test your knowledge
How the world got lost on
the road to an anti-aging pill
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March 26, 2013: by Bill Sardi
Reply to Bill Gifford’s demand (New Republic online) for a red wine pill to materialize that lives up to its calling as a molecular mimic of a calorie-restricted diet to reliably produce unprecedented prolongation of the human healthspan as well as achieve maximum lifespan.
Bill Gifford, writing online for the New Republic, asks “Where’s My Red Wine Pill?” in the wake of confusing headlines which recently said the quest for an anti-aging pill is back on track now that a Harvard scientist has re-confirmed resveratrol (rez-vair-a-trol) targets the Sirtuin-1 survival gene and that a 150-year lifespan may soon be common.
The confusion emanates from the many incongruent facts that surround this scientific re-discovery, the most prominent being the European drug company that purchased a developmental red wine pill company located near Boston is now shutting its U.S.-based operation down — an announcement that followed the gene-target breakthrough by just a few days.
Of course, connecting the dots may be difficult for some, but not for all, especially those longevity seekers who have been following this pharmacological shell game for some time now.
That’s not to say that resveratrol isn’t living up to its promised expectation as a longevity pill. A Harvard professor just said it is. But the public is being asked to buy into the idea that the goal of achieving long sought-after super-longevity will have to be accomplished by some synthetic molecule that doesn’t molecularly resemble resveratrol.
Furthermore, to achieve what is being demonstrated in the laboratory and now among humans with resveratrol-like drugs would require a dose of resveratrol that is found in 100-glasses of red wine, said David Sinclair PhD at Harvard Medical School and co-founder of Sirtris Pharmaceuticals. Dr. Sinclair intimated humanity will have to wait for its powerful drug-version of resveratrol to achieve super-longevity.
But wait, a 5-ounce glass of dark, aged red wine provides ~1-milligram of resveratrol and there are plenty of 100 mg resveratrol pills available in health food shops these days. So should humanity hold its breath for Sirtris’ “new chemical entities” that are supposed to mimic resveratrol?
Before you stop reading and head off to buy a bottle of these vino pills, you might want to know not just any red wine pill will do. A recent published study found only three of fourteen brands of commercially available resveratrol pills to be biologically active. So the dietary supplement industry has its own shell game going.
The difference between what laboratory scientists use — research-grade resveratrol (that is preserved and stored in an airtight, opaque vial that is stored at minus-20 degrees Centigrade), and available dietary supplements, may be the fragility of resveratrol. It is a molecule that is degraded into a different form when exposed to ultraviolet light as well as by heat and oxygen. Very few companies make any effort to stabilize resveratrol before it is tableted or encapsulated.
Even if its active form, trans resveratrol, is preserved during manufacturing, it may not be active months later when it is consumed.
What laboratory scientists and clinical researchers have been doing is over-dosing animals and human subjects on resveratrol in what appears to be an intentional effort to produce null or negative results. Large doses of resveratrol may actually increase damage to the heart after a heart attack, but similar large doses are now being planned for a large human study which may preclude any benefit and could doom the future of resveratrol. Only a specially formulated brand of resveratrol avoids this cardio-toxic effect at high dose.
Resveratrol works, as Bill Gifford points out in his New Republic article, but only in the dosage range of 3-to-5 glasses per day, producing an unparalleled reduction in coronary artery disease mortality to 90 per 100,000 in the red wine-drinking French versus 200-240 per 100,000 in North America.
Another recent experiment shows resveratrol activates different gene pathways depending upon dose and that the Sirtuin-1 pathway is generally better activated by lower-dose resveratrol. This is borne out by another recent paper citing low-dose but not high-dose resveratrol as being effective for diabetes among humans.
While 3-to-5 glasses of red wine would only provide 3-to-5 milligrams of resveratrol, that much wine would provide 180 to 300 milligrams of total polyphenols, the molecules believed to be responsible for its health benefits. (There are 60 milligrams of polyphenols like resveratrol, quercetin, catechin, ferulic acid, in a glass of red wine.) So the total milligram-dose of these molecules, not just resveratrol alone, is believed to produce its anti-aging effect.
That was demonstrated in a laboratory mouse study in 2008 when it was shown that a life-prolonging calorie-restricted diet activated 198 longevity genes, resveratrol 225 genes but resveratrol combined with other molecules 1711 genes, the latter being a commercially-available dietary supplement.
That resveratrol pill (trade name Longevinex®) switched 677 (81.5%) of 831 longevity genes in the same direction (on or off) as a calorie restricted diet, making it the closest molecular mimic to a food deprivation diet to date. And it takes life-long adherence to a calorie-restricted diet to activate 831 longevity genes, something that Longevinex® exceeded by 9-fold in the human equivalent of a month.
