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On Jul 11, 5:46 am, François Rose <fr.r...@free.fr> wrote:

Some additional information from the paper needs to be given from what
François provided, and some additional consideration of the data needs
to be done with respect to that given by Olafur and François.

The full paper states:
"Here, we test the hypothesis that resveratrol imparts health
benefits by inducing DR physiology. At 1 year of age, C57BL/
6NIA mice were placed on a standard control diet (SD) or DR
by every-other-day feeding (EOD) with or without resveratrol.
We present evidence that long-term resveratrol treatment slows
age-related degeneration and functional decline and mimics the
gene expression patterns induced by DR. We discuss the potential
implications of these findings for human health.
RESULTS
We previously reported that resveratrol improves the health and
survival of obese mice fed a high-calorie diet (Baur et al., 2006).
This raised two key questions: (1) Can resveratrol improve the
health of nonobese mice, and (2) if so is this due to an ability to
mimic the effects of DR? To answer these questions, we examined
the effects of resveratrol on mice fed SD ad libitum, subjected
to EOD feeding, or fed a high-calorie diet (HC) ad libitum.
Initially, each dietary group was divided into no resveratrol
(negative
control; SD, EOD, or HC), low resveratrol (100 mg/kg of
food, SDLR, EODLR, or HCLR), or resveratrol (400 mg/kg of
food, SDR, EODR, or HCR). Later, additional groups of mice
were given a higher dose of resveratrol along with the standard
or HC diets (2400 mg/kg of food, SDHR, or HCHR). The HC
plus resveratrol (HCR) group was the subject of a previous
report, and that nomenclature is preserved herein (Baur et al.,
20"06)."

And from the EXPERIMENTAL PROCEDURES section:

"Animals and Diets
Male C57BL/6NIA were purchased from the National Institute on Aging
Aged
Rodent Colony (Harlan Sprague-Dawley, Indianapolis, IN). Beginning at
1 year of age, mice were fed a standard AIN-93G diet (SD and EOD) or
AIN-93G modified to provide 60% of calories from fat (HC) plus 0%,
0.01%,
or 0.04% resveratrol. Average daily doses over the course of the study
(mg/kg/day) were: 7.9 ± 0.2 (SDLR), 30.9 ± 0.6 (SDR), 7.6 ± 0.2
(EODLR),
30.4 ± 0.6 (EODR), 5.4 ± 0.2 (HCLR), 24.2 ± 0.8 (HCR), 204 ± 4 (SDHR),
and
167 ± 16 (HCHR, ages 12–18 months). Additional details are provided in
the
supplemental material."

Therefore it is clear that there are two groups of mice: standard diet
high resveratrol (SDHR) and high calorie high resveratrol (HCHR)
(unfortunately no EODHR group), about which there is only fragmentary
information given in the paper, some of which is in tables and figures
in the supplemental material, and for which the experimenters
apparently did not test survival. (However, when I attempted to access
the supplemental material I found nothing there. Hopefully, it will
appear later.)

This means that it may distort the facts and intention of the paper
when Francois and Olafur refer to the 400mg/kg food groups as having
been fed a *high* dosage of resveratrol. Therefore, in the rest of my
comments, I will use the terms "low resveratrol" and "resveratrol" for
the 100mg/kg and 400mg/kg groups, respectively, just as the paper
authors did.

Note also in the first paragraph of the above that the abbreviation
"DR" (for dietary restriction) was used as a general description of
what every other day (EOD) feeding was intended to accomplish. And the
actual amounts of resveratrol ingested daily in mg/kg body weight by
the EOD groups (something not generally provided when dosages are
already given in mg/kg food) shows that the EOD groups consumed
substantially less food than the SD groups *without any extra
supplementation of vitamins/minerals* (ie the EOD groups were
effectively food restricted!). And this is confirmed by the average
weights shown in figure 4A of the paper. As shown there the EOD groups
weighed about 30g on average while the SD groups weight about 34g - an
average weight reduction of 12%!. (Exact numbers cannot be determined
because no tabular weight data is provided - perhaps in the missing
supplementary material.)

