Elsevier

Free Radical Biology and Medicine

Volume 66, 8 January 2014, Pages 88-99
Free Radical Biology and Medicine

Review Article
The effects of dietary restriction on oxidative stress in rodents

https://doi.org/10.1016/j.freeradbiomed.2013.05.037Get rights and content

Highlights

  • • DR tends to have no effect but otherwise reduces mitochondrial ROS production.

  • DR tends to have no effect but otherwise increases endogenous antioxidants.

  • DR often reduces oxidative damage to macromolecules.

  • DR tends to increase redox antioxidants like glutathione.

  • DR during aging is more likely to affect oxidative stress parameters.

Abstract

Oxidative stress is observed during aging and in numerous age-related diseases. Dietary restriction (DR) is a regimen that protects against disease and extends life span in multiple species. However, it is unknown how DR mediates its protective effects. One prominent and consistent effect of DR in a number of systems is the ability to reduce oxidative stress and damage. The purpose of this review is to comprehensively examine the hypothesis that dietary restriction reduces oxidative stress in rodents by decreasing reactive oxygen species (ROS) production and increasing antioxidant enzyme activity, leading to an overall reduction of oxidative damage to macromolecules. The literature reveals that the effects of DR on oxidative stress are complex and likely influenced by a variety of factors, including sex, species, tissue examined, types of ROS and antioxidant enzymes examined, and duration of DR. Here we present a comprehensive review of the existing literature on the effect of DR on mitochondrial ROS generation, antioxidant enzymes, and oxidative damage. In a majority of studies, dietary restriction had little effect on mitochondrial ROS production or antioxidant activity. On the other hand, DR decreased oxidative damage in the majority of cases. Although the effects of DR on endogenous antioxidants are mixed, we find that glutathione levels are the most likely antioxidant to be increased by dietary restriction, which supports the emerging redox-stress hypothesis of aging.

Introduction

Denham Harman conceived the first iteration of the free radical theory of aging in 1956 [1]. Harman based his theory on the presumption that life span is dependent on metabolic rate—a hypothesis that has since fallen out of favor [2]. He proposed that toxic by-products of metabolism, notably the hydroxyl radical and protonated superoxide, can damage proteins and nucleic acids and lead to cancer and aging. The observations that mitochondria produce the majority of oxygen radicals in the cell and that reactive oxygen species include nonradicals like hydrogen peroxide led to the development of the oxidative stress theory of aging [3]. Oxidative stress results from an imbalance in the rate of reactive oxygen species (ROS) production and detoxification. There is strong support for the oxidative stress theory of aging in invertebrate models, especially Drosophila, although data in rodent models are inconclusive as to whether and how oxidative stress affects the aging process [4]. Even more recently, a spinoff of the oxidative stress theory of aging, the redox-stress hypothesis, implicates redox-sensitive signaling pathways in the aging process. The redox stress hypothesis is supported by an oxidizing shift in the cellular redox balance during aging [5], [6], [7], [8], which is regulated by the glutathione and thioredoxin systems [9], [10], [11], [12]. This redox imbalance can lead to altered protein function and gene transcription [13].

Oxidative stress has conclusively been shown to be associated with aging and age-related diseases, including cancer [14], [15], neurodegeneration [16], [17], cardiovascular disease [18], [19], and diabetes [20]. A number of studies suggest that dietary restriction can protect against these oxidative stress related diseases, including cancer [21], neurodegeneration [22], and cardiovascular disease [23], [24], [25]. DR also prevents a number of age-related pathologies, including loss of myenteric neurons [26], hearing loss [27], cataracts [28], insulin resistance [29], [30], and skeletal muscle loss [31], [32]. Although DR is generally thought to reduce oxidative stress, these data are mixed and have not been comprehensively reviewed. Three mechanisms may be responsible for the antioxidant effects of dietary restriction. Specifically, DR could reduce reactive oxygen species production, increase antioxidant enzyme activity or increase the turnover of oxidized macromolecules. These mechanisms are interrelated and often result in confounding results. For example, DR might lead to decreased expression of antioxidant enzymes, but this could be due to reduced production of reactive oxygen species [33]. Here we will review the effects of DR on ROS production, antioxidant enzyme activity, and oxidative damage and discuss potential mechanisms for how these effects are achieved.