This suggests the full effect of plain resveratrol pills would be achieved only after life-long use. Strangely, the researchers who made this exciting discovery have never lectured about it and never mentioned it when they were interviewed on a 60-Minutes TV report in 2009, but ironically are reported to take this pill personally.
David Sinclair focuses his research on a single gene pathway, Sirtuin-1, but aging in humans is controlled by ~295 genes. The idea of focusing on a single gene pathway may be a narrow way of looking at aging genetically. Resveratrol is mischaracterized as a “dirty gene” that targets many genes when that is one of its unique advantages. In fact, single gene-targeted drugs have been criticized as being too simplistic and have been met with disappointment.
Preservation of resveratrol is one issue that may spoil its promise as an anti-aging pill, and dosage is another. But the Harvard professor himself winks at his audience when he says (as quoted in Mr. Gifford’s report): “We know the science is real; the problem now is to push it over the goal line. If they don’t end up as drugs in our lifetime, it’s not the fault of scientists, and more of a business decision.”
Does Big Pharma really intend to bring this mega-pill to market? Did Sirtris Pharmaceuticals parent company penalize this breakthrough by yanking it from its geographical roots?
Dr. Sinclair seems to be bravely standing up to his employer when he is quoted to say: “”I’m advising [GSK] and my advice would be to continue being optimistic about clinical trials. That’s where the next big discovery will come from.”
Isn’t Dr. Sinclair tacitly saying Big Pharma may only be pretending it wants to bring this cure-all to market? Did Big Pharma buy up Sirtris to take resveratrol pills off the market? According to Dr. Sinclair, a resveratrol-like drug would address maybe 20 different age-related diseases in one pill. Can we expect Big Pharma to put itself out of business?
Modern medicine’s latest answer to the problem posed by multiple medications (known as polypharmacy) is to combine many problematic drugs into one pill. But imagine the side effects and cost? Drugs address symptom relief, not the cause of age-related diseases as do resveratrol and polyphenols.
Yet a larger question is how long can humanity go on over-drugging seniors in the latter years of their lives and bankrupting health insurance pools as well? Wouldn’t a pill that slows down the rate of aging address all the age-related diseases and spare health plans from inevitable insolvency?
Recall that executives at Sirtris Pharmaceuticals actually made a dietary supplement version of its SRT501 resveratrol pill and began selling it online, but its parent company Glaxo-Smith-Kline, forbade this. Wasn’t that an implied admission a resveratrol dietary supplement could be equivalent to Sirtris’ resveratrol drug? What kind of shell game is Big Pharma playing on humanity?
Gifford goes on to question the bioavailability of resveratrol, saying most of it ends up in your bladder as expensive urine and mistakenly concludes that results in humans are “only modestly positive and far from overwhelming.”
While many resveratrol researchers continue to maintain resveratrol can’t possibly work because the liver intercepts it and attaches it to detoxification molecules, rendering it too large a combination molecule to pass through cell walls and enter genetic machinery within living cells, it is producing spectacular results in the human eye where it must pass through the liver and then the blood/ocular barrier to produce changes in gene activity.
One brand of resveratrol has, in early small group use, managed to remarkably restore lost vision to aged eyes when medications were ineffective, abolishes the first sign of arterial disease (loss of flow-mediated dilatation or widening of arteries upon physical exertion or mental stress) about twice as well as plain resveratrol, turned experimental mortal heart attacks in laboratory animals into non-mortal events and protected millions more heart muscle cells from damage than plain resveratrol (a similar human study would be unethical), and may, due to its demonstrated ability to inhibit new abnormal blood vessels, be a potent anti-cancer weapon. So humanity may be closer than it is being told to a bona fide anti-aging pill.
A Ft. Lee, New Jersey preventive cardiologist, who recommends Longevinex® to all of his patients, reports a Medicare reviewer noted that none of his first-time heart attack patients have experienced a second event and none of his high-risk patients have experienced a first-time heart attack.
Researcher David Sinclair wrote his first paper on resveratrol and the French Paradox in late 2003. It’s almost 10 years since that paper was published. David Sinclair didn’t wait for all the science to be sorted out before he began taking resveratrol pills. But he was forbidden by his university to reveal the brand of resveratrol pill (Longevinex®) he chose to use.
In summary, we’ve got a journalist asking “Dude, where’s my red wine (anti-aging) pill?;” researchers obfuscating its discovery by employing potentially problematic doses; an array of resveratrol dietary supplements (427 brands in all says the Natural Medicine’s Comprehensive Database) that are offered in a wide dosage range and are of specious quality, and leading researchers who aren’t waiting for the science to be sorted out to begin taking red wine pills themselves but aren’t forthcoming about the brand of resveratrol pill they personally use.
Bill Sardi is managing partner for Longevinex® located in Las Vegas, Nevada.
