Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, LaFerla FM. Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J Neurosci. 2008 Nov 5;28(45):11500-10. PubMed.
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Harvard Medical School
One must be careful when calling nicotinamide an "inhibitor" in this experiment. While it is true that our lab showed that nicotinamide is a direct inhibitor of SIRT1 enzyme, it is also a precursor of NAD+, and NAD+ is a co-substrate (i.e., activator) of SIRT1.
In vivo, there is an abundant enzyme called Nampt in cells and serum that initiates the conversion of nicotinamide to NAD+. Therefore we should entertain the possibility that nicotinamide is activating SIRT1 in vivo, not inhibiting it. This would fit with other papers showing that SIRT1 is neuroprotective.
View all comments by David SinclairThe experimental dose used in the study was 200 mg/kg/day. This would translate to a daily dose of nearly 14,000 mg for a 70 kg (154 lb.) person. Yet in the proposed clinical trial the experimental group will be receiving a daily dose of 3,000 mg. How does one explain the lower dose being used in the clinical trial?
View all comments by William PolskyI am responding to William Polsky's comment on computation of the human dose of nicotinamide.
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. This statement shows a lack of understanding of 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 Journal 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 the comment refers (1). Immediately after that paper was published, the popular press—along with a contingent of the scientific community—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 = 1,792 mg/day. Furthermore, the media 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. The media concluded that the human equivalent dose of the Sinclair study was ridiculously large and impractical.
This does an injustice to the researchers, not to mention impede implementation. It's 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 a downside as yet.
Applying this line of reasoning to nicotinamide yields about 1,298 mg/day for a 80-kg person (200 * 0.081 * 80).
References:
Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008 Mar;22(3):659-61. PubMed.
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