Pronounced long-jev-in-ex
The Official Website
Pronounced long-jev-in-ex
The Official Website
July 26, 2010: by Bill Sardi
Inquiry: Read an article in today’s NYT about Situin and it’s potential in preventing Alzheimer’s. Resveratrol was mentioned as promoting Sirtuin but the article was not clear if it did so past the brain/blood barrier. I would appreciate if you could shed some light on this.
Comment: First, I am obligated to say that at no time in my answer below am I suggesting any resveratrol-based dietary supplement is proven for the cure for a brain disorder like Alzheimer’s disease. It can only be said it is a very promising molecule in regard to aging in the brain.
Second, resveratrol pills have been marketed avidly in the U.S. now for about 6 years and we simply haven’t received reports from patients or families of Alzheimer’s patients that any resveratrol pill restored memory, though we do frequently receive reports from healthy individuals that they experience improved mental alertness and clarity of thinking and that their recall (memory) is a lot faster.
Third, yes, resveratrol does pass the protective blood-brain barrier as it is a small molecule (this will be elaborated upon below). However, resveratrol traverses the blood circulation complexed with glucuronate or sulfate, two detoxification molecules that attach to resveratrol as it passes through the liver, temporarily rendering resveratrol as a non-bioavailable molecule (can’t pass through cell walls attached to these other molecules). However, an unlocking enzyme, glucuronidase, which is 16 times more abundant at sites of inflammation, infection and malignancy, frees resveratrol as an unbound molecule, which is nature’s drug delivery system. Metabolism of resveratrol in the liver also prolongs the half-life of resveratrol from ~14 minutes to 9 hours.
Third, what is reported in The New York Times by Nicholas Wade, whose articles about SIRTRIS pharmaceuticals over the past six years have been quite popular, appears to be a defense of Sirtuin1 gene activating drugs. Sirtris’ SRT501 botanical-based stabilized, emulsified, micronized resveratrol pill has come under fire with the recent discovery a fluorescent compound in the gene activation test was responsible for the Sirtuin1 activation, not resveratrol. This doesn’t diminish the promise of resveratrol, but it does cast a cloud over its intended gene target.
Nicholas Wade’s article (Potential Found In New Approach to Alzheimer’s) emanates from a newly published report in Cell (Volume 142, Issue 2, pages 320-32, July 23, 2010),which can be viewed online here (click the tabs to view all the parts of the report). The title of the report is “SIRT1 Suppresses β-Amyloid Production by Activating the α-Secretase Gene ADAM10.” (Interpretation: A gene called Sirtuin1and its proteins inhibit the formation of beta-amyloid plaque via the activation of an enzyme, alpha secretase — plaque that is implicated in the onset of memory loss typically seen in Alzheimer’s disease.
You can visualize beta amyloid accumulation in the brain in the PET scan images presented below. The PET scans revealed beta-amyloid plaque in the brains of three Alzheimer’s disease patients (left) and three normal controls (right). The yellow indicates high uptake of a label that targets beta-amyloid plaque, and the red indicates medium uptake.
A problem with this study is that overproduction of beta amyloid plaque is not the primary problem in the aged brain. The problem is the inability to get rid of beta amyloid. It hardens and becomes a toxic form of plaque. This is believed to be due to the accumulation of copper and other heavy metals in the brain over time. Very small amounts of inorganic copper (not bound to a protein) in tap water, 10-times less than what the Environmental Protection Agency allows, inhibits the efflux (removal) of beta amyloid.
What researcher George Brewer at the Departments of Human Genetics and Internal Medicine, University of Michigan Medical School, points out is that inorganic copper, iron and other heavy metals, largely acquired from drinking water and vitamin supplements, hardens the beta amyloid plaque and inhibits the efflux of beta amyloid from the brain. Resveratrol, being a copper chelator, is certainly a potential antidote in this regard. However, unbound iron is also a problem and resveratrol does not chelate (key-late) iron. The addition of an iron chelator such as quercetin or IP6 would be desirable in this regard.
