Life-long vitamin C supplementation ... decreases expression of antioxidant protection genes

[Curious]

Life-long vitamin C supplementation in combination with cold exposure
does not affect oxidative damage or lifespan in mice, but decreases
expression of antioxidant protection genes.Selman C, McLaren JS, Meyer
C, Duncan JS, Redman P, Collins AR, Duthie GG, Speakman JR.
Aberdeen Centre for Energy Regulation and Obesity (ACERO), School of
Biological Sciences, University of Aberdeen, Aberdeen AB24 2TZ, UK.

Oxidative stress is suggested to be central to the ageing process, with
endogenous antioxidant defence and repair mechanisms in place to
minimize damage. Theoretically, supplementation with exogenous
antioxidants might support the endogenous antioxidant system, thereby
reducing oxidative damage, ageing-related functional decline and
prolonging life- and health-span. Yet supplementation trials with
antioxidants in animal models have had minimal success. Human
epidemiological data are similarly unimpressive, leading some to
question whether vitamin C, for example, might have pro-oxidant
properties in vivo. We supplemented cold exposed (7+/-2 degrees C)
female C57BL/6 mice over their lifespan with vitamin C
(ascorbyl-2-polyphosphate), widely advocated and self administered to
reduce oxidative stress, retard ageing and increase healthy lifespan. No
effect on mean or maximum lifespan following vitamin C treatment or any
significant impact on body mass, or on parameters of energy metabolism
was observed. Moreover, no differences in hepatocyte and lymphocyte DNA
oxidative damage or hepatic lipid peroxidation was seen between
supplemented and control mice. Using a DNA macroarray specific for
oxidative stress-related genes, we found that after 18 months of
supplementation, mice exhibited a significantly reduced expression of
several genes in the liver linked to free-radical scavenging, including
Mn-superoxide dismutase. We confirmed these effects by Northern blotting
and found additional down-regulation of glutathione peroxidase (not
present on macroarray) in the vitamin C treated group. We suggest that
high dietary doses of vitamin C are ineffective at prolonging lifespan
in mice because any positive benefits derived as an antioxidant are
offset by compensatory reductions in endogenous protection mechanisms,
leading to no net reduction in accumulated oxidative damage.

PMID: 17092545
--
"I don't wanna die, there's no future in it!"
-Curly Howard

[Kofi]

It might work better if you randomized antioxidants, taking some gamma E
one day, C and then folate the next days. That might prevent the body's
compensatory mechanisms from kicking in.

[Kofi]

Clearly, to lower overall oxidative stress (which may or may not be
desirable), one needs to hit the oxidative stress thermostat otherwise
it's going to outfox you.

I do wonder if this result might be helpful for people with diseases
like ALS which may involve a damaging mutation in some of these
oxidative stress protectors. If you can force downregulation of the
damaged gene through exogenous supplementation, you might be able to
slow down progression of the disease.

[Olafur Pall Olafsson]

Hi Curious,

Interestingly the dose they used was not particularily large according
to the full text article. Here is the relevant quote:

"Over a period of 4 weeks of acclimation to 7 ± 2 °C, bedding
material was gradually removed and individuals randomly assigned a
'control' RM1 diet (10 mg kg-1 ascorbyl-2-polyphosphate) group or
on a vitamin C supplemented diet group (RM1 + 180 mg kg-1 of
ascorbyl-2-polyphosphate, equivalent to 18× the unsupplemented dietary
level)."

According to the full text the hepatic gene expression levels of Mn
SOD, CAT and GPx were significantly lower in the vitamin C treated
group after 18 months of supplementation and there was also a non
significant trend towards decreased gene expression levels of
Cu-Zn-SOD. On the positive however there was a non significant trend
towards decreased TBARS in the livers of the mice supplemented with
vitamin C which suggests that the antioxidant genes were downregulated
because there was less need for their presence in the vitamin C group.
Also although there was no significant difference in the lifespan of
the two goups it seems to me that there was a trend towards squaring of
the survival curve in the vitamin C group. This is evident by the quote
below:

"No significance in median lifespan (747 ± 139 days compared with 710
± 131 days) between the vitamin C supplemented group and the control
group, respectively, was observed"

Perhaps the difference in lifespan would've have been significant if a
larger group of mice had been tested.

Furtheremore this study is one more reason why it is important to
exercise regularily. It is quite possible that the regular increase in
oxidative stress caused by regular exercise may prevent downregulation
of antioxidant genes as seen in this study.