The following three hypotheses provide a useful framework to test the role of oxidative stress in aging. First, oxidative damage should increase with age; second, manipulations that delay aging should attenuate the age-related change in oxidative damage; and third, specifically modulating the presumptive age determinants in old animals should reverse functional decline. For the first hypothesis, a number of studies have observed increased reactive oxygen species production and oxidative damage, although increased oxidative stress is not universal, as discussed below. For the second hypothesis, dietary restriction, reducing growth hormone, and insulin-like growth factor 1 signaling as well as reducing mammalian target of rapamycin signaling with rapamycin are common dietary, genetic, and pharmacological interventions, respectively [34], [35], [36], [37]. Dietary restriction is the antiaging paradigm most commonly used to test the oxidative stress theory of aging, and will be discussed extensively in this review. The third hypothesis has generated the most damning evidence against the oxidative stress theory of aging. Attempts to modulate oxidative stress using mice deficient in or overexpressing antioxidant enzymes do not generally support the oxidative stress theory of aging [38]. Two exceptions to this generalization are the mitochondrially targeted catalase overexpressing mouse [39], which is long-lived, and the copper zinc superoxide dismutase deficient mouse, which is short-lived [40]. The purpose of this review is not to make a definitive statement on the role of oxidative stress in aging. Rather, our primary objective is to determine the effect of dietary restriction on oxidative stress. As an aside, we will evaluate the effects of DR on oxidative stress during aging.

Dietary restriction is the most well-studied aging intervention in rodents, although the effects of DR depend on the extent of restriction, age, sex, species, strain and duration of restriction. Dietary restriction extends life span in many, but not all, strains of mice and rats [41], [42]. Protocols for dietary restriction in rodents vary in extent and duration of feeding, with reductions in food from 10 to 60% and durations from 1 week to the entire postweaning life span. If a standard protocol exists for long term DR, it would be a gradual reduction in food availability after maturation to 40% relative to animals fed ad libitum, and then maintaining this level throughout the study. Some studies use a nutrient supplement for the restricted group, which is considered calorie restriction, while other studies use alternate day feeding or intermittent fasting, in which animals are fed ad libitum on some days and fed nothing on others. Although less well studied, alternate day feeding and intermittent fasting produces many, but not all [43], [44], [45], of the beneficial effects of DR, including increasing life span [41]. The variety of restriction protocols makes comparisons among studies difficult, but in this review we comprehensively surveyed the available literature to search for trends in the effects of dietary restriction on oxidative stress.

Section snippets

Dietary restriction and reactive oxygen species production

For all of our analyses, we included models of DR with differing duration and percentage restriction without regard to sex, species, or strain. Because mitochondria are a major source of reactive oxygen species (ROS) production in the cell, and because other sources of ROS have been minimally studied with dietary restriction, we only included studies of mitochondrial ROS production. A systematic review of the literature uncovered 157 observations of mitochondrial ROS production using dietary

Effect of DR on antioxidant enzyme activity

We again took an unbiased approach to comprehensively survey the literature on the effects of DR on antioxidant enzyme activity and levels of the redox peptide glutathione in rodents. We included models of DR with differing duration and percentage restriction as well as the relatively common model of every other day feeding. There were 372 recorded comparisons (Supplemental Table 2) on the activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione S

Effects of DR on antioxidant enzyme protein and mRNA levels

We found 100 recordings of antioxidant protein or mRNA levels with dietary restriction [78], [79], [90], [91], [94], [96], [100], [137], [138], [139], [140]. Included in those measurements are mRNA and protein levels of the same enzymes used for activity assays as well as the redox protein thioredoxin and the redox enzyme thioredoxin reductase. Microarray analyses were not included. Thioredoxins are used to reduce oxidized antioxidant enzymes, including methionine sulfoxide reductases and