If you attempt to upregulate Sirtuin 1 but fail to stop the intake or inorganic copper, what have you accomplished? As an aside, it is interesting to note that Alzheimer’s is a disease largely exhibited in advanced civilizations that rely upon copper plumbing. More primitive cultures do not exhibit Alzheimer’s among their aged.
One of the problems with gene expression studies like this is that it is not known if this is a cause or consequence of the disease. In the New York Times today Leonard Guarente of MIT shows that increased expression of Sirtuin1 protein not only inhibits beta amyloid plaque formation but slows the typical decline in memory seen in this inbred species of laboratory animal. (Note that it was not demonstrated to reduce existing memory impairment in this experiment, which would make it therapeutic rather than just preventive. However, other resveratrol studies do point to therapeutic or restorative action.)
It is important to understand the workings of epigenetics here in contrast to structural genetics (gene sequencing, mutation, etc). The science of epigenetics, in contrast to gene structure that was discovered by Charles Crick and Francis Watson in 1953, is that gene protein-making is governed by environmental factors such as food, lack of food, radiation exposure (sunlight), and temperature. Small molecules known to activate the same genes as a calorie restricted diet, for example, would serve as an example of molecular medicine, a short-cut where these environmental factors are mimicked. However, if the environmental factor (i.e. copper accumulation) continues, it may override any gene activator.
It is encouraging to learn that resveratrol has been shown to promote the clearance of beta amyloid plaque from the brain. The chart below compares resveratrol with two other small natural molecules in their ability to reduce beta amyloid plaque. (Total sAβ = total beta amyloid plaque in nanograms per milliliter. The numbers across the bottom indicate microMolar concentration of resveratrol.)
Another problem with this research is that while over-activation of Sirtuin1 gene protein (SIR2 in animals) may be beneficial in the brain, it may be deleterious in other organs, such as the heart. Furthermore, Leonard Guarente, MIT professor, the lead researcher in this study presented in the New York Times, conducted research which shows that calorie restriction (CR), the unequivocal dietary practice that doubles lifespan of all living organisms tested, does not universally differentiate the Sirtuin1 gene in all tissues and organs. Therefore, stimulation of this gene cannot be used as a gauge of whether a molecule like resveratrol is a mimic of a CR diet.
Since Alzheimer’s disease and aging itself involve many genes, a gene array study may be revealing. Resveratrol is a small molecule (228 Daltons molecular weight), so it passes the blood-brain barrier, and through cell walls, where it influences genetic machinery indirectly via the FOXO1 gene in the cytoplasm or directly in the nucleus.
This is in contrast to other Sirtuin-activating drugs (SRT1720, SRT 1460, SRT2183) which are larger molecules and unable to traverse the blood-brain barrier.
Transresveratrol
The glory of resveratrol and other small molecules like it is it regulates many genes, not just one. There is also synergism noted when multiple small molecules like quercetin are employed with resveratrol.
For example, Longevinex® (resveratrol, quercetin, IP6) was put to the test in a laboratory mouse study. In a gene array study, Longevinex® was shown to activate, in the rodent brain:
Total # genes analyzed: 20,341 in rodent brain tissue
(Note: half of these genes will be duplicate or dysfunctional genes)
# genes changed by CALORIE RESTRICTION: 124
# genes changed by RESVERATROL: 424
# genes changed by LONGEVINEX: 2,560
# genes changed by All three treatments: 5
A more profound genomic effect, 6-fold greater than plain resveratrol and 21 times greater than a calorie-restricted diet, was produced by a resveratrol-based nutriceutical matrix (Longevinex®).
While it is true that very low nanomolar concentrations (parts per million) of resveratrol have been shown to reduce beta amyloid plaque in the brain of animals, Alzheimer’s disease involves many factors, not just a single gene, nor just beta amyloid plaque. Some people have a lot of brain tangles and beta amyloid and experience no loss of memory in their retirement years.
