test your knowledge
How the world got lost on
the road to an anti-aging pill
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August 12, 2010: by Bill Sardi
Note: see late-breaking bulletin at bottom of story
The regulatory status of resveratrol as both an investigational drug (SRT501, Sirtris Pharmaceuticals, Cambridge, Mass.) and widely sold dietary supplement has presented a number of conjectural problems.
What would happen if the drug version of this molecule were nothing better than what is available as a dietary supplement? Furthermore, to further blur the difference between dietary supplement and pharmaceutical drug, the dietary supplement industry today is now working under FDA-prescribed Good Manufacturing Practices which, if complied with, may no longer give pharmaceuticals such a big advantage over dietary supplements in quality.
In fact, Sirtris Pharmaceuticals, in a Securities Exchange Commission filing a couple of years back, said one of the risks involved in marketing their SRT501 resveratrol pill is that it is a stabilized, emulsified, micronized resveratrol, kind of like saying it is resveratrol with chrome bumpers, a souped-up gear box and spinning hubcaps, but it was still just resveratrol.
Now today’s news story (August 12, 2010) issued by xconomy.com was a stunner — the highly-touted SRT-501 drug, heralded as the first credible anti-aging pill and Sirturin1 survival gene activator, which sold to Glaxo-Smith-Kline for $720 million along with other designer Sirtuin1 activators, just became a dietary supplement.
Former executives of Sirtris have started a non-profit venture to offer look-alike version of Sirtris’ SRT501 as a nutriceutical rather than a pharmaceutical.
But was the world holding its breath and waiting for the drug version of this molecule as claimed in today’s news story? After all, resveratrol supplement users aren’t dropping dead like flies from poor quality pills and waiting for a better quality product to arrive.
Former Sirtris exec Michelle Dipp, who is marketing an SRT501 clone at the Healthy Lifestyle Institute website, says “that their group is the only one she knows of that manufactures resveratrol in a completely synthetic process with the same high standards for sterilization and purity that govern pharmaceutical production.” (Xconomy quote)
Uh, what are we missing here? Sterilization of resveratrol would subject this light and heat-sensitive molecule to radiation and/or high temperature. That doesn’t sound wise.
Furthermore, Dipp alludes to the synthetically-produced pure form of resveratrol, produced by fermentation, rather than a botanical extract, usually derived from Giant Knotweed (botanical name Polygonum cuspidatum) or red grapes. But the pure form of resveratrol is also widely available in dietary supplements and has not been shown to be advantageous over the botanically-extracted molecule. In fact, at some times in the past, Sirtris said it was using the botanical version of resveratrol in its SRT501 drug.
So if souped-up resveratrol is worth $720 million, then what is a well-tested nutriceutical version of resveratrol worth, like Longevinex®, which filed patents ahead of Sirtris and was shown to exert a far greater genomic effect than plain resveratrol in an Affymetrix gene array study?
Inexplicably, Michelle Dipp says neither she nor any other Glaxo executive can endorse the nutriceutical version of resveratrol, but Healthy Lifestyle co-founder Christolph Westphal along with David Sinclair, who is still working with Sirtris, both claim to take the drug now morphed into supplement version of the product. If that isn’t an endorsement, what is?
Certainly it is hoped that the Healthy Lifestyle Institute will bring a higher level of credibility to the resveratrol marketplace which is riddled with outlaw marketers making unfounded claims for their products. But it is off to a specious start.
And this development also brings back Sinclair, the pied piper for so many resveratrol pill users, as a non-endorsing promoter of the product (whatever that is?).
Another point of contention is David Sinclair’s memorable recommendation that consumers wait for Sirtris’ more powerful Sirtuin1-gene activating drugs since the biological effects demonstrated in the laboratory with resveratrol would require the consumption of 1000-bottles of red wine per day. Nobody knows how many 250-mg resveratrol pills the good associate professor at Harvard is taking per day, but at $1.50 per pill, 1000-mgs would cost $6.00 a day.
Subsequent dosing studies conducted in animals at the University of Connecticut show optimal benefit for the heart at 175 mg of resveratrol, with some loss of benefit starting at 350 mg and doses exceeding 1750 mg per day clearly increase the amount of damaged heart-muscle tissue in the event of heart attack and 3500-mg “kills” the rodent heart every time.
What does this say about resveratrol supplement companies like Rev Genetics and Biotivia which got into business offering mega-dose resveratrol pills (500 and 1000 mg per pill) based upon Sinclair’s recommendations, and suggested up to 7000 mg per day without adequate safety studies being performed? Many resveratrol supplement companies today have no medical advisors and their executives can’t even decipher the lingo in a published journal article.
The cost for 250 milligrams of this miraculous SRT501 look-alike pill, which has now been abandoned as an investigational drug for diabetes, is $45 for 1-month supply, or $540 a year. This is one and the same “drug” that was employed at a 5000-mg dose in a human cancer trial that had to be halted earlier this year due to severe side effects (kidney failure).
The Healthy Lifestyle Institute website states that resveratrol has been found to prolong the lifespan of yeast cells, fruit flies, roundworms and mice, though the latter longevity claim was only produced among rodents who were given a fat-engorged diet. A later study showed that the human equivalent of 365 mg or 1565 mg of resveratrol slightly shortened the lifespan of animals fed a normal-fat calorie diet.
The best available evidence today shows modest doses of plain resveratrol best mimic the effect of a calorie restricted diet.
If all this doesn’t cast a dark cloud over the prospect of resveratrol as an anti-aging pill, the fact that resveratrol failed to activate the widely flaunted Sirtuin1 survival gene as originally reported in 2003, further muddies the prospect of a longer life for users of these pills.