Effect of DR on oxidative damage

A limitation in the study of oxidative modifications is the reliability of reported biomarkers used to measure oxidative damage. Common measurements include carbonyls for proteins, lipid hydroperoxides and aldehydes for lipids, and 8-hydroxy-2-deoxyguanosine for DNA. While bulk measurements of oxidative damage may be indicative of the overall cellular state, it is likely that specific modifications on specific sites of individual proteins, lipids, and DNA differentially affect function, similar

Effects of dietary restriction on oxidative stress during aging

Although this review was not intended to comprehensively review the effects of oxidative stress during aging, a large number of studies examined here were on old animals, and the results in this section are likely reflective of all age-reported changes in oxidative stress. For example, we found a similar degree of effect for DNA oxidation compared with a recent comprehensive analysis of all age-related changes in DNA oxidation [187]. Related to the study of DR on old animals, the duration of DR

Concluding remarks

Recent evidence from rodent studies calls into question the oxidative stress theory of aging. In this review, we analyzed the effects of dietary restriction, the gold standard for antiaging interventions, on oxidative stress. Our analysis is limited in that we did not take into account strain or sex due to the diversity of strains tested and the lack of studies done in females. Statistical analysis was included only when there were sufficient numbers of observations. Furthermore, our analysis

Acknowledgments

This work was supported by an NIA Training Grant on the Biology of Aging (M.E.W., T32AG021890) and a National Institutes of Health – National Institute on Aging Grant (H.V.R., P01AG20591).

References (229)

  • E. Marzetti et al.

    Modulation of age-induced apoptotic signaling and cellular remodeling by exercise and calorie restriction in skeletal muscle

    Free Radic. Biol. Med.

    (2008)
  • R. Weindruch et al.

    The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake

    J. Nutr.

    (1986)
  • V. Pérez et al.

    Is the oxidative stress theory of aging dead?

    Biochim. Biophys. Acta

    (2009)
  • W. Swindell

    Dietary restriction in rats and mice: a meta-analysis and review of the evidence for genotype-dependent effects on lifespan

    Ageing Res. Rev

    (2012)
  • K. Varady et al.

    Alternate-day fasting and chronic disease prevention: a review of human and animal trials

    Am. J. Clin. Nutr.

    (2007)
  • A. Lass et al.

    Caloric restriction prevents age-associated accrual of oxidative damage to mouse skeletal muscle mitochondria

    Free Radic. Biol. Med.

    (1998)
  • M. López-Torres et al.

    Influence of aging and long-term caloric restriction on oxygen radical generation and oxidative DNA damage in rat liver mitochondria

    Free Radic. Biol. Med

    (2002)
  • R. Pamplona et al.

    Oxidative, glycoxidative and lipoxidative damage to rat heart mitochondrial proteins is lower after 4 months of caloric restriction than in age-matched controls

    Mech. Ageing Dev

    (2002)
  • R. Sohal et al.

    Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction in the mouse

    Mech. Ageing Dev.

    (1994)
  • Drake Butterfield et al.

    A. Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid β-peptide

    Trends Mole. Med

    (2001)
  • T. Prolla et al.

    Molecular mechanisms of brain aging and neurodegenerative disorders: lessons from dietary restriction

    Trends Neurosci

    (2001)
  • T. Armeni et al.

    Studies on the life prolonging effect of food restriction: glutathione levels and glyoxalase enzymes in rat liver

    Mech. Ageing Dev.

    (1998)
  • L. Castello et al.

    Alternate-day fasting protects the rat heart against age-induced inflammation and fibrosis by inhibiting oxidative damage and NF-kB activation

    Free Radic. Biol. Med.

    (2010)
  • L.H. Chen et al.

    Effects of age, dietary restriction and germ-free environment on glutathione-related enzymes in Lobund-Wistar rats

    Arch. Gerontol. Geriatr.

