Elsevier

Experimental Gerontology

Volume 48, Issue 10, October 2013, Pages 1091-1095
Experimental Gerontology

Maintaining good hearing: Calorie restriction, Sirt3, and glutathione

https://doi.org/10.1016/j.exger.2013.02.014Get rights and content

Abstract

Reducing calorie intake extends the lifespan of a variety of experimental models and delays progression of age-related hearing loss (AHL). AHL is a common feature of aging and is characterized by age-related decline of hearing associated with loss of sensory hair cells, spiral ganglion neurons, and/or stria vascularis degeneration in the cochlea. Sirtuins are a family of NAD+-dependent enzymes that regulate lifespan in lower organisms and have emerged as broad regulators of cellular fate. Our recent study indicated that mitochondrial Sirt3, a member of the sirtuin family, mediates the anti-aging effects of calorie restriction (CR) on AHL in mice. Interestingly, we also found that weight loss alone may not be sufficient for maintaining normal hearing. How does CR slow the progression of AHL through regulation of Sirt3? Here we review the evidence that during CR, Sirt3 slows the progression of AHL by promoting the glutathione-mediated mitochondrial antioxidant defense system in mice. A significant reduction in food consumption in one's daily life may not be a desirable and realistic option for most people. Therefore, identification/discovery of compounds that induce the activation of SIRT3 or glutathione reductase, or that increase mitochondrial glutathione levels has potential for maintaining good hearing through mimicking the anti-aging effects of CR in human inner ear cells.

Highlights

► Age-related hearing loss (AHL) is a common feature of aging. ► Calorie restriction (CR) is known to delay the onset of AHL. ► We review the roles of mitochondrial Sirt3 and glutathione in maintaining normal hearing under CR. ► Potentially relevant mechanisms for the CR-mediated prevention of AHL are discussed.

Introduction

Calorie restriction (CR) is the only intervention to slow the rate of aging and to extend lifespan in diverse species (Fontana et al., 2010, Weindruch and Walford, 1988). CR also delays the onset of age-related diseases such as diabetes, cancer, cardiovascular disease, Parkinson's disease, Alzheimer's disease, and age-related hearing loss in rodents and humans (Fontana et al., 2010, Someya et al., 2010, Weindruch and Walford, 1988). In monkeys, two studies found that CR reduces the incidence of obesity, diabetes, and tumor (Colman et al., 2009, Mattison et al., 2012). Importantly, CR reduced age-related mortality in these long-lived primates (Colman et al., 2009). In mice, CR results in significant reduction of the levels of oxidative protein damage in aged brains, hearts, and livers (Balaban et al., 2005, Weindruch and Walford, 1988). Although research on the anti-aging effects of CR in humans is still at an early stage, CR reduces obesity incidence and levels of cholesterol, blood pressure, oxidative stress, and inflammation, and increases insulin resistance in humans (Fontana et al., 2010). How does CR slow the rate of aging? The Mitochondrial Free Radical Theory of Aging postulates that aging and age-related diseases result from accumulated oxidative damage caused by reactive oxygen species (ROS), originating from the mitochondria (Balaban et al., 2005). In agreement with this theory, overexpression of the mitochondrial antioxidant enzyme Sod2 (superoxide dismutase 2) significantly increases the lifespan of Drosophila (Sun et al., 2002), while overexpression of a mitochondrially-targeted catalase transgene results in reduced age-related pathology in the heart and increases lifespan in mice (Schriner et al., 2005). There are two major antioxidant defense systems in mitochondria: the glutathione and thioredoxin systems (Halliwell and Gutteridge, 2007, Mari et al., 2009). Glutathione acts as the major antioxidant in cells and is found mostly in the reduced form in healthy mitochondria from young mice (Mari et al., 2009). Consistent with these reports, aging results in a decreased ratio of reduced glutathione (GSH):oxidized glutathione (GSSG) in the mitochondria of brain, heart, eye, and testis from aged mice, while CR prevents the decline (Rebrin & Sohal, 2008). Yet, whether the anti-aging action of CR in the sensory organs such as inner ear is a regulated process and/or is associated with the mitochondrial antioxidant defense pathways still remains unclear.

