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How the world got lost on
the road to an anti-aging pill
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November 6, 2011: by Bill Sardi
The science of human aging is accelerating at a rapid pace. The monthly calendar causes a number of scientific breakthroughs to be announced all at once as scientific journals are published around the 1st day of the month. Three stunning developments were announced this first week of November 2011. Summarily they were:
Conclusion: There is a lot that biologists don’t reveal in their published reports. Available remedies to the problem of aging are often hidden as these researchers attempt to develop their own patentable synthetic molecules for commercialization. All biological roads for longevity lead to resveratrol, a widely available molecule.
These three newly discovered anti-aging strategies are discussed in more detail below with links to published reports in the scientific literature. In the past few days it has become apparent that humanity may truly be on the precipice of practical strategies that can prolong the human healthspan.
1. While it seems just like yesterday researchers were saying the red wine molecule resveratrol is no fountain of youth, almost a complete scientific reversal has now been announced. Overweight men taking a modest-dose (150 mg) resveratrol (rez-vair-ah-troll) supplement for 30 days exhibited modest but consistent improvements in metabolism, blood pressure and a decline in fatty liver, consistent with what is found in animals given a limited calorie diet. Suddenly the prospect of an anti-aging pill is back on the drawing board. The full text of the report is found in a recent issue of Cell Metabolism.
The surprising secondary findings were that men metabolize resveratrol quite differently than laboratory mice and that this comparatively modest dose of resveratrol produced blood concentrations equal to that of lab animals given much higher doses.
Resveratrol’s marked effect upon blood pressure, lowering systolic pressure by 5 points, is equivalent to what the best blood pressure drugs achieve. However, the study, obviously pushed into publication because of a declining interest in resveratrol by consumers, needs to continue for six months to see if these are truly lasting effects.
Another lesson learned here is that there is growing science for lower doses of resveratrol. The false notion that the amount of resveratrol needed to duplicate the beneficial effects produced in the animal lab, equivalent to 1000 bottles of wine, was an unsubstantiated overstatement probably designed to cause consumers to hold up on the idea of taking resveratrol diet supplements and to wait for a man-made Sirtuin1-gene activating pill that was alleged to work 1000-times better. Sometime later the Sirtuin1 gene target was dismissed and this pill would likely have been beyond the reach of most consumers anyway. Unless insurance elects to pay for a drug that is proposed to avert all age-related disease before they occur, an anti-aging pill will probably have to sell for no more than a dollar a day.
2. The second dramatic discovery was that researchers have found the key enzyme (protein) responsible for the effects of a limited calorie diet. A 50% reduction in calorie intake roughly doubles the lifespan of laboratory animals. The newly published research (Molecular Cell) reveals that caloric restriction slows down aging by preventing the enzyme known as peroxiredoxin (Prx1) from being inactivated.
Peroxiredoxin is an antioxidant enzyme that internally produced but can be stimulated molecularly. Prx1 is damaged during aging and becomes inactive. Caloric restriction counteracts increases the production of another enzyme, Srx1, which then repairs peroxiredoxin. (For unexplained reasons, this study was actually published in the Sept 2011 issue of Molecular Cell but not reported by the news media till November.)
Peroxiredoxin protects against toxic levels of DNA damage. Consistent with the mineral overload theory of aging, blockage of peroxiredoxin (Tsa1) activity exacerbates iron toxicity.
Furthermore the peroxiredoxin Tsa1-gene becomes more active when there is a zinc deficiency. This becomes even more intriguing to biologists because zinc counteracts copper toxicity. A shortage of zinc allows copper to reign free in creating free radicals that can damage DNA. This may be another reason why resveratrol is such a strong player in anti-aging as it is a copper-binding antioxidant.
It has been known for some time that the absence of peroxiredoxin Tsa1 results in gene mutations and undesirable chromosomal re-arrangements.
Dr. Dipak Das writes an instructive report showing antioxidants produced naturally inside the body are more powerful than any dietary or supplemental antioxidants, though the activity of these endogenously-produced antioxidants may be enhanced by consumption of certain molecules such as resveratrol.
Internally produced antioxidants such as catalase, superoxide dismutase (SOD) and glutathione are better known. Another group of internal antioxidants is known as the thioredoxin family (glutaredoxin, peroxiredoxin and glutathione peroxidase).
