Reduction in glutathione peroxidase 4 increases life span through increased sensitivity to apoptosis.

Glutathione peroxidase 4 (Gpx4) is an antioxidant defense enzyme that plays an important role in detoxification of oxidative damage to membrane lipids. Because oxidative stress is proposed to play a causal role in aging, we compared the life spans of Gpx4 heterozygous knockout mice (Gpx4(+/-) mice) and wild-type mice (WT mice). To our surprise, the median life span of Gpx4(+/-) mice (1029 days) was significantly longer than that of WT mice (963 days) even though the expression of Gpx4 was reduced approximately 50% in all tissues of Gpx4(+/-) mice. Pathological analysis revealed that Gpx4(+/-) mice showed a delayed occurrence of fatal tumor lymphoma and a reduced severity of glomerulonephritis. Compared to WT mice, Gpx4(+/-) mice showed significantly increased sensitivity to oxidative stress-induced apoptosis. Our data indicate that lifelong reduction in Gpx4 increased life span and reduced/retarded age-related pathology most likely through alterations in sensitivity of tissues to apoptosis.

[1]  R. Bronson,et al.  Reduction in rate of occurrence of age related lesions in dietary restricted laboratory mice. , 1991, Growth, development, and aging : GDA.

[2]  M. Schlame,et al.  Binding of 10-N-nonyl acridine orange to cardiolipin-deficient yeast cells: implications for assay of cardiolipin. , 2005, Analytical biochemistry.

[3]  M. Ratinaud,et al.  10N-nonyl acridine orange interacts with cardiolipin and allows the quantification of this phospholipid in isolated mitochondria. , 1992, European journal of biochemistry.

[4]  Ultracentrifugal analysis of the quaternary structure of the raf represser from Escherichia coli , 1990, FEBS letters.

[5]  J. Morrow,et al.  Mass spectrometric quantification of F2-isoprostanes in biological fluids and tissues as measure of oxidant stress. , 1999, Methods in enzymology.

[6]  M. Emond,et al.  Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria , 2005, Science.

[7]  C. McMahan,et al.  Senescent terminal weight loss in the male F344 rat. , 2003, American journal of physiology. Regulatory, integrative and comparative physiology.

[8]  H. Imai,et al.  Mitochondrial Phospholipid Hydroperoxide Glutathione Peroxidase Suppresses Apoptosis Mediated by a Mitochondrial Death Pathway* , 1999, The Journal of Biological Chemistry.

[9]  P. Tsao,et al.  Cardiomyocyte-specific Bcl-2 overexpression attenuates ischemia-reperfusion injury, immune response during acute rejection, and graft coronary artery disease. , 2004, Blood.

[10]  J. Curtsinger,et al.  Why do life spans differ? Partitioning mean longevity differences in terms of age-specific mortality parameters. , 2000, The journals of gerontology. Series A, Biological sciences and medical sciences.

[11]  T. Montine,et al.  Formation of Isoprostane-like Compounds (Neuroprostanes) in Vivo from Docosahexaenoic Acid* , 1998, The Journal of Biological Chemistry.

[12]  F. Antunes,et al.  PHGPx and phospholipase A2/GPx: comparative importance on the reduction of hydroperoxides in rat liver mitochondria. , 1995, Free radical biology & medicine.

[13]  V. Bohr,et al.  DNA damage, mutation and fine structure DNA repair in aging. , 1995, Mutation research.

[14]  A. Girotti,et al.  Role of mitochondrial cardiolipin peroxidation in apoptotic photokilling of 5-aminolevulinate-treated tumor cells. , 2005, Archives of biochemistry and biophysics.

[15]  A. J. Lambert,et al.  Effect of ageing and caloric restriction on specific markers of protein oxidative damage and membrane peroxidizability in rat liver mitochondria , 2004, Mechanisms of Ageing and Development.

[16]  H. Imai,et al.  Biological significance of phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) in mammalian cells. , 2003, Free radical biology & medicine.

[17]  B. Yu,et al.  Modulation of membrane phospholipid fatty acid composition by age and food restriction. , 1993, Gerontology.

[18]  J. Morrow,et al.  Isoprostanes. Novel markers of endogenous lipid peroxidation and potential mediators of oxidant injury. , 1994, Annals of the New York Academy of Sciences.