The dosage data given above together with these average weights can
then be used to calculate the ratio of the daily food intake. By my
calculation from these figures, the EODLR group was actually 15% food
restricted with respect to the SDLR group, while the EODR was only 13%
food restricted with respect to the SDR group. This also shows that
not only were the dosages for the EOD groups less than for the
corresponding SD groups but the absolute daily intake of resveratrol
was considerably lower (because of the lower food intake).Without more
exact weight data it is impossible to tell, but from the dosage
figures above it may even be true that the resveratrol had a small
crypto-CR effect on both the SD groups and the EOD groups. The weight
difference from figure 4A (34g versus 30g) amounts to a weight
reduction of about 12% of the EOD groups from the SD groups, is
consistent with the food restriction effect. (and is consistent with
what has been found for EOD in general - it is hard to do EOD and not
get some CR effect as well). Also note that the weight bar graph of
figure 4A clearly shows that the amount of weight decrease (from
whatever physiological causes) was proportional to resveratrol dosage.

Based on this additional analysis of the data from the paper, in the
context of the small lifespan differences between the groups, the lack
of any supplemental vitamins/mineral going along with this restriction
and the fact that EOD feeding for a mouse is much more strenuous than
EOD feeding for a human (due their relative metabolic rates and even
more drastic lifespan differences), I think that it is both premature
to say that resveratrol is a CR mimetic (see more on this below), and
also premature to suggest that the lower dosage of resveratrol may be
more healthful and life extending for humans.

It is also important to realize that, since the authors did do the
necessary work to determine actual daily animal dosages (for which I
commend them), it is these figures that should be used for the
purposes of relating to human dosages rather than the amount of
resveratrol per kg of food.

Also note that if one uses the actual weights of the experimental mice
(average 34g for the SD mice) to calculate the mouse to human (70 kg
standard) dosage conversion factor for this experiment, one gets
(70000/34)**0.25 = 6.7 (the 7.3 figure supplied by Olafur is based on
a 25g mouse and the mice of this experiment were a 36% heavier type).

Since mice are, in many ways, not a good model for the study of
longevity in humans - for example "resveratrol did not suppress
lymphoma, a major cause of mortality in C57BL/6 mice", the relevance
of these results for humans is not likely strong.

In summary, although this paper does give some reason for pause to
those who are espousing that healthy people with BMI's under 25 should
take resveratrol dosages of at least 5 mg/kg to achieve maximum
benefit, and I have reduced my personal dosage of resveratrol somewhat
as a result of it, I think that it is premature for any very definite
conclusion and that many more studies will be needed before optimal
human dosages can even be realistically guessed at.

BTW, with respect to the thought of resveratrol being a CR mimetic,
note the following paragraph from the discussion section:

"One clear difference between EOD and resveratrol
was that EOD strongly upregulated glutathione metabolism,
whereas resveratrol had no effect. Thus, there may be differences
in mechanisms by which EOD and resveratrol reduce oxidative
stress. Another difference was that while both increased
expression of ribosomal proteins in liver, heart, and adipose, only
EOD had this effect in skeletal muscle. Since increased protein
synthesis in skeletal muscle has previously been implicated as
a major effect of DR (Lee et al., 1999), this result highlights a
potentially
important difference in the resveratrol-treated animals."

In every study of CR (or DR) mimetics that I have seen the result were
similar.

"Whether it is possible to find a DR mimetic that is also safe for
long-term consumption is of considerable debate in the field."

In some ways the protocol was a mimetic, but not in all ways, which
means there is no complete CR mimetic yet and, IMO, there is not
likely to be any one chemical that is a complete mimetic.

In closing I think that the experimental results and even the above
text is contradictory to the author's concluding statements about
resveratrol being a CR mimetic (which conclusion text is even self
contradictory, IMO). Ie. the author's conclusions are not supported by
their results when these results are carefully analyzed.

"In conclusion, long-term resveratrol treatment of mice can
mimic transcriptional changes induced by dietary restriction
and allow them to live healthier, more vigorous lives. In addition
to improving insulin sensitivity and increasing survival in HC
mice, we show that resveratrol improves cardiovascular function,
bone density, and motor coordination, and delays cataracts,
even in nonobese rodents. Together, these findings confirm
the feasibility of finding an orally available DR mimetic.
Since cardiovascular disease is a major cause of age-related
morbidity and mortality in humans but not mice, it is possible
that DR mimetics such as resveratrol could have a greater impact
on humans. However, resveratrol does not seem to mimic
all of the salutary effects of DR in that its introduction into the
diet of normal 1-year-old mice did not increase longevity."

--Paul Wakfer

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