Moreover, resveratrol has been publicized as a molecular mimic of a calorie-restricted diet. But Leonard Guarente of MIT has clearly shown that the Sirtuin1 gene is not consistently up-regulated in all tissues and organs in an animal given a limited-calorie diet. So Sirtuin1 may not be a universal gene target for longevity.
Imagine a dietary supplement that exhibited the same failed product claims and misdirection as SIRT501? It would have been placed in the regulatory pillory box and demolished by the FDA and FTC. But this pill carries the imprimatur of Harvard Medical School and the prestige of an ethical drug company such as GlaxoSmithKline. Maybe the pill is meant to be a status symbol rather than confer any real longevity? Who knows in today’s crazy world of drugs and circuses.
Still, there would be no impetus to develop an anti-aging pill had Sinclair not published that infamous report in Nature Magazine in late 2003 showing yeast cells lived longer when given a red wine molecule.
Sinclair and his laboratory brought everybody to the party. His jaw-dropping presentations at scientific meetings and television interviews captured the imagination of many. God knows, the world needs such a pill. Putting the idea of super-longevity aside for a moment, if a confirmed anti-aging pill were available today and it would delay the onset of aging by just 7 years, it would spare Medicare from insolvency and avoid many nursing home admissions among retirees.
Based upon best available evidence to date, the closest thing to a valid anti-aging pill, aside from French red wine, which is producing unprecedented numbers of centenarians in France, is Longevinex®.
This resveratrol-based nutriceutical offers an array of small molecules, just as red wine does, and in a dose (100 mg resveratrol, 250 mg total polyphenolic molecules) that is in the same range as the amount of red wine molecules provided in 3 to 5 glasses of dark red wine (60 mg per 5-oz glass, or 180-300 mg), which is considered to be optimal for human health. And it also has some good science behind it.
When Longevinex® was put to the comparison test in a gene array study, it activated 9-times more longevity genes than a calorie-restricted diet or plain resveratrol. Furthermore, it appears most consumers taking resveratrol pills may be wasting their money.
It has been demonstrated that short-term compliance to a limited-calorie diet activates 198 genes, while the full genomic effect of calorie restriction, activation of 832 genes, requires life-long adherence to a deprivation diet.
Resveratrol in the short-term (2 months) only activated 225 genes in laboratory mice. It would presumably take many decades of use of a plain resveratrol pill to activate the same number of genes activated by a life-long calorie-restricted diet.
However, Longevinex® exerted a profound genomic effect in the short-term, 1711 genes, with 633 of these genes being switched in the same direction as calorie restriction. Longevinex® seemed to deliver a similar gene-switching profile to a limited-calorie diet at an early point in time.
Furthermore, Longevinex® is poised to release a bevy of scientific studies showing its nutriceutical matrix is far superior to plain resveratrol.
The first of these studies, which has been submitted for publication in a scientific journal, shows Longevinex® is the first resveratrol pill that has been demonstrated to limit damage to the heart in the event of a heart attack, theoretically working better than a baby-aspirin at preventing mortal outcomes in animal studies. About half of the people who die of a sudden mortal heart attack were taking a baby aspirin tablet on the day of their demise. Similar human studies cannot be performed for ethical reasons. It appears many thousands of adults are dying needlessly from sudden heart attacks – deaths that could be prevented with resveratrol pills.
A second scientific study, also submitted for publication, shows Longevinex® exhibits an unprecedented level of safety and non-toxicity in animals, even up to 7000 mg human- equivalent dose. Given that a 3500 mg dose of plain resveratrol “kills” the rodent heart every time, this is an eyebrow-raising finding.
The third scientific study, now in peer review, shows Longevinex® exerted powerful beneficial effects in laboratory mice subjected to an induced heart attack. Blood flow in the aorta (first blood vessel outside the heart) and coronary arteries was significantly better following a heart attack than what was produced with plain resveratrol, and the heart pumping action in the left side of the heart was superior to that of plain resveratrol as well. Longevinex® limited damage to heart muscle slightly better than plain resveratrol.
All these heart-protective properties correlated with an unprecedented effect Longevinex® has on microRNA, short RNA strands that are known to control whole networks of genes. Longevinex’® microRNA-controlling properties were superior to that of plain resveratrol.
There are an estimated 290 brands of resveratrol pills being sold today sharing a market that was estimated in 2008 at $30 million (~$100,000 of sales per brand). Most of these brands use borrowed science, pointing to scientific studies that used research-grade resveratrol that is frozen in storage at -80°C and sealed in an airtight opaque vial.
Resveratrol is a light-sensitive molecule that is subject to degradation unless efforts are made to protect it from light, heat and oxygen. Longevinex® was the first company to stabilize resveratrol and protect it from light and heat and today offers a microencapsulated resveratrol pill that is enfolded in plant starches and dextrins to protect it from environmental degradation.
Many outlaw companies sell resveratrol pills online today, using bloggers as front-men to generate inquiries and offering kickbacks to bloggers in the form of affiliate fees. The public has been bilked by free-bottle offers, often made by off-shore companies that are beyond the reach of the law. Online consumers have found their credit cards being billed for product they never ordered. So far, the FTC has taken no action against these outlaw companies.
LATE BULLETIN – As this report was going to press, GlaxoSmithKline in England issued a press release stating its former executives at Sirtris are being sanctioned by the company for selling a resveratrol dietary supplement behind the company’s back. Christolph Westphal and Michelle Dipp, former Sirtris execs, will resign from their positions with the Healthy Lifestyle Institute and the product sold online will be withdrawn from sale. Glaxo says the version of resveratrol pill being sold as a dietary supplement by Healthy Lifestyle Institute is not as potent as the drug version. Yet both pills offer the same exact molecule at the same dose per capsule. Stay tuned for further developments. © 2010 Bill Sardi, ResveratrolNews.com