[high protein diet (was: Re: LowCarb or LowAGEs?)

[Guest guest]

Of course, that famous german study from last year always keeps

rudely intruding upon any neat consideration of the carbohydrate vs

protein question and the role of supplementation in relation to

oxydative stress and lifespan:

1: Cell Metab. 2007 Oct;6(4):280-93. Links

Glucose restriction extends Caenorhabditis elegans life span by

inducing mitochondrial respiration and increasing oxidative

stress.Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M.

Department of Human Nutrition, Institute of Nutrition, University of

Jena, D-07743 Jena, Germany.

Increasing cellular glucose uptake is a fundamental concept in

treatment of type 2 diabetes, whereas nutritive calorie restriction

increases life expectancy. We show here that increased glucose

availability decreases Caenorhabditis elegans life span, while

impaired glucose metabolism extends life expectancy by inducing

mitochondrial respiration. The histone deacetylase Sir2.1 is found

here to be dispensable for this phenotype, whereas disruption of aak-

2, a homolog of AMP-dependent kinase (AMPK), abolishes extension of

life span due to impaired glycolysis. Reduced glucose availability

promotes formation of reactive oxygen species (ROS), induces catalase

activity, and increases oxidative stress resistance and survival

rates, altogether providing direct evidence for a hitherto

hypothetical concept named mitochondrial hormesis or " mitohormesis. "

Accordingly, treatment of nematodes with different antioxidants and

vitamins prevents extension of life span. In summary, these data

indicate that glucose restriction promotes mitochondrial metabolism,

causing increased ROS formation and cumulating in hormetic extension

of life span, questioning current treatments of type 2 diabetes as

well as the widespread use of antioxidant supplements.

PMID: 17908557 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/17908557

Fllowing up on this:

Reductive stress on life span extension in C. elegans

Markus Ralser1 and Ivor J 2

1Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195

Berlin, Germany

2University of Utah School of Medicine, 30 North 1900 East, Salt Lake

City, UT 84132, USA

Corresponding author.

Markus Ralser: ralser@...; Ivor J :

ivor.benjamin@...

Received March 16, 2008; Accepted June 4, 2008.

This is an Open Access article distributed under the terms of the

Creative Commons Attribution License

(http://creativecommons.org/licenses/by/2.0), which permits

unrestricted use, distribution, and reproduction in any medium,

provided the original work is properly cited.

Top AbstractRecently, Schulz and colleagues have contributed to the

ongoing controversy on the unproven role of oxidative stress in the

aging process in their well-performed study 'Glucose restriction

extends Caenorhabditis elegans life span by inducing mitochondrial

respiration and increasing oxidative stress' (Cell Metab 2007, 6: 280–

293). Here, we suggest an alternative hypothesis that reductive

stress can prevent calorie-restriction induced life span extension.

We draw attention to this condition as an explanation for some

contradictory observations including the deleterious effects from

antioxidants.

References Discussion

How – or if at all – free radicals, oxidants, and oxidative stress

contribute to the aging process is a fundamental, voluminous but

still controversial research topic. In a recent Edition of Cell

Metabolism, Schulz and colleagues report their important and well-

controlled observations of 2-Deoxy-D-Glucose (DOG or 2-DG)-induced

caloric restriction on life span in C. elegans [1]. The authors

observe that treatment with 2-DG (a glucose analogue and inhibitor of

two glycolytic enzymes) increases C. elegans' life span as well as

mitochondrial respiration, resulting in increased generation of

reactive oxygen species (ROS). However, when animals were treated

with antioxidants such as N-acetylcysteine (NAC, a precursor of

reduced glutathione (GSH)), the effects of 2-DG on life span

extension were abolished. To explain these intriguing findings, these

authors suggested that glucose restriction induces mild oxidative

stress originating from mitochondria and increases protective

mechanisms, termed 'mitohormesis,' resulting in the increased

longevity of the model organism and extension of C. elegans life span

(see [2] for a review). Notwithstanding, the relationship between

hormesis and the 'oxidative-stress' theory of ageing remains

uncertain (see [3] for a review).

Although the oxidative stress theory of aging is widely accepted, the

mechanisms underlying mammalian aging remains poorly understood as

several animals models in which oxidative stress is enhanced have

neither shortened life span nor recapitulated aging phenotypes in

mice [4].

First, cellular redox homeostasis in organisms is highly dependent on

both enzymatic and non-enzymatic pathways. Cells exposed to oxidative

stress conditions have increased activity of the pentose phosphate

pathway, which replenishes cellular reduction of NADP+ to NADPH [5-

7]. For example, in response to ROS production, reducing equivalents

in the form of NADPH and GSH, both which serve to neutralize pro-

oxidants (i.e., anti-reductant), are generated by the anti-oxidative

machinery to restore redox homeostasis. This mechanism allows the

cell to restore the redox state under the aforementioned oxidative

stress conditions, principally from high levels of (reduced) NADPH

and/or recycling the synthesis of glutathione (GSH), which are

required by the cellular antioxidant systems [8].

However, reductive stress in the form increased GSH production has

been genetically and causally linked to dysregulation of

antioxidative pathways in mice [9,10]. Indeed, recent results show

deleterious effects of reductive stress in different organisms,

including reduced life span of yeast and C. elegans and age-related

protein aggregation disease in mice [7,10], unpublished studies from

IJB). How does reductive stress prevent life span extension in

mammals? By presenting partially understood mechanisms, we

hypothesize that activation of compensatory pathways such as

activated by the glucose 6-phosphate dehydrogenase (G6PD), the rate-

limiting enzyme of the anaerobic pentose phosphate shunt, escapes

feedback control, triggering excess amounts of reducing equivalents

into deleterious zone. In conditions promoting ROS production without

consumption of the newly produced reducing equivalents (a situation

that could be provoked by combining pro- and anti-oxidative

treatments), we envision plieotrophic effects on gene expression,

protein folding and metabolic processes.

If ROS production is not a significant cause of aging in C. elegans,

further studies are needed to clarify the alternative roles of

glucose restriction and 2-DG treatment on generation of reducing

equivalents. For example, we suggest that the impact of antioxidant

treatment on the ageing process needs to be clarified at the level of

glutathione synthesis (i.e. gamma glutathione synthetase) and

recycling (e.g., glutathione reductase). Cellular and molecular

studies such as gene deletion or knock-down of antioxidant and pro-

oxidant systems, careful titration of oxidants and reductants might

be combined with biochemical analyses of the cellular redox state,

especially of the NAD(H), NADP(H) and GS(S)H pools.

Notwithstanding, we fully agree with and wish to highlight the

authors' conclusion that the rationale for the use of antioxidants in

the arsenal against aging and health maintenance and/or prevention

needs to be revisited.

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> > > Can you please post the source for this statement???

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> > > This is almost diametrically opposed to Rod¹s methionine

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> > > TIA

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> > > From: bill4cr <bill4cr@>

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> > > Reply-< >

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> > > Date: Fri, 29 Aug 2008 14:11:42 -0000

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> > > Subject: [ ] Re: LowCarb or LowAGEs?

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> > > Mice on CR lived longer on a higher protein diet.

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