Review ArticleThe effects of dietary restriction on oxidative stress in rodents
Graphical abstract
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).
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