BY BILL GIFFORD
It’s been a confusing couple of weeks for lovers of red wine and longevity. On March 8, Science published a paper demonstrating the mechanism by which certain molecules activate a family of proteins called sirtuins, which are thought to be responsible for some of the benefits of caloric restriction. (Those would include improved metabolism, resistance to cancer, and possibly increased longevity.)
Then, last Tuesday, GlaxoSmithKline suddenly announced that it was shutting down its Sirtris division, the Boston-based company that was actually supposed to be making the “red wine pills,” and which GSK had bought for $720 million just five years ago. Wait, what? Since one of those molecules was resveratrol, a compound found in red wine, headline writers across the globe freaked out. “ ‘Red Wine Pill’ Like Drinking 100 Glasses a Day Could Cure Major Diseases,” blared Fox News. Even Pravda weighed in, with “Red Wine Pill Could Extend Human Life Expectancy to 150 Years.”
The announcement marked a new, confusing phase in the long red-wine-pill saga, which kicked off with a front-page story in the New York Times on November 2, 2006. As the Times reported, Harvard researchers led by David Sinclair had found that resveratrol extended the lifespans of obese laboratory mice; that is, the mice pigged out on high-fat food, but their health did not seem to suffer. Thanks to the resveratrol, they lived just as long as normal mice. If anything, they did better: In videos, the chubby, resveratrol-treated mice jogged away happily on treadmills.
If ever there was a drug tailor-made for overweight Americans, this seemed to be it. Six months later, Sirtris—the company Sinclair cofounded to develop resveratrol-based drugs—had its IPO. Eleven months after that, in April 2008, GSK bought Sirtris outright for $720 million, or nearly double its stock-market valuation. Five years later, contra the headlines, there are still no red-wine longevity pills on the horizon. What happened?
Resveratrol itself is amazing stuff. It’s produced in the skins of grapes, late in their maturation, as a kind of natural antifungal agent. In 2003, Sinclair had discovered that it seemed to activate a longevity-promoting gene in yeast called SIR2. Similar genes are present in nearly all animals, including humans; in mammals, they’re called sirtuins, and they appear to be activated by caloric restriction. Resveratrol seemed to offer an easier, starvation-free route to sirtuin activation, and Sinclair and others then found that the stuff had similar effects on nematode worms, mice, and even fish. In a 2008 study, Sinclair even found that resveratrol helped turn normal mice into super-athletes with extraordinary endurance. (Paging Lance Armstrong…)
Beyond that, resveratrol also seemed to combat certain kinds of cancers, and it is a powerful antioxidant. It also has strong cardioprotective effects, and was thought to be responsible for the “French paradox,” the mysterious French ability to remain (relatively) healthy despite pigging out on Camembert and confit de canard. And it has been shown to fight diabetes, inflammation, and even neurological disorders.
As a pharmaceutical, though, resveratrol has issues. Sinclair calls it “a dirty drug,” meaning it has too many targets in the cell. But that may be moot, because it seems to have extremely low “bioavailability” in humans. (Translation: Most of it exits via your bladder.) That doesn’t stop people from spending $30 million a year on resveratrol supplements, including Sinclair himself (as he told the Times in 2006). But relatively few human studies have been done on resveratrol, and the results are modestly positive, but far from overwhelming, particularly in healthy adults.
Finally, and fatally, as a natural compound, resveratrol itself cannot be patented and sold by a pharmaceutical company. It was Sirtris’s job to try to make new, improved, and potentially profitable versions of resveratrol, as well as entirely new compounds that would target the sirtuins. The company launched several clinical trials of possible sirtuin-activating drugs. But then, one by one, those trials were halted, at least two of them due to unexpected side effects. That leaves only one Sirtris compound, SRT2104, still under active study, for psoriasis and ulcerative colitis.
In the labs, as well, the sirtuin theory of aging was taking heavy fire. In 2011, another group published a paper in Nature that challenged Sinclair’s research directly: His results, it was claimed, were an artifact of the way he did his experiments. The Science paper, published earlier this month, was Sinclair’s triumphant rebuttal, outlining in precise detail how resveratrol and friends actually work on the sirtuin pathway. Just four days later, GSK pulled the plug. A GSK spokeswoman says the company will continue to work on sirtuin activators, but says that aside from SRT2104, there are none in the pipeline. Also, she adds, “they don’t have anything to do with red wine.”
Says Sinclair, who is still a scientific adviser to GSK: “We know the science is real; the problem now is to push it over the goal line. If they don’t end up as drugs in our lifetime, it’s not the fault of scientists, and more of a business decision.”
Which is too bad, but at least red wine itself is still good for you. And until that longevity pill comes along, it’s all we’ve got. Just be sure you use a proper dose: In at least two major studies of wine and health, the greatest benefits were seen in people who consumed between three and five glasses of the red stuff. Per day.