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They say that high dose of RSV increase mortality due to heart
failure ... Well I think the RSV has to be titrated to the PUFAs and
particularly AA in the body. Profound benefits were found in mice who
were engorged with a very-high fat diet - 60% fat calorie - of course,
60% Omega-6 will produce huge oxidative stress!

Taka

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From Longevinex:

Follow-Up Resveratrol Mouse Study Confirms Red Wine Molecule Exerts
Profound Positive Effects Upon Health, But Also Produces A Surprise
Finding

In a follow-up study to the widely publicized 2006 mouse/resveratrol
study published in Nature Magazine (November 1, 2006), researchers now
provide more complete long-term analysis of the biological effects of
resveratrol as a molecular mimic of calorie restriction in animals.

The results, published in the journal Cell Metabolism, are jaw-
dropping, but they also come with a surprise. Resveratrol-fed elderly
mice show a marked reduction in signs of aging, including:

• Reduced albumin (a blood protein; elevated albumin often occurs with
heart failure)
• Decreased inflammation
• Superior blood-vessel health
• Increased elasticity of the aorta (the first blood vessel
outside the heart)
• Greater balance and coordination (motor function)
• Strikingly reduced cataract formation (even better than a
reduced-calorie diet)
• Preserved bone mineral density.


But surprisingly, while supplemental resveratrol did, as previously
reported, prolong the lifespan of mice who were engorged with a very-
high fat diet (60% fat calories, which no human could tolerate),
resveratrol did not prolong life in mice fed a standard calorie diet.

Two doses of resveratrol were employed in the mouse study, lower-dose
resveratrol (100 mg/kilogram of food (or ~364 milligrams for a 160-
pound/70 kilogram adult), or 400 mg/kilogram of food (~1565 milligrams
for the 160-pound/70 kilogram adult). While there were no long-term
detrimental effects noticed at modest doses, the lower-dose
resveratrol group appeared to consistently live a bit longer in all
groups than the higher-dose resveratrol groups (see chart). The
authors of the paper cite another animal study which showed that
18,000 mg/kilogram of body weight (likely to be difficult for humans
to even intentionally achieve) did increase mortality due to heart
failure in a mouse study. So there may be decreasing health benefits
with increasing dosage.

The effects of a calorie-restricted diet on longevity are diminished
when the regimen is initiated at increasing ages. This drawback may
be overcome by resveratrol.

Of great interest is the effect resveratrol exerted over the Sirtuin1
gene, the gene that is activated when calorie restricted diets are
employed. However, “microarray data on the effects of SIRT1 over-
expression in these tissues are not available, making it currently
difficult to assess whether SIRT1 is a mediator of these effects,”
said researchers.

Matt Kaeberlein, a noted Sirtuin gene researcher at the University of
Washington in Seattle, offered his commentary, entitled “The Ongoing
Saga of Sirtuins and Aging,” in an accompanying article in Cell
Metabolism. Dr. Kaeberlein said:

Unfortunately, what has often been lost in reviews of the sirtuin
literature and reports in the popular media are the many complexities
and inconsistencies in our understanding of sirtuin biology as it
relates to aging. For example, in yeast, Sir2 over-expression
increases replicative life span (the span of time when a mother yeast
cell produces daughter cells, but shortens chronological life span,
which is a measure of the length of time a yeast cell can survive in a
non-dividing state.

Multiple labs have reported that sirtuins are not always
required for life-span extension from dietary restriction in either
yeast or worms. What makes the study by Li et al. particularly
interesting is the observation that Sirtuin1 gene inhibition causes
some phenotypes (groups with inherited genetic mutations) more
consistent with a slower rate of aging. For example, they show that
Siruin1 inhibition leads to increased IRS-2 acetylation, decreased
Insulin Growth Factor-1 signaling, and decreased Ras/ERK signaling.
Decreased Ras gene signaling increases life span in yeast, and reduced
insulin/Insulin Growth Factor-1-like signaling is associated with
increased life span in worms, flies, and mice. Supporting the idea
that inhibition of Sirtuin1 may slow aspects of aging in mice, studies
show enhanced resistance to oxidative stress in neuronal cells after
Sirtuin1 knockdown and reduced oxidation of proteins and lipids in
brains of Sirtuin1 knockout animals.

Taken together, these data may indicate that inhibition of
Sirtuin1 can be nerve-protective in aging animals and that some
features of aging are slowed rather than accelerated in animals whose
Sirtuin1 gene has been eliminated.

The one thing that seems clear is that sirtuin activators are
unlikely to be a ‘‘magic bullet’’ for aging. A more realistic hope is
that, as we continue to unravel the complexities of sirtuin biology,
targeted activation or inhibition of Sirtuin1—and perhaps other
sirtuins as well—will prove therapeutically useful toward a subset of
age-associated diseases. Such an achievement would be a huge step
forward in the transition of aging-related science from the laboratory
to the clinic, and we eagerly await the next chapter in the unfolding
saga that is sirtuin biology. --Matt Kaeberlein. (Cell Metabolism
July 2008)


The next chapter will be written by Longevinex®, which will unveil its
mouse study which measures the global-gene array effects of a calorie-
restricted diet, a resveratrol-fortified diet and a Longevinex®-
fortified diet. Of considerable interest, this upcoming study, to be
published in Experimental Gerontology, does not show that resveratrol
increases Sirtuin1 gene activity, as measured by messenger RNA. –
Copyright 2008 Resveratrol Partners LLC

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