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      Mitochondria in the signaling pathways that control longevity and health span

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          Abstract

          Genetic and pharmacological intervention studies have identified evolutionarily conserved and functionally interconnected networks of cellular energy homeostasis, nutrient-sensing, and genome damage response signaling pathways, as prominent regulators of longevity and health span in various species. Mitochondria are the primary sites of ATP production and are key players in several other important cellular processes. Mitochondrial dysfunction diminishes tissue and organ functional performance and is a commonly considered feature of the aging process. Here we review the evidence that through reciprocal and multilevel functional interactions, mitochondria are implicated in the lifespan modulation function of these pathways, which altogether constitute a highly dynamic and complex system that controls the aging process. An important characteristic of these pathways is their extensive crosstalk and apparent malleability to modification by non-invasive pharmacological, dietary, and lifestyle interventions, with promising effects on lifespan and health span in animal models and potentially also in humans.

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          Most cited references 192

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          Oxidative stress shortens telomeres.

          Telomeres in most human cells shorten with each round of DNA replication, because they lack the enzyme telomerase. This is not, however, the only determinant of the rate of loss of telomeric DNA. Oxidative damage is repaired less well in telomeric DNA than elsewhere in the chromosome, and oxidative stress accelerates telomere loss, whereas antioxidants decelerate it. I suggest here that oxidative stress is an important modulator of telomere loss and that telomere-driven replicative senescence is primarily a stress response. This might have evolved to block the growth of cells that have been exposed to a high risk of mutation.
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            AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.

            Activation of AMP-activated kinase (AMPK) in skeletal muscle increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing gene expression in these pathways. However, the transcriptional components that are directly targeted by AMPK are still elusive. The peroxisome-proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) has emerged as a master regulator of mitochondrial biogenesis; furthermore, it has been shown that PGC-1alpha gene expression is induced by exercise and by chemical activation of AMPK in skeletal muscle. Using primary muscle cells and mice deficient in PGC-1alpha, we found that the effects of AMPK on gene expression of glucose transporter 4, mitochondrial genes, and PGC-1alpha itself are almost entirely dependent on the function of PGC-1alpha protein. Furthermore, AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter. These data indicate that AMPK phosphorylation of PGC-1alpha initiates many of the important gene regulatory functions of AMPK in skeletal muscle.
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              daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans.

              A C. elegans neurosecretory signaling system regulates whether animals enter the reproductive life cycle or arrest development at the long-lived dauer diapause stage. daf-2, a key gene in the genetic pathway that mediates this endocrine signaling, encodes an insulin receptor family member. Decreases in DAF-2 signaling induce metabolic and developmental changes, as in mammalian metabolic control by the insulin receptor. Decreased DAF-2 signaling also causes an increase in life-span. Life-span regulation by insulin-like metabolic control is analogous to mammalian longevity enhancement induced by caloric restriction, suggesting a general link between metabolism, diapause, and longevity.
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                Author and article information

                Journal
                101128963
                29630
                Ageing Res Rev
                Ageing Res. Rev.
                Ageing research reviews
                1568-1637
                1872-9649
                26 August 2020
                12 August 2019
                September 2019
                09 September 2020
                : 54
                : 100940
                Affiliations
                [a ]Center for Healthy Aging, Department of Cellular and Molecular Medicine, SUND, University of Copenhagen, 2200, Copenhagen N, Denmark
                [b ]Institute of Cell and Molecular Biosciences and Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK
                [c ]Laboratory of Molecular Gerontology, National Institute on Aging, 251 Bayview Blvd, Baltimore, USA
                Author notes
                [* ]Corresponding author at: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 251 Bayview Blvd, Suite 100, Rm 06B133, Baltimore, MD, 21224, USA. vbohr@ 123456nih.gov (V.A. Bohr).
                Article
                NIHMS1623320
                10.1016/j.arr.2019.100940
                7479635
                31415807

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

                Categories
                Article

                aging, mitochondria, dna repair, energy, lifespan, metabolism

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