Computing the Amount of Resveratrol

Q I am curious regarding your new NanoResveratrol product. You recommend a daily amount of 100 mg of resveratrol. Yet this amount is far short of the 22.4 mg per kg of body weight used in the Sinclair study [by Baur et al.; see Ref. 1 below – Ed.]. And the results of the Auwerx study [by Lagouge et al.; see Ref. 2 below – Ed.], which used 400 mg per kg of body weight, suggest that the amount might need to be higher still.

Can you explain the science, and perhaps provide links to the research articles that allowed you to arrive at the amount recommended for your product? I would greatly appreciate it. Keep up the good work!

STEVEN, New York City

A Following the publication of a study on the use of resveratrol in mice to improve their health and maximum lifespan, the press reported that a human would have to consume an enormous amount of wine or supplements to gain similar benefits. That’s because the press did not bother to understand the appropriate criteria for dosage translations between species.

There are a number of acceptable ways to compute the human equivalent dose from animal studies. The key is to consider energy-expenditure differences between species. Energy expenditure is a measure of metabolic rate. The method favored by the FDA (see www.fda.gov/cber/gdlns/dose.htm) uses the body surface area (BSA) normalization method. Basal metabolic rate is directly related to surface area. As the FDA notes, the BSA method correlates well across several mammalian species with several parameters of biology, including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins, and renal function. However, there are important differences, such as different sensitivities, that make the BSA method a guide rather than a rule.

A recent article in the FASEB Journal3 criticized the media for its misunderstanding (or ignorance) of what a human equivalent dose would be for the amount of resveratrol used in the Sinclair mouse study to which you refer.1 Immediately after that paper was published, the popular press—along with a significant contingent of the scientific community (alas!)—voiced concerns regarding the relevance to humans of the resveratrol dose used by the researchers. Almost without exception, the press scaled the amount of resveratrol given to the mice—22.4 mg per kg of body weight—to humans on a straight weight basis. According to their reports, a person weighing 175 lb (about 80 kg) would have to ingest 22.4 x 80 = 1792 mg/day. Furthermore, they typically wrote that to get that much resveratrol from red wine (using an estimate of 2 mg of resveratrol per bottle), a person would have to drink 896 bottles per day!

Pharmacology 101 teaches us, however, that ratios involving body weight, energy expenditure, and body surface area are far more realistic than weight ratios alone in scaling dosages from one species to another. This has been known for over a century, and the relevant scaling factors are familiar to most scientists—but not, apparently, to the media, which concluded that the human equivalent dose of the Sinclair study was ridiculously large and impractical.

This is a grave injustice to the researchers, not to mention a severe impediment to any notion of possible implementation. And it’s all the more frustrating considering that resveratrol has been found to be safe in extremely large doses.

Returning to the article in the FASEB Journal, the authors assert that the mouse dose in the Sinclair study should be multiplied by the appropriate mouse/human scaling factor of 3/37, which gives a value of 1.82 mg per kg per day. Using the 80-kg person as an example again, the human dosage would therefore be 1.82 x 80 = 146 mg/day, an amount easily achieved with supplements, but not so easily with wine (73 bottles!). But the mice were not fed wine.

We do not know for certain if resveratrol can do for humans what it does for mice and other creatures, but the upside potential is great, and there does not appear to be any downside. Furthermore, studies have been conducted by Sirtris Pharmaceuticals using up to 5000 mg/day of their proprietary resveratrol on human subjects for up to a month. This proprietary formulation is said to employ the use of polyethylene glycols (PEGs), materials mentioned repeatedly in their patent application, “Sirtuin modulating compounds” (#7,345,178).

Life Enhancement’s NanoResveratrol goes one step further by using nanosphere technology. While this technology is believed to increase bioavailability substantially, testing has not yet identified exactly how much more bioavailable it is compared to the oral forms. Yet we believe its bioavailability to be such that 100 mg is the equivalent of several multiples of oral resveratrol and possibly much higher.

References

  1. 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.
  2. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 2006 Dec 15;127(6):1109-22.
  3. Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J 2007 Oct 17. [Epub ahead of print]

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