It is clear that many factors (poor circulation, gene expression, heavy metals (particularly iron, copper, lead, mercury, aluminum, manganese), chronic viral infection, lack of thiamin (vitamin B1) which is often caused by over-consumption of sugar or alcohol, may be involved and any proposed therapy will have to address multiple etiologies.
Chronic inflammation is a hallmark of aging and what has been termed “inflammaging” is believed to be central to the onset of Alzheimer’s disease. This is likely due to the unequivocal fact that chronic brain inflammation, as evidenced by an inflammator agent (cytokine) known as tumor necrosis factor (TNF), interrupts transmission of brain chemicals across the synapse (gap) between brain cells (neurons).
The injection of a TNF-inhibiting drug (etanercept) directly into the brain via a neck vein has been demonstrated to produce almost immediate memory repair in humans, but the effect only lasts about 6 days and costs ~$10,000 to $40,000 a year. While unaffordable and impractical, this does tell us that neurons are intact and inflammation plays a strong role in brain deterioration.
Of interest to readers here, resveratrol, quercetin, and vitamin D3, ingredients in Longevinex®, are strong TNF-inhibitors. However, it should be noted that over-inhibition of TNF is potentially deleterious as it stunts the immune system and drastically elevates the risk for leukemia (cancer of the blood) and lymphoma as well as tuberculosis (lung infection). This suggests modest dosage, which is what Longevinex® provides (100 mg resveratrol). Over-dosage may be why mice on high-dose resveratrol (365 and 1565 milligrams, human equivalent dose) experienced a shortened life span and mostly succumbed to lymphoma.
While experiments like these gain much attention in the news media, they don’t help to explain why humans age at different rates. Aging is not a shortage of Sirtuin1 protein per se, as researchers may mislead us into believing. We may or may not have been producing a lot of Sirtuin1 protein in brain tissues when we were young and our brains were working well.
I maintain the rate of aging is controlled by the accumulation of minerals. There are three speeds of human aging:
There is no other explanation given as to why humans age at three different speeds. It is the minerals that then switch the genes.
Bill Sardi, managing partner,
Resveratrol Partners LLC © 2010
Posted in Resveratrol
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Question: Using your mineral hypothesis, which seems plausible, might the calcium taken by post-menopausal women to prevent osteoporosis (I take 800 mg. daily, for example) possibly hasten the aging process, all else being equal (see your second and third speeds of aging, above)?
Longevinex.com:
YES, SUPPLEMENTAL CALCIUM HASTENS AGING. WOMEN IN NEW ZEALAND TAKING A CALCIUM SUPPLEMENT IN MENOPAUSE EXPERIENCED 45% INCREASE IN MORTAL HEART ATTACKS. THE DIET PROVIDES SUFFICIENT CALCIUM.
Does taking multiple vitamins at the same time as taking Resveratrol affect the results that should be attained from just taking Resverartol alone.
James J.Nicholson
Longevinex.com:
THERE IS NO DATA ON THIS, BUT THE LAB RATS ARE GIVEN CHOW
THAT IS FORTIFIED WITH VITAMINS AND MINERALS, ESSENTIALLY
A MULTI-VITAMIN OF SORTS.
Dr. Sardi,
Excellent article. You make a very good case for Longevinex and its manufacturing process as the key to getting the most out of trans-resveratrol.
Is it any wonder Jesus Christ used the fruit of the vine, grape juice or wine, to symbolize his blood that gives “eternal life” to all who believe? It’s extraordinary.
David Lowe
Bill Sardi:
The wine of Jesus’ day was unfiltered. It contained 25 times more polphenolic-molecules like resveratrol and quercetin. It was surely medicinal and less was needed to produce an anti-aging effect. Today, traditionally-made dark, aged red wine fermented and bottled in France, produces unusual longevity. But 3-5 glasses are need to produce optimal health, which is a level of consumption that certainly approaches or achieves inebriation. Just one glass of wine in Bible days would have been equivalent.
