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      • Record: found
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      Mitochondrial dysfunction in aging: Much progress but many unresolved questions

      research-article
      Author(s): , *
      Publication date PMC-release:
      Journal: Biochimica et Biophysica Acta
      Publisher: Elsevier Pub. Co
      Keywords: DNA, Mitochondrial, Aging

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          Abstract

          The free radical theory of aging is almost 60 years old. As mitochondria are the principle source of intracellular reactive oxygen species (ROS), this hypothesis suggested a central role for the mitochondrion in normal mammalian aging. In recent years, however, much work has questioned the importance of mitochondrial ROS in driving aging. Conversely new evidence points to other facets of mitochondrial dysfunction which may nevertheless suggest the mitochondrion retains a critical role at the center of a complex web of processes leading to cellular and organismal aging.

          Highlights

          • •

            Mitochondrial dysfunction retains a central position in aging theory.

          • •

            Clonal expansion of mtDNA mutations occurs in aging post-mitotic tissues.

          • •

            ROS may have both deleterious and beneficial roles.

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          Most cited references77

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          Antioxidants prevent health-promoting effects of physical exercise in humans.

          Michael Ristow, Kim Zarse, Andreas Oberbach … (2009)
          Exercise promotes longevity and ameliorates type 2 diabetes mellitus and insulin resistance. However, exercise also increases mitochondrial formation of presumably harmful reactive oxygen species (ROS). Antioxidants are widely used as supplements but whether they affect the health-promoting effects of exercise is unknown. We evaluated the effects of a combination of vitamin C (1000 mg/day) and vitamin E (400 IU/day) on insulin sensitivity as measured by glucose infusion rates (GIR) during a hyperinsulinemic, euglycemic clamp in previously untrained (n = 19) and pretrained (n = 20) healthy young men. Before and after a 4 week intervention of physical exercise, GIR was determined, and muscle biopsies for gene expression analyses as well as plasma samples were obtained to compare changes over baseline and potential influences of vitamins on exercise effects. Exercise increased parameters of insulin sensitivity (GIR and plasma adiponectin) only in the absence of antioxidants in both previously untrained (P < 0.001) and pretrained (P < 0.001) individuals. This was paralleled by increased expression of ROS-sensitive transcriptional regulators of insulin sensitivity and ROS defense capacity, peroxisome-proliferator-activated receptor gamma (PPARgamma), and PPARgamma coactivators PGC1alpha and PGC1beta only in the absence of antioxidants (P < 0.001 for all). Molecular mediators of endogenous ROS defense (superoxide dismutases 1 and 2; glutathione peroxidase) were also induced by exercise, and this effect too was blocked by antioxidant supplementation. Consistent with the concept of mitohormesis, exercise-induced oxidative stress ameliorates insulin resistance and causes an adaptive response promoting endogenous antioxidant defense capacity. Supplementation with antioxidants may preclude these health-promoting effects of exercise in humans.
          Article 0 comments Cited 475 times – based on 0 reviews     Review now
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            Telomere dysfunction induces metabolic and mitochondrial compromise.

            Ergun Sahin, Simona Colla, Marc Liesa … (2011)
            Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α and PGC-1β, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1α expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1α and PGC-1β promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.
            Article 0 comments Cited 469 times – based on 0 reviews     Review now
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              Decline in skeletal muscle mitochondrial function with aging in humans.

              Kevin R. Short, Maureen L Bigelow, Jane C. Kahl … (2005)
              Cumulative mtDNA damage occurs in aging animals, and mtDNA mutations are reported to accelerate aging in mice. We determined whether aging results in increased DNA oxidative damage and reduced mtDNA abundance and mitochondrial function in skeletal muscle of human subjects. Studies performed in 146 healthy men and women aged 18-89 yr demonstrated that mtDNA and mRNA abundance and mitochondrial ATP production all declined with advancing age. Abundance of mtDNA was positively related to mitochondrial ATP production rate, which in turn, was closely associated with aerobic capacity and glucose tolerance. The content of several mitochondrial proteins was reduced in older muscles, whereas the level of the oxidative DNA lesion, 8-oxo-deoxyguanosine, was increased, supporting the oxidative damage theory of aging. These results demonstrate that age-related muscle mitochondrial dysfunction is related to reduced mtDNA and muscle functional changes that are common in the elderly.
              Article 0 comments Cited 402 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Patrick F. Chinnery
                Journal
                Journal ID (nlm-ta): Biochim Biophys Acta
                Journal ID (iso-abbrev): Biochim. Biophys. Acta
                Title: Biochimica et Biophysica Acta
                Publisher: Elsevier Pub. Co
                ISSN (Print): 0006-3002
                Publication date PMC-release: 1 November 2015
                Publication date (Print): November 2015
                Volume: 1847
                Issue: 11
                Pages: 1347-1353
                Affiliations
                Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, UK
                Author notes
                [* ]Corresponding author. patrick.chinnery@ 123456ncl.ac.uk
                Article
                Publisher ID: S0005-2728(15)00109-7
                DOI: 10.1016/j.bbabio.2015.05.022
                PMC ID: 4580208
                PubMed ID: 26050973
                SO-VID: 0f61b3f1-d889-4029-873f-3511e039f21c
                Copyright © Crown Copyright © 2015 Published by Elsevier B.V. All rights reserved.
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 19 March 2015
                Date revision received : 21 May 2015
                Date accepted : 26 May 2015
                Categories
                Subject: Article

                ScienceOpen disciplines: Biochemistry
                Keywords: dna,mitochondrial,aging
                Data availability:
                ScienceOpen disciplines: Biochemistry
                Keywords: dna, mitochondrial, aging

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