[coon...@amestwp.com]

I haven't followed the thread in detail, curiosity led me to the full
article, here is the summary section:

"5. Summary

Although we did not confirm any of these hepatic gene expression
changes at the protein or enzyme activity level, these data do
provide
a preliminary working model for understanding why treatment with a
powerful antioxidant like vitamin C does not bring the anticipated
benefits in reduced oxidative stress or increases in either mean or
maximum lifespan (in this and in common with other supplementation
studies) in cold exposed mice. We suggest that the absence of such
effects may come about primarily because, despite its proven
antioxidant capabilities, there are compensatory changes in the
endogenous protection system. The mechanism by which the endogenous
antioxidant system is down-regulated will be of key significance. If
the protective genes are down-regulated because the cells sense a
reduction in ROS being generated, and hence a lower requirement for
protection, the prognosis for any antioxidant based treatment that
aims to extend lifespan via a reduction in oxidative damage will be
poor. In this context it is perhaps significant that a recent
meta-analysis of supplementation treatments with vitamin E in humans
concluded there was no evidence of significant benefits (Pham and
Plakogiannis, 2005). However, if the mechanism involves a more direct
effect of vitamin C on gene expression then the hope remains that
alternative antioxidant therapies might be found that reduce
free-radical production, but do not trigger the same responses. We
suggest that our novel findings in cold exposed mice following
vitamin
C supplementation should now be extended to mice under more
`conventional' housing temperatures, or indeed to mice maintained
within their thermoneutral zone as this is likely to be the most
similar to those experienced by the majority of humans during their
lifespan.

[L Shaddai]

Or maybe one anti-oxidant isn't such a good thing.

--
Thoughts become things... choose the good ones
<coon...@amestwp.com> wrote in message
news:4564d6b0$0$24649$1c46...@selenium.club.cc.cmu.edu...

[beni]

L Shaddai כתב:
> Is this strain of mouse producing vit C ?
There are a lot of researches which found many positive effects on men,
so one research can not change the picture , especially when the
amount was not big enough.
beni.

[glenhappy]

beni wrote:
> L Shaddai ëúá:

Ah, yes, good question... Are they making their own vitamin C. Humans,
unlike most mammals, do not produce the vitamin. So mouse studies may
not be that applicable to us.

[soowhat...@hotmail.com]

> We suggest that
> high dietary doses of vitamin C are ineffective at prolonging lifespan
> in mice because any positive benefits derived as an antioxidant are
> offset by compensatory reductions in endogenous protection mechanisms,
> leading to no net reduction in accumulated oxidative damage.
> PMID: 17092545

The study below suggests that cancer cells resist apoptosis by the
intake of vitamin C, which as an antioxidant it decreases ROS
cytotoxicity. Since cancer is a main cause of death in mice then
adding vitamin C might shorten their life.

Arbor

Apoptosis. 2006 Oct 6; [Epub ahead of print] Links
Caspase-8 dependent trail-induced apoptosis in cancer cell lines is
inhibited by vitamin C and catalase.Perez-Cruz I, Carcamo JM, Golde DW.

Program in Molecular Pharmacology and Chemistry, Memorial
Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10021,
USA.

TNF-related apoptosis-inducing ligand (TRAIL/ Apo-2L) is a member of
the TNF family of apoptosis-inducing proteins that initiates apoptosis
in a variety of neoplastic cells while displaying minimal or absent
cytotoxicity to most normal cells. Therefore, TRAIL is currently
considered a promising target to develop anti-cancer therapies.
TRAIL-receptor ligation recruits and activates pro-caspase-8, which in
turn activates proteins that mediate disruption of the mitochondrial
membranes. These events lead to the nuclear and cytosolic damage
characteristic of apoptosis. Here we report that TRAIL-induced
apoptosis is mediated by oxidative stress and that vitamin C (ascorbic
acid), a potent nutritional antioxidant, protects cancer cell lines
from apoptosis induced by TRAIL. Vitamin C impedes the elevation of
reactive oxygen species (ROS) levels induced by TRAIL and impairs
caspase-8 activation. We found that the removal of hydrogen peroxide by
extracellular catalase during TRAIL-induced apoptosis also impairs
caspase-8 activation. These data suggest that hydrogen peroxide is
produced during TRAIL-receptor ligation, and that the increase of
intracellular ROS regulates the activation of caspase-8 during
apoptosis. Additionally we propose a mechanism by which cancer cells
might resist apoptosis via TRAIL, by the intake of the nutritional
antioxidant vitamin C.
PMID: 17031493