Resveratrol Longevity Science Makes Dramatic U-Turn, But Resveratrol Supplements...

Wed Sep 10, 2008 5:00am EDT

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Resveratrol Longevity Science Makes Dramatic U-Turn, But Resveratrol
Supplements Remain Unchanged
Mega-dose Resveratrol, Sirtuin1 gene Target Discredited; Lower Dose, Array of
Small Molecules (Longevinex(R)) Exert Greater Effect

SAN DIMAS, Calif., Sept. 10 /PRNewswire/ -- While the red wine molecule
resveratrol (rez-vair-ah-trawl) has recently attracted scientific and public
attention as a longevity molecule that allegedly mimics the effects of a
calorie-restricted diet, the science surrounding this molecule has taken a
dramatic turn in recent months, according to Bill Sardi, spokesperson for
Longevinex(R) (long-jev-in-ex), a major brand resveratrol supplement.
    Published research studies now show:
    --  Mice fed high-dose resveratrol did not live as long as mice fed a
plain standard calorie diet.  Animals on the lower dose (360 milligram human
equivalent) lived longer than those on the higher dose (1565 mg) of
resveratrol.  [Resveratrol Delays Age-Related Deterioration and Mimics
Transcriptional Aspects of Dietary Restriction without Extending Life Span.
Cell Metabolism 2008 Aug;8(2):157-68]
    --  The Sirtuin1 gene, once called the "holy grail" of longevity and
believed to be the gene target of calorie restriction, has not been found to
be universally activated by a limited calorie diet.  A calorie-restricted diet
results in more Sirtuin1 gene-derived proteins by exerting stabilization
effects, not by activation of the gene.  This new finding throws a scientific
cloud over the use of Sirtuin1 gene activation tests as a measure of
resveratrol activity. [Tissue-specific regulation of SIRT1 by calorie
restriction.  Genes Dev. 2008 Jul 1; 22(13):1753-7; Regulation of SIRT1
protein levels by nutrient availability.  FEBS Letters. 2008 Jul 9;
    --  While researchers once advised consumers to wait for stronger
synthetic molecules that can stimulate the Sirtuin1 gene by 1000-fold or more,
actual studies with warm-blood mammals showed over-activation of the Sirtuin1
gene increases the occurrence of heart failure by more than 7.5 fold.  [Sirt1
regulates aging and resistance to oxidative stress in the heart.   Circulation
Research 2007; 100: 1512-21]
    --  While it was initially believed only mega-dose resveratrol would be
effective, and that strong Sirtuin1 gene activators would be required, a much
lower dose of resveratrol (100 milligrams human equivalent of trans
resveratrol, 4 to 320 times lower than previous studies, when provided in a
patent-applied for matrix of other small molecules), exerted a 9-fold greater
genomic effect than plain resveratrol or a calorie-restricted diet. In this
study, calorie restriction significantly differentiated (up or down-regulated)
198 genes, and resveratrol, its molecular mimic, significantly influenced 225
genes, while resveratrol-based matrix (Longevinex(R)) significantly
differentiated 1711 genes. [Short-term consumption of a resveratrol-containing
nutraceutical mixture mimics gene expression of long-term caloric restriction
in mouse heart.  Experimental Gerontology 2008 Sep;43(9):859-66]
    Sardi says websites selling resveratrol supplements still parrot earlier
but now outdated news reports about Sirtuin1 genes and mega-doses appear
oblivious to the striking changes in resveratrol science that have been
recently published.  "Paying heed to the current data now available, mega-dose
resveratrol is ill-advised and may be related to uncommon but reported side
effects, namely Achilles heel tendon inflammation, skin rash, joint
stiffening, flu-like symptoms and numbness in fingertips, all which are
reversible," says Sardi.
    Some marketers of resveratrol supplements still misguidedly refer to the
2006 study published in Nature Magazine where mice lived longer on a
resveratrol-fed diet, but these mice were fed a 60% fat-calorie diet which
could not possibly be achieved by humans.  (Humans consume about 35% fat
calories).  The fat-engorged mice did live longer on resveratrol, but this
experiment is not comparable to humans eating a normal diet.  [Resveratrol
improves health and survival of mice on a high-calorie diet.  Nature 2006 Nov
16; 444(7117):337-42]
    The Sirtuin1 gene does not appear to be the "holy grail" of longevity by
itself, as once claimed.  The Sirtuin family of genes works in tandem with
other genes, such as FOXO1 and PGc1alpha.  [Interaction of aging-associated
signaling cascades: inhibition of NF-kappaB signaling by longevity factors
Foxos and SIRT1. Cell Mol Life Science. 2008 Apr; 65(7-8):1049-58; Acetylation
of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation.
Proceedings National Academy of Science:  2005 Aug 9; 102(32):11278-83]
    Nor does a singular molecule such as resveratrol appear to work as well as
resveratrol combined with quercetin or other small molecules.  [Combined
resveratrol, quercetin, and catechin treatment reduces breast tumor growth in
a nude mouse model.  Translational Oncology 2008 March; 1(1):19-27; Enhanced
inhibition of adipogenesis and induction of apoptosis in 3T3-L1 adipocytes
with combinations of resveratrol and quercetin.  Life Science 2008 May 7;
    Sardi says other key genes, particularly the FOXO1 gene, which plays a key
role in a variety of biological processes, including metabolism, cell
proliferation, and oxidative stress response, may play a stronger role than
the Sirtuin1 gene in producing longevity.
    At the National Library of Medicine online there are now 706 published
journal reports on FOXO1, and 471 on Sirtuin1.  In the gene array study
published in the September 2008 issue of Experimental Gerontology, only
Longevinex(R), and not calorie restriction of plain resveratrol, activated the
FOXO1 gene.
    Longevinex(R) has since abandoned the Sirtuin1 gene activation test as a
measure of dietary supplement activity.  In the Longevinex(R) mouse study, the
Sirtuin1 gene was down-regulated, however, Longevinex(R) still could have
resulted in more Sirtuin1 gene-derived protein via stabilization pathways.
Only messenger RNA, not Sirtuin1 gene protein, was measured in this genomic
    Longevinex(R) was formulated as an emulsified, stabilized, and
bioavailability-enhanced resveratrol supplement over four years ago and a
patent applied for in 2004.  The 3rd generation Longevinex(R) now features
micronized and microencapsulated trans resveratrol in a matrix of quercetin,
rice bran phytate, vitamin D3 and ferulic acid.  To learn more, visit
SOURCE  Resveratrol Partners, LLC

Bill Sardi of Resveratrol Partners, LLC, +1-909-596-9507,
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