Noah wouldn’t be found without wine. After the ark landed on dry land Noah built an altar to God, followed by planting a vineyard. Wine was his second priority. His children found him drunk. The Bible suggested mingled (diluted with water) to avoid inebriation.
Jesus’s first miracle was to turn water to wine at a wedding in Cana. So He wasn’t a party spoiler. Recognize wine will turn to vinegar unless the fermentation is stopped in some fashion.
The art of making wine in Bible days was to allow it to ferment in an amphora jar (grapes have a natural yeast for fermentation). Various herbs or sulfur might be added to stop fermentation. At a later point in time the amphora jar was capped with clay and turned on its side, to mix the wine solids and allow fermentation gases to escape out of a small hole in the side of the jar. The skill was to know when to seal the hole and create an airtight container. The Romans shipped wine to Egypt on boats and the first thing the Egyptians did was to cut off a clay cap with the swish of a sword and taste the wine. If it was vinegar, they wouldn’t pay for it.
What the dark amphora jar and the seal did was preserve the polyphenolic molecules. Today we know resveratrol needs to be kept away from UV light or it will degrade from trans to cis resveratrol, its inactive form. This is why Longevinex is microencapsulated (enfolded in plant starches and sugars) to protect from light, heat and oxygen.
The article would seem to indicate that limiting intake of iron and copper and perhaps other minerals would be a strategy for slowing the aging process. To that end de-mineralizing water might be an effective tactic. Also should more be made of eliminating mineral accumulation from the body, e.g., IP-6 through foods or supplements?
Longevinex.com:
Yes, as stated, lands where people consume less iron and calcium (red meat and dairy) tend to have lower mortality rates, longer life expectancy.
Thanks great information.How do you reach a steady state of iron?
Longevinex.com:
Automatically occurs in late life as proteins (melanin, ferritin) that bind to iron cannot hold any more iron ions. Storage limit has been reached (ferritin).
Thanks, Bill for the clarity of this info. My quest. How long it takes to fill improvement with your pills in a 77 years old male with prostatic cancer and and some memory impairment?
Longevinex.com:
The response from prostate sufferers has been that Longevinex reduces nighttime visits to the bathroom, and quells inflammation. This usually kicks in within a month. Sometimes longer.
Thank you–how should longevinex be stored (?refridgerator/freezer/room temperature)-how long after the noted expiry date is it still good for
Longevinex.com:
Longevinex should be stored in cool, dry, dark place. Refrigeration causes condensation of moisture and caking of the powder in the capsules.
thank you for responding–but again if the “best before” date on the package says 6/10 (June 2010)-can the product still be used?
Longevinex.com:
The FDA says 2-year shelf life is the target. We have to keep the product for a couple of years, testing it frequently during that time, and then we find it actually has a 3-year shelf life. We stick with the 2-year outdate, but it actually is good for 3 years or more, if stored properly. These are stable molecules, not like B vitamins that are easily aged. –B Sardi
In view of your comments on the damage caused by accumulation of minerals, is there a value to chelation therapy in this regard?
Longevinex.com:
Yes, there is some value to chelation therapy, though it is so poorly practiced. It is mostly performed to overcome angina. Validation of chelation therapy, conducted by administration of EDTA intravenously, because of cost cannot be done on a regular basis. The oral chelation route is what is making the French live so long. Doctors who administer EDTA replace minerals, fearful of depletion, particularly calcium. They don’t fully understand that calcium is the real culprit in artery disease and that it not only is deposited in arteries from the diet but also from the bones with the onset of osteoporosis. Phyto-estrogens like resveratrol help to restore the estrogen signal and hold calcium in bones. – Bill Sardi, LONGEVINEX
Thanks for the informative article…..