was lowered considerably after a heart attack (-4.0), then returned to up-regulation following a heart attack by resveratrol (up 61.5) and Longevinex® (up 59.3), which suggests protective pre-conditioning prior to the event.

MicroRNA 539 exhibited the highest level of up-regulation (214 fold) following a heart attack, which suggests a protective response.  Resveratrol diminished this response (down from 214-fold to 172.4 fold) while Longevinex® further enhanced this microRNA response, from 214-fold to 314.6-fold increase.   MicroRNA 539 controls of a number of genes involved in healing heart tissue following a heart attack.

The study was performed in the animal laboratory at the National Institutes of Health in Bethesda, Maryland in collaboration with investigators at the NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA).  The NIAAA’s involvement was predicated upon its mandate to study the effects of alcohol and alcohol-related molecules found in wine, like resveratrol.

The entire report published in PLos One can be viewed here.  For further information about Longevinex®, visit www.longevinex.com A slide show that graphically explains this current discovery is located at  http://www.longevinex.com/microRNA/

While the evidence for molecular preconditioning the heart to withstand a heart attack using resveratrol is growing, there is unexplained lack of interest from cardiologists.  Given that safety concerns are answered, there is little standing in the way of cardiologists beginning to prescribe resveratrol pills today.

A lone cardiologist who has extensively prescribed Longevinex® indicates there have been no significant side effects among hundreds of his patients.  Thousands of Americans are taking resveratrol pills in an unguided fashion without reported serious side effects, which is a safety study of sorts.  Furthermore, physicians may mistakenly demand human studies be conducted before they prescribe for their patients.  However, this is impractical.

Since interventional human studies involving mortality cannot be conducted for ethical reasons, and it would take many years to acquire data in retrospective population studies it is obvious that thousands and thousands of people may needlessly succumb to an otherwise avoidable mortal heart attack before doctors place their imprimatur on resveratrol pills, presumably years from now.

Furthermore, FDA regulations regarding health claims for dietary supplements are cumbersome and will surely result in greater loss of life.  While FDA regulations forbid a dietary supplement to claim it cures, treats of prevents a disease, is mortality a disease?  What good is a regulation that does not protect the public and results in higher mortality rates?

The only clear alternative is to consume red wine, but this poses the risk of over-consumption since optimal health benefits are achieved only with consumption at the point of inebriation — 3-to-5 glasses of dark red wine per day (not the common store-bought wines that are not aged properly), which would cost $3-7 a day.  A red wine pill, providing red wine solids without alcohol, is safer, provides a more reliable dose, and is more affordable (less than $1 per day).

If this animal lab research translates into lessons for human health, then get some resveratrol.  If you are a full-grown male or a menopausal female, get some now.  Get a modest dose, ~100 mg, not more than 175 mg.  Higher doses are counterproductive and can even have mortal consequences in the event of a heart attack.  Mega-dose resveratrol pills should be voluntarily removed from the marketplace.  The problem is in finding accurately labeled products that fit these requirements.  These would be unproven products at best, using borrowed science which assumes what was used in the laboratory is equivalent to what is used in a particular brand of res-pill.

For those consumers who must consider affordability, it may be counterproductive to obtain a low-priced res pill and hope what is on the label is in the jar of pills (misleading labels on cheap products sold at Walmart and Costco give consumers the false impression they are purchasing more resveratrol than is actually in the pills).  There is now clear evidence here that the optimally desired “red wine effect” sans alcohol is only achieved by the provision of an array of small molecules, as demonstrated in Longevinex®.   It would be better for economy-minded consumers to take one Longevinex® every other day than to take a product that simply won’t work, or is only imagined to work.

A cardiology group that recommends Longevinex® relays that their patients often opt for more economical yet unreliable store-bought brands of resveratrol pills, despite the lack of any evidence these products are equivalent to what is being used in the laboratory.  The unexpected problem is that the company that bears the financial burden of research studies may not find their R&D investment translates into sales, at least not for their own product, which is the current situation Longevinex® finds itself in.

Resveratrol pills should have become a multibillion business.  Today only a few million dollars of res pills are sold annually, divided among more than 290 brands.  Only three of these brands have undergone any research in published studies (two were failed or problematic studies).  The rest rely upon borrowed science.

As a guesstimate, maybe less than 250,000 Americans take a res-pill every morning against a target population of ~88 million baby boomers (age 42-60) and 35 million seniors (over age 65).  That’s about 2/10ths of 1% of this target group.

If just 10-20% of these two population groups elected to take a proven resveratrol pill that lived up to its promise of improving the healthspan and lifespan of Americans, there would be an anticipated steep downturn in coronary artery-related mortality rate.  The nation’s medical bills would tumble.  But at the present time, Americans spend more money on pet food, cigarettes, and lattes than res-pills.  There are more online searches for hemorrhoid treatment than resveratrol pills.  It’s the way things are in America.

Resveratrol has fast become a commodity as flour is in a cake mix.  Will any old resveratrol pill do?  What Longevinex® has demonstrated is that it is an entire recipe of ingredients, in the proper proportions and carefully fashioned (microencapsulated), not a single ingredient, which produces the full benefits of a resveratrol pill.  Sadly, if this laboratory mouse study is correct, consumers who purchase res-pills at Wal Mart or Costco may end up paying for these pretender resveratrol pills with their life.

Even more disconcerting is that consumers, even after reading the PLoS ONE report on how resveratrol may avert sudden cardiac, may stick with their 10-cent aspirin tablet that isn’t working.  Low-dose 81 mg- aspirin is insufficient to prevent blood clots in coronary arteries that supply the heart with oxygenated blood, and the 325 mg aspirin tablets induce gastric bleeding and brain hemorrhages in what has been called disease substitution rather than disease prevention.

The vagaries of American consumers defy the science.  Even in the face of their doctor’s recommendation, they opt for unproven products.  Often seduced by online bloggers who serve as front-men for outlaw manufacturers of res-pills who offer the bloggers kickbacks in the form of affiliate fees to recommend their products, and by free-bottle offers that covertly place consumers on automatic monthly shipments, consumers buy into these make-believe pills by pretending they will actually work.

Somewhere in the back of their mind consumers feel they can buy the same thing for less and that responsible producers like Longevinex® are gouging them.  Reading deceptive label on res-pill jars aids and abets this problem.  Efforts to purchase the most affordable products can backfire on spendthrift consumers.  An inadequate dose will yield little benefit.  A mega-dose can harm, even lead to premature death.  In animal studies, res-pills begin to lose their effect at 350 mg (human equivalent dose) and are potentially toxic at 1750 mg and produce sudden stoppage of the excised mouse heart every time at 3500 mg.  While plain resveratrol pills work to some extent, damaged heart muscle cells do not regenerate rapidly.  Optimally minimizing the damage, should a heart attack occur, is primary.

The lack of a response to this exciting science by physicians is not likely to change.  The status quo will likely prevail.  Statin drugs and aspirin have not significantly reduced coronary artery disease mortality rates.  The public’s apathy while crying for more affordable health care is another perplexing issue. The federal government isn’t going to mandate res-pills like they have seat belts in automobiles.  Endorsement of res-pills by Oprah and Dr. Oz only spawned a slew of outlaw brands that bilked consumers of their money. While upcoming science may more clearly validate the promise of resveratrol pills, human idiosyncrasies are likely to thwart any real human progress.   – Bill Sardi, managing partner, Longevinex®   December, 2010