Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage

被引:4
作者
Page, Melissa M. [1 ]
Withers, Dominic J. [2 ]
Selman, Colin [1 ]
机构
[1] Univ Aberdeen, Inst Biol & Environm Sci, Aberdeen AB24 2TZ, Scotland
[2] Univ London Imperial Coll Sci Technol & Med, Med Res Council, Ctr Clin Sci, Metab Signaling Grp, London W12 0NN, England
基金
英国惠康基金; 英国生物技术与生命科学研究理事会;
关键词
Insulin receptor substrate-1; Irs1; Lifespan; Antioxidant enzymes; Oxidative damage; Ageing; LIFE-SPAN EXTENSION; MN-SUPEROXIDE-DISMUTASE; AMES DWARF MICE; CAENORHABDITIS-ELEGANS; GROWTH-HORMONE; STRESS RESISTANCE; NUTRIENT HOMEOSTASIS; DROSOPHILA; CATALASE; DEFENSE;
D O I
10.1007/s11357-012-9395-9
中图分类号
R592 [老年病学]; C [社会科学总论];
学科分类号
03 ; 0303 ; 100203 ;
摘要
Insulin receptor substrate-1 null (Irs1 (-/-)) mice are long lived and importantly they also demonstrate increased resistance to several age-related pathologies compared to wild type (WT) controls. Currently, the molecular mechanisms that underlie lifespan extension in long-lived mice are unclear although protection against oxidative damage may be important. Here, we determined both the activities of several intracellular antioxidants and levels of oxidative damage in brain, skeletal muscle, and liver of Irs1 (-/-) and WT mice at 80, 450, and 700 days of age, predicting that long-lived Irs1 (-/-) mice would be protected against oxidative damage. We measured activities of both intracellular superoxide dismutases (SOD); cytosolic (CuZnSOD) and mitochondrial (MnSOD), glutathione peroxide (GPx), glutathione reductase (GR), catalase (CAT), and reduced glutathione (GHS). Of these, only hepatic CAT was significantly altered (increased) in Irs1 (-/-) mice. In addition, the levels of protein oxidation (protein carbonyl content) and lipid peroxidation (4-hydroxynonenal) were unaltered in Irs1 (-/-) mice, although the hepatic GSH/GSSG ratio, indicating an oxidized environment, was significantly lower in long-lived Irs1 (-/-) mice. Overall, our results do not support the premise that lifespan extension in Irs1 (-/-) mice is associated with greater tissue antioxidant protection or reduced oxidative damage.
引用
收藏
页码:647 / 658
页数:12
相关论文
共 57 条
[1]   Lifespan extension by increased expression of the Drosophila homologue of the IGFBP7 tumour suppressor [J].
Alic, Nazif ;
Hoddinott, Matthew P. ;
Vinti, Giovanna ;
Partridge, Linda .
AGING CELL, 2011, 10 (01) :137-147
[2]   Single-gene mutations and healthy ageing in mammals [J].
Bartke, Andrzej .
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, 2011, 366 (1561) :28-34
[3]   The free radical theory of aging matures [J].
Beckman, KB ;
Ames, BN .
PHYSIOLOGICAL REVIEWS, 1998, 78 (02) :547-581
[4]   Extended longevity in mice lacking the insulin receptor in adipose tissue [J].
Blüher, M ;
Kahn, BB ;
Kahn, CR .
SCIENCE, 2003, 299 (5606) :572-574
[5]   Long-Lived Ames Dwarf Mice Are Resistant to Chemical Stressors [J].
Bokov, Alex F. ;
Lindsey, Merry L. ;
Khodr, Christina ;
Sabia, Marian R. ;
Richardson, Arlan .
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES, 2009, 64 (08) :819-827
[6]   Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity:: Cues for an evolutionarily conserved mechanism of life span control [J].
Bonafè, M ;
Barbieri, M ;
Marchegiani, F ;
Olivieri, F ;
Ragno, E ;
Giampieri, C ;
Mugianesi, E ;
Centurelli, M ;
Franceschi, C ;
Paolisso, G .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2003, 88 (07) :3299-3304
[7]   Low utilization of circulating glucose after food withdrawal in Snell dwarf mice [J].
Brooks, Natasha L. ;
Trent, Chad M. ;
Raetzsch, Carl F. ;
Flurkey, Kevin ;
Boysen, Gunnar ;
Perfetti, Michael T. ;
Jeong, Yo-Chan ;
Klebanov, Simon ;
Patel, Kajal B. ;
Khodush, Valerie R. ;
Kupper, Lawrence L. ;
Carling, David ;
Swenberg, James A. ;
Harrison, David E. ;
Combs, Terry P. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (48) :35069-35077
[8]   Insulin/IGF-like signalling, the central nervous system and aging [J].
Broughton, Susan ;
Partridge, Linda .
BIOCHEMICAL JOURNAL, 2009, 418 :1-12
[9]   Mitochondrial oxidant generation and oxidative damage in ames dwarf and GH transgenic mice [J].
Brown-Borg H. ;
Johnson W.T. ;
Rakoczy S. ;
Romanick M. .
Journal of the American Aging Association, 2001, 24 (3) :85-96
[10]   Catalase expression in delayed and premature aging mouse models [J].
Brown-Borg, HM ;
Rakoczy, SG .
EXPERIMENTAL GERONTOLOGY, 2000, 35 (02) :199-212