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Mitochondrial Respiratory Function Decline in Aging and Life-Span Extension by Caloric Restriction

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Aging and Age-Related Disorders

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Abstract

Extensive studies have established that progressive accumulation of somatic mutations in mitochondrial DNA (mtDNA) leads to a decline in mitochondrial bioenergetic function and contributes to human aging. Mitochondrial respiratory chain dysfunction not only causes inefficient ATP production but also increases mitochondrial generation of reactive oxygen species (ROS), which can induce further oxidative damage and mutation to mtDNA during the aging process. Indeed, a wide spectrum of mtDNA mutations has been found to occur in somatic tissues of elderly subjects. Besides, mitochondrial abnormalities have been associated with age-related diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). On the other hand, age-associated reduction in the efficiency of oxidative phosphorylation (OXPHOS) may cause alterations of gene expression in affected tissues for the sake of compensation or adaptation. Recent studies have revealed that the expression levels of several clusters of genes and posttranslational modifications of proteins are changed in various tissues of old animals and cultured cells from elderly subjects. In addition, the changes in age-associated gene expression profiles were tissue-specific, which suggests that different tissues are subject to different degree of oxidative stress during the aging process. Surprisingly, the majority of the age-related alterations in gene expression can be reversed by caloric restriction (CR) through the elevation of sirtuin 1 (Sirt1) expression, which promotes survival in organisms ranging from yeast to rodents and primates. The anti-aging effects of Sirt1 mediated by CR could be conferred by the activation of mitochondrial biogenesis and respiratory function. On the other hand, the mitochondrial sirtuins (Sirt3, Sirt4, and Sirt5) also play a critical role not only in the upregulation of mitochondrial function but also in the protection against oxidative stress and culminate in the extension of the life span of animals. Taking these findings together, we suggest that mitochondrial dysfunction, accumulation of mtDNA mutation, enhanced oxidative stress, and alteration of gene expression are important contributors to human aging. On the other hand, Sirt1 and mitochondrial sirtuins could be the therapeutic targets for the treatment of various age-related diseases such as mitochondrial disorders, neurodegenerative diseases, and metabolic syndrome.

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Acknowledgments

The results described in this chapter were supported by research grants from the National Science Council (NSC96-2320-B-010-006 and NSC97-2320-B-010-013-MY3), Executive Yuan, Taiwan. One of the authors, Yau-Huei Wei, withes to express his appreciation to the Nation Science Council of Taiwan for the long-term support on the studies of the mitochondrial role in human aging and age-related diseases.

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  1. Department of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, 112, Taiwan

    Shi-Bei Wu, Yu-Ting Wu, Chih-Hao Wang, Wan-Yu Lee & Yau-Huei Wei

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  3. Chih-Hao Wang
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Correspondence to Yau-Huei Wei .

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  1. Center for Occupational & Environmental, Department of Medicine, University of California, Irvine, Room 320, Med Surge II, Irvine, 92697, California, USA

    Stephen Bondy

  2. New Jersey Medical School, Department of Neurology and Neuroscience, University of Medicine & Dentistry of Ne, South Orange Avenue 185, Newark, 07101, New Jersey, USA

    Kenneth Maiese

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Wu, SB., Wu, YT., Wang, CH., Lee, WY., Wei, YH. (2010). Mitochondrial Respiratory Function Decline in Aging and Life-Span Extension by Caloric Restriction. In: Bondy, S., Maiese, K. (eds) Aging and Age-Related Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-602-3_7

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