X-Message-Number: 22441
From: "michaelprice" <>
References: <>
Subject: Re: sirtuin activating compounds & life extension
Date: Sun, 31 Aug 2003 05:55:12 +0100

Thanks Doug for posting the article on sirtuins.

The implication of Drs Guarente, Sinclair, and Howitz's work
taken all together is that resveratrol acts though the sirtuins
(SIR2 proteins).  NAD (the coenzyme form of vitamin B3) is a
substrate for sirtuins, which consequently up-regulates sirtuin
activity.  Ergo you might get the same life-extension effect from
inositol hexanicotinate (a dietary precursor of NAD & a form
of vitamin B3) as resveratrol, namely a life-extension
comparable with calorie restriction (i.e. 30-50% LE).
Niacinamide (another form vitamin B3), like resveratrol, has
extended the lifespan of fruitflies, but not yet been tested for
LS effects on a mammal.  NAD is also a substrate for PARP
which repairs DNA damage.  This is believed to be why
consumption of vitamin B3, in large doses (see ref's below)
reduces carcinogensis by over 40%.

Vitamin B3 may turn out to be the most potent of all the
B-vitamins to slow down aging.  The safest form to take
vitamin B3 as is inositol hexanicotinate.

There is an on-going discussion of these topics on the
newsgroup sci.life-extension.

[27a] Requirement of NAD and SIR2 for life-span extension by calorie
restriction in Saccharomyces cerevisiae.  Lin SJ, Defossez PA, Guarente L in
Science 2000 Sep 22;289(5487):2126-2128   PMID: 11000115

[27b] Manipulation of a Nuclear NAD+ Salvage Pathway Delays Aging without
Altering Steady-state NAD+ Levels.  Anderson RM, Bitterman KJ, Wood JG,
Medvedik O, Cohen H, Lin SS, Manchester JK, Gordon JI, Sinclair DA in J Biol
Chem 2002 May 24;277(21):18881-90.  PMID: 11884393

[27c] Oral Niacin Prevents Photocarcinogenesis and Photoimmunosuppression in
mice.  Gensler HL, Williams T, Huang AC, Jacobson EL in Nutrition and Cancer
34(1) (1999), pg 36-41.   PMID: 10453439
The relationship between dietary intake of niacin and tissue NAD elevation
is detailed in the main body of the article.  The UV-irradiated mice on a
diet with 0.003%, 0.1%, 0.5% & 1.0% niacin had a 0.72, 0.60, 0.48 & 0.40
tumours/mouse, respectively; a 44% reduction. The authors hypothesize that
the cancer-protective effect is mediated by NAD-induced PARP activity.

[27d] Mapping the role of NAD metabolism in prevention and treatment of
carcinogenesis.  Jacobson EL, Shieh WM, Huang AC in Mol Cell Biochem 1999
Mar;193(1-2):69-74    PMID: 10331640
NAD is elevated by niacin in many human tissues.

[27e] Evaluating the role of niacin in human carcinogenesis.  Jacobson EL,
Dame AJ, Pyrek JS, Jacobson MK.  Biochimie 1995;77(5):394-8   PMID: 8527495

[27f] Protective effect of nicotinamide on bracken fern induced
carcinogenicity in rats.  Pamukcu AM, Milli U, Bryan GT in Nutr Cancer
1981;3(2):86-93   PMID: 6213941
0.5% nicotinamide in diet cut the induced cancer rate by 40%

[27g] Fifteen year mortality in Coronary Drug Project patients: long-term
benefit with niacin.  Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L,
Prineas RJ, Friedewald W in J Am Coll Cardiol 1986 Dec;8(6):1245-55   PMID:
"With a mean follow-up of 15 years, nearly 9 years after termination of the
trial, mortality from all causes in each of the drug groups, except for
niacin, was similar to that in the placebo group.  Mortality in the niacin
group was 11% lower than in the placebo group (52.0 versus 58.2%; p =
0.0004). "

[27h] Pharmacological intakes of niacin increase bone marrow
poly(ADP-ribose) and the latency of ethylnitrosourea-induced carcinogenesis
in rats.  Boyonoski AC, Spronck JC, Jacobs RM, Shah GM, Poirier GG, Kirkland
JB in J Nutr 2002 Jan;132(1):115-20   PMID: 11773517
"This study was designed to test the effects of supplementing an already
high quality diet with pharmacologic levels of niacin. [...] Supplementation
with NA or Nam at 4.0 g/kg diet (combined analysis) increased the latency of
the ENU-induced morbidity curve, relative to niacin-adequate controls.
Morbidity could be attributed in almost all cases to some form of neoplasm,
with leukemias the predominant form. In short-term studies, supplementation
with either NA or Nam caused dramatic increases in bone marrow NAD(+) (1- to
1.5-fold), basal poly(ADP-ribose) (3- to 5-fold) and ENU-induced
poly(ADP-ribose) levels (1.5-fold). These data show that supplementation of
a niacin-adequate, high quality diet with pharmacologic levels of nicotinic
acid or nicotinamide increases NAD(+) and poly(ADP-ribose) levels in bone
marrow and may be protective against DNA damage."

Michael C Price

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