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      Hypoxia and aging

      review-article
      Experimental & Molecular Medicine
      Nature Publishing Group UK
      Senescence, Experimental models of disease

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          Abstract

          Eukaryotic cells require sufficient oxygen (O 2) for biological activity and survival. When the oxygen demand exceeds its supply, the oxygen levels in local tissues or the whole body decrease (termed hypoxia), leading to a metabolic crisis, threatening physiological functions and viability. Therefore, eukaryotes have developed an efficient and rapid oxygen sensing system: hypoxia-inducible factors (HIFs). The hypoxic responses are controlled by HIFs, which induce the expression of several adaptive genes to increase the oxygen supply and support anaerobic ATP generation in eukaryotic cells. Hypoxia also contributes to a functional decline during the aging process. In this review, we focus on the molecular mechanisms regulating HIF-1α and aging-associated signaling proteins, such as sirtuins, AMP-activated protein kinase, mechanistic target of rapamycin complex 1, UNC-51-like kinase 1, and nuclear factor κB, and their roles in aging and aging-related diseases. In addition, the effects of prenatal hypoxia and obstructive sleep apnea (OSA)-induced intermittent hypoxia have been reviewed due to their involvement in the progression and severity of many diseases, including cancer and other aging-related diseases. The pathophysiological consequences and clinical manifestations of prenatal hypoxia and OSA-induced chronic intermittent hypoxia are discussed in detail.

          Aging: Low oxygen levels promote aging-associated diseases

          Deficient oxygen supplies to the body’s tissues and a reduced ability to deal with the cellular stress of low oxygen availability both contribute to the ageing process. Eui-Ju Yeo from Gachon University in Incheon, South Korea, reviews the links between insufficient oxygen, a condition known as hypoxia, and the functional decline associated with getting old. Yeo highlights the role that the oxygen-sensing proteins known as hypoxia-inducible factors (HIFs) play in facilitating oxygen supply and regulating energy production under limited oxygen conditions. HIFs also interact with a series of signaling proteins that, when abnormally activated, contribute to many aging-associated diseases. Yeo singles out two hypoxia-related health problems, prenatal hypoxia during early brain development and obstructive sleep apnea, and discusses how they can accelerate aging in various ways.

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          Most cited references95

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          HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.

          HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). We found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and Fe(2+), this protein modification may play a key role in mammalian oxygen sensing.
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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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              AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.

              Replicative cell division is an energetically demanding process that can be executed only if cells have sufficient metabolic resources to support a doubling of cell mass. Here we show that proliferating mammalian cells have a cell-cycle checkpoint that responds to glucose availability. The glucose-dependent checkpoint occurs at the G(1)/S boundary and is regulated by AMP-activated protein kinase (AMPK). This cell-cycle arrest occurs despite continued amino acid availability and active mTOR. AMPK activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate AMPK-dependent cell-cycle arrest. AMPK-induced p53 activation promotes cellular survival in response to glucose deprivation, and cells that have undergone a p53-dependent metabolic arrest can rapidly reenter the cell cycle upon glucose restoration. However, persistent activation of AMPK leads to accelerated p53-dependent cellular senescence. Thus, AMPK is a cell-intrinsic regulator of the cell cycle that coordinates cellular proliferation with carbon source availability.
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                Author and article information

                Contributors
                +82 32 899 6050 , euiju@gachon.ac.kr
                Journal
                Exp Mol Med
                Exp. Mol. Med
                Experimental & Molecular Medicine
                Nature Publishing Group UK (London )
                1226-3613
                2092-6413
                20 June 2019
                20 June 2019
                June 2019
                : 51
                : 6
                : 67
                Affiliations
                ISNI 0000 0004 0647 2973, GRID grid.256155.0, Department of Biochemistry, College of Medicine, , Gachon University, ; Incheon, 21999 Republic of Korea
                Article
                233
                10.1038/s12276-019-0233-3
                6586788
                31221957
                06510462-5a88-4836-bdb3-3dc6c1ffd642
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 6 December 2018
                : 20 December 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100003725, National Research Foundation of Korea (NRF);
                Award ID: 2017R1D1A1B03033499
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2019

                Molecular medicine
                senescence,experimental models of disease
                Molecular medicine
                senescence, experimental models of disease

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