For followers of this antioxidant story who want to investigate its history, peroxiredoxin was once called glutaredoxin(Grx) and finally renamed peroxiredoxin (Prx). Different forms of peroxiredoxin are found in the watery cytoplasm of living cells (Prx I and II) and in mitochondria (Prx III).
Peroxiredoxins are a family of proteins that are extremely effective at scavenging peroxides. Peroxiredoxin works by mopping up hydrogen peroxide (H2O2) that damages cells and tissues. Mitochondria, the small atomic power plants inside living cells, are a major source of hydrogen peroxide. Peroxiredoxin-3 counters up to 90% of hydrogen peroxide generated in the mitochondria.
Resveratrol is a small natural molecule that can traverse the blood-brain barrier and enter the mitochondria in living cells. Resveratrol has been shown in a lab dish study to favorably alter genes involved in boosting peroxiredoxin activity. This may be significant since commonly consumed antioxidants such as vitamins C and E may not cross the blood-brain barrier effectively to reach brain tissues. Some studies show resveratrol does in fact protect against mitochondrial dysfunction. Indeed, resveratrol has been shown to work favorably in reducing markers of inflammation and gene expression patterns (peroxiredoxins) in brain cells (neurons) in a lab dish.
3. The third anti-aging breakthrough may breach beyond what anyone could ever imagine – the visible and overt physical effects of progressive aging, such as wrinkles, cataracts and muscle loss can be halted even in old age. These effects were demonstrated in laboratory mice bred to age prematurely. This could be a biological dream come true.
The hybrid mice did not live any longer, which provokes a question: given the choice of taking a pill to live longer or look younger, which pill would you elect to take? Our off-the-cuff surveys show most Americans would choose the latter. Just look at how much money Americans spend to look younger (skin creams, hair thickeners, wigs, contact lenses, plastic surgery) versus live longer.
The discovery has to do with senescent cells, cells that no longer reproduce daughter cells. After so many generations of replication, some cells begin to senesce. Leonard Hayflick in 1965 was the first to describe a limit to the number of times a cell can replicate itself. Maybe 10-15% of cells in an older adult are senescent. What we know now, from this experiment, is that senescent cells are not benign – they accelerate aging.
Senescent cells secrete a molecule called p16. A variant of that gene called p16Ink4a is turned on in most of the body’s senescent cells and induces them to assume the senescent state. Researchers altered this gene in a breed of fast-aging mice both at the time the animals were weaned (3 weeks of age) and at 5 months of age so the gene’s proteins would react with a synthetic drug, AP20187, and cause the senescent cells to die off. The drug had no effect upon normal cells.
Once senescent cells were eliminated the onset of cataracts and muscle loss were delayed. The animals given the drug later in life had increased muscle mass and improved treadmill exercise performance, however their cataracts, which had already developed at 5 months of age, did not regress.
There was a marked slowing of aging but no reversal of aging. Furthermore, the drug is not sensitive to cells in the heart, so it had no effect there and the animals tended to die of heart disease and the AP20187 drug-treated animals lived no longer than untreated animals. Researchers intend repeat the experiment and use AP20187 in an ordinary strain of mouse that normally live 3 years or more to observe whether this drug extends lifespan of these animals.
What is AP20187? It is a synthetic drug first reported to be used experimentally in 2001. It is not a novel new drug by any means.
Shall we wait around for researchers to come up with some form of drug therapy targeted at our senescent cells, anti-aging therapy that may be years or even decades away, or would there be any other available technology widely available today?
A search of the medical literature reveals the red wine molecule resveratrol inhibits the development of replicative senescence via the same INK4a gene in human dermal (skin) fibroblasts (collagen-making cells). The idea of slowing the onset of aging by delaying cellular senescence may be within reach today and may be no further away than the nearest health food store.
Something that was quite revealing in this experiment was that researchers took cells from these mice and grew them in a lab dish and added rosiglitazone, a drug that can induce cellular senescence and p16 Ink4a. What is rosiglitazone? It is the troublesome anti-diabetic drug marketed under the brand name Avandia that has been withdrawn from human use in Europe but continues to be used with certain warnings on its label in the USA. Why would modern medicine employ a drug to treat diabetes that is known to induce premature aging experimentally? — © 2011 Bill Sardi, ResveratrolNews.com Not for posting on other websites.