It is well documented that hearing gradually declines during aging in laboratory animals as well as humans (Gates & Mills, 2005), and as such, age-related hearing loss (AHL) is a robust marker and common feature of mammalian aging. AHL or presbycusis is generally classified into three types based on the relationship between cochlear pathology and hearing levels: sensory hearing loss (loss of sensory hair cells), neuronal hearing loss (loss of spiral ganglion neurons), and metabolic hearing loss (stria atrophy) (Gates and Mills, 2005, Schuknecht, 1955), and most cases of AHL exhibit a mixture of these pathological changes (Gates & Mills, 2005). Evidence indicates that cochlea from aged C57BL/6 and CBA/J mice displays loss of spiral ganglion neurons and hair cells, and increased oxidative damage in the cochlea (Jiang et al., 2007, Someya et al., 2009), while overexpression of catalase in mitochondria reduces loss of hair cells and spiral ganglion neurons and oxidative DNA damage in the cochlea, and slows the progression of AHL in mice (Someya et al., 2009). Therefore, AHL is thought to result from accumulated oxidative damage in cochlear cells caused by ROS, originating from the mitochondria (Fig. 1) (Someya & Prolla, 2010). Our recent study indicated that mitochondrial Sirt3, a member of the sirtuin family, mediates the anti-aging effects of CR on AHL by promoting the glutathione-mediated mitochondrial antioxidant defense system in mice (Someya et al., 2010). How does CR slow the progression of AHL through the regulation of Sirt3? Can we maintain our good hearing by simply reducing calorie intake? To answer these questions, we review the roles of mitochondrial Sirt3 in regulating mitochondrial metabolism, the roles of mitochondrial glutathione in protecting cells against oxidative stress, and the evidence that during CR, Sirt3 slows the progression of AHL by promoting the glutathione-mediated mitochondrial antioxidant defense system in mice.

Section snippets

Mitochondria and sirtuins

Lin et al. uncovered Sir2, a member of the sirtuin family and NAD+-dependent deacetylases, is essential for the extension of lifespan by CR in yeasts (Lin et al., 2004), implicating a link between sirtuins and the anti-aging action of CR. Subsequent studies in Caenorhabditis elegans and Drosophila also identified Sir2 homologues as a determinant of lifespan, and showed that CR increases Sir2 levels in these organisms (Finkel et al., 2009). So far, seven sirtuins have been identified in humans,

Mitochondrial glutathione and ROS

Mitochondria are the major source of reactive oxygen species (ROS) (Balaban et al., 2005). An elaborate antioxidant system has evolved to control the damaging effects of ROS. The system includes the antioxidant enzymes SOD, catalase, GPX (glutathione peroxidase), and GSR (glutathione reductase), and a variety of small-molecule antioxidants such as glutathione and thioredoxin (Halliwell & Gutteridge, 2007). In mitochondria, glutathione acts as the major antioxidant protecting key mitochondrial

Sirt3 slows the development of AHL under CR

We have recently shown that during CR, mitochondrial Sirt3 slows the progression of AHL by promoting the glutathione-mediated mitochondrial antioxidant defense system (Someya et al., 2010): using Sirt3 knockout (KO) and WT mice, we conducted a 10 month CR dietary study (a 25% CR) and measured hearing levels in these animals by the auditory brainstem response (ABR) analysis. As expected, aging resulted in increased ABR hearing thresholds in WT mice on control diets. Surprisingly, CR did not delay

Do ROS play an essential role in the CR-mediated prevention of AHL?

It is widely accepted that ROS plays a role in aging and age-related disease and that the Free Radical Theory of Aging is a popular explanation of how we lose our hearing during aging. Yet, recent studies have shown that overexpression of the antioxidant enzymes such as cytosolic Sod1, mitochondrial Sod2, or catalase does not extend the lifespan of mice (Pérez et al., 2009), conflicting with the Free Radical Theory of Aging and our previous finding that overexpression of Cat in mitochondria

Conflict of interest

The authors have no conflicts of interests.

Acknowledgments

S.S. is supported by the NIH/NIDCD (1R03DC011840-01), the American Federation for Aging Research Foundation, and the Claude D. Pepper Older Americans Independence Center Junior Scholar Award.

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