    (1992)
  • C. Cho

    Modulation of glutathione and thioredoxin systems by calorie restriction during the aging process

    Exp. Gerontol

    (2003)
  • X. Gong et al.

    Antioxidant enzyme activities in lens, liver and kidney of calorie restricted Emory mice

    Mech. Ageing Dev.

    (1997)
  • J. Kim

    Exercise and diet modulate cardiac lipid peroxidation and antioxidant defenses

    Free Radic. Biol. Med

    (1996)
  • A. Koizumi et al.

    Influences of dietary restriction and age on liver enzyme activities and lipid peroxidation in mice

    J. Nutr.

    (1987)
  • S. Laganiere et al.

    Effect of chronic food restriction in aging rats. II. Liver cytosolic antioxidants and related enzymes

    Mech. Ageing Dev.

    (1989)
  • C.V. Mura et al.

    Effects of calorie restriction and aging on the expression of antioxidant enzymes and ubiquitin in the liver of Emory mice

    Mech. Ageing Dev

    (1996)
  • Z. Radák et al.

    Effect of aging and late onset dietary restriction on antioxidant enzymes and proteasome activities, and protein carbonylation of rat skeletal muscle and tendon

    Exp. Gerontol.

    (2002)
  • G. Rao et al.

    Effect of dietary restriction on the age-dependent changes in the expression of antioxidant enzymes in rat liver

    J. Nutr

    (1990)
  • I. Rebrin et al.

    Effects of age and caloric restriction on glutathione redox state in mice

    Free Radic. Biol. Med.

    (2003)
  • I. Semsei et al.

    Changes in the expression of superoxide dismutase and catalase as a function of age and dietary restriction

    Biochem. Biophys. Res. Commun

    (1989)
  • E. Xia et al.

    Activities of antioxidant enzymes in various tissues of male Fischer 344 rats are altered by food restriction

    J. Nutr.

    (1995)
  • D. Harman

    Aging: a theory based on free radical and radiation chemistry

    J. Gerontol.

    (1956)
  • J. Speakman

    Body size, energy metabolism and lifespan

    J. Exp. Biol.

    (2005)
  • D. Harman

    The biologic clock: the mitochondria?

    J. Am. Geriatrics Soc

    (1972)
  • T. Tanaka et al.

    Redox regulation by thioredoxin superfamily; protection against oxidative stress and aging

    Free Rad. Res

    (2000)
  • J.G. de la Asuncion et al.

    Mitochondrial glutathione oxidation correlates with age-associated oxidative damage to mitochondrial DNA

    FASEB J

    (1996)
  • H. Liu et al.

    Glutathione metabolism during aging and in Alzheimer disease

    Ann. N. Y. Acad. Sci.

    (2004)
  • V. Adler et al.

    Role of redox potential and reactive oxygen species in stress signaling

    Oncogene

    (1999)
  • D.M. Ziegler

    Role of reversible oxidation-reduction of enzyme thiols-disulfides in metabolic regulation

    Ann. Rev. Biochem

    (1985)
  • E. Arnér et al.

    Physiological functions of thioredoxin and thioredoxin reductase

    Eur. J. Biochem.

    (2000)
  • H.J. Sung et al.

    Ambient oxygen promotes tumorigenesis

    PLoS ONE

    (2011)
  • J. Andersen

    Oxidative stress in neurodegeneration: cause or consequence?

    Nat. Med

    (2004)
  • B. Halliwell

    Oxidative stress and neurodegeneration: where are we now?

    J. Neurochem.

    (2006)
  • N.S. Dhalla et al.

    Role of oxidative stress in cardiovascular diseases

    J. Hypertens.

    (2000)
  • K. Griendling et al.

    Oxidative stress and cardiovascular injury

    Circulation

    (2003)
  • A. Ceriello et al.

    Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited

    Arterioscler. Thromb.Vasc. Biol.

    (2004)
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