I thought it was funny that the researchers thought a very high fat diet
could not be tolerated by humans ...
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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)
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Cell Metabolism July 2008 early online doi:10.1016/j.cmet.2008.06.011
Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional
Aspects of Dietary Restriction without Extending Life Span
Abstract: A small molecule that safely mimics the ability of dietary
restriction (DR) to delay age-related diseases in laboratory animals is
greatly sought after. We and others have shown that resveratrol mimics
effects of DR in lower organisms. In mice, we find that resveratrol induces
gene expression patterns in multiple tissues that parallel those induced by
DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show
a marked reduction in signs of aging, including reduced albuminuria,
decreased inflammation, and apoptosis in the vascular endothelium, increased
aortic elasticity, greater motor coordination, reduced cataract formation,
and preserved bone mineral density. However, mice fed a standard diet did
not live longer when treated with resveratrol beginning at 12 months of age.
Our findings indicate that resveratrol treatment has a range of beneficial
effects in mice but does not increase the longevity of ad libitum-fed
animals when started midlife.
<http://www.longevinex.com/images/cellmetabolismjuly2008.png>
<http://www.longevinex.com/images/legend_bodyweight.png>
Figure 4. Effects of Resveratrol Treatment on Longevity(A) Mean body
weights over the entire life span. EOD feeding lowered body weight, and HC
diet increased it (p < 0.001). Resveratrol did not affect body weight in
mice fed the SD or EOD diets. The HCLR group was significantly heavier than
the HC control group (p < 0.01), while the HCR group showed a slight trend
toward decreased body weight that did not reach statistical significance.
Error bars indicate SEM.(B) Kaplan-Meier Survival Analyses were performed on
the SD, SDLR, and SDR groups, and the curves were not significantly
different by the logrank or Wilcoxon tests; n = 60 (SD), 55 (SDLR), and 54
(SDR) at the beginning of the experiment.(C) Kaplan-Meier Survival Analyses
were performed on the SD, EOD, EODLR, and EODR groups. There were no
significant differences between the three EOD diet groups; however, the
EODLR had increased survival compared to the SD control group as determined
by both logrank (÷2 = 7.46, p = 0.006) and Wilcoxon (p = 0.0016) tests; n =
60 (SD) and 55 (EOD, EODLR, and EODR) at the beginning of the experiment.(D)
Kaplan-Meier survival analyses were performed on the SD, HC, HCLR, and HCR
groups. The HC control group had decreased survival compared to the SD
control group (logrank: ÷2 = 11.65, p = 0.0006, Wilcoxon: p = 0.0003),
whereas, survival in the HCLR and HCR groups did not differ significantly
from that of SD controls. When compared to HC controls, survival was
significantly increased in both the HCLR group (logrank: ÷2 = 8.31, p =
0.004, Wilcoxon: p = 0.005) and the HCR group (logrank: ÷2 = 4.83, p = 0.03,
Wilcoxon: p = 0.001); n = 60 (SD) and 55 (HC, HCLR, and HCR) at the
beginning of the experiment.(E) Maximum life span was calculated as the mean
of the final 20% of mice in each group as determined by Kaplan-Meier
Analysis. Compared to the SD control group, the maximum life span was
significantly increased in the EODLR (p = 0.03) and significantly decreased
in the HC control (p = 0.003) groups. In addition, HCLR had significantly
increased maximum life span compared to the HC control group (p = 0.04), and
there was a trend toward increased life span in HCR mice compared to HC
controls. *, p < 0.05 versus SD control; #, p < 0.05 versus HC control.
Error bars indicate SEM.(F) Kaplan-Meier Survival Analyses were performed on
the SD and SDHR groups, and the curves were not significantly different. The
earlier SD survival curve (broken line) is shown for reference; n = 48 (SD,
SDHR), and 60 (previous SD control) at the beginning of the experiment.
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