[19]  C. Epstein,et al.  Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. , 2003, Physiological genomics.

[20]  G. Stark,et al.  Functional Consequences of Oxidative Membrane Damage , 2005, The Journal of Membrane Biology.

[21]  G. Basso,et al.  Induction of apoptosis by photoexcited tetracyclic compounds derivatives of benzo[b]thiophenes and pyridines. , 2006, Journal of photochemistry and photobiology. B, Biology.

[22]  F. Ursini,et al.  The role of selenium peroxidases in the protection against oxidative damage of membranes. , 1987, Chemistry and physics of lipids.

[23]  Freya Q. Schafer,et al.  Phospholipid hydroperoxide glutathione peroxidase protects against singlet oxygen-induced cell damage of photodynamic therapy. , 2001, Free radical biology & medicine.

[24]  A. Girotti,et al.  Hyperresistance to cholesterol hydroperoxide-induced peroxidative injury and apoptotic death in a tumor cell line that overexpresses glutathione peroxidase isotype-4. , 2001, Free radical biology & medicine.

[25]  Jason G. Belter,et al.  The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. , 2003, Free radical biology & medicine.

[26]  Martin Holzenberger,et al.  IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice , 2003, Nature.

[27]  J. Petit,et al.  Specific interaction of the new fluorescent dye 10‐N‐nonyl acridine orange with inner mitochondrial membrane , 1990, FEBS letters.

[28]  H. Imai,et al.  Mitochondrial phospholipid hydroperoxide glutathione peroxidase inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycaemia-induced apoptosis. , 2000, The Biochemical journal.

[29]  M. Saito,et al.  Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene. , 2003, Biochemical and biophysical research communications.

[30]  C. Franceschi,et al.  Cell proliferation, cell death and aging , 1989, Aging.

[31]  J. Cailhier,et al.  Apoptosis in glomerulonephritis. , 2004, Rheumatic diseases clinics of North America.

[32]  F. Mannello,et al.  Melatonin reduces early changes in intramitochondrial cardiolipin during apoptosis in U937 cell line. , 2007, Toxicology in vitro : an international journal published in association with BIBRA.

[33]  J. A. Vale,et al.  Mechanisms of Toxicity, Clinical Features, and Management of Diquat Poisoning: A Review , 2000, Journal of toxicology. Clinical toxicology.

[34]  A. Richardson,et al.  Glutathione peroxidase 4 protects cortical neurons from oxidative injury and amyloid toxicity , 2006, Journal of neuroscience research.

[35]  D. Ceccarelli,et al.  Use of the fluorescent dye 10-N-nonyl acridine orange in quantitative and location assays of cardiolipin: a study on different experimental models. , 2004, Analytical biochemistry.

[36]  N. Porter,et al.  Mechanisms of free radical oxidation of unsaturated lipids , 1995, Lipids.

[37]  Matthias Blüher,et al.  Extended Longevity in Mice Lacking the Insulin Receptor in Adipose Tissue , 2003, Science.

[38]  J. Ward,et al.  Pathology of Aging B6;129 Mice , 2001, Toxicologic pathology.

[39]  M. Portero-Otín,et al.  Oxidative, glycoxidative and lipoxidative damage to rat heart mitochondrial proteins is lower after 4 months of caloric restriction than in age-matched controls , 2002, Mechanisms of Ageing and Development.

[40]  Qing Zhao,et al.  Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors , 2005, Nature chemical biology.

[41]  R. Pamplona,et al.  Is the mitochondrial free radical theory of aging intact? , 2006, Antioxidants & redox signaling.

[42]  H. Remmen,et al.  Effects of Age and Caloric Restriction on Lipid Peroxidation : Measurement of Oxidative Stress by F 2-Isoprostane Levels , 2005 .

[43]  R. Bronson,et al.  Delayed occurrence of fatal neoplastic diseases in ames dwarf mice: correlation to extended longevity. , 2003, The journals of gerontology. Series A, Biological sciences and medical sciences.

[44]  R. Brigelius-Flohé.  Tissue-specific functions of individual glutathione peroxidases. , 1999, Free radical biology & medicine.

[45]  P. Pelicci,et al.  Apoptosis and aging: role of p66Shc redox protein. , 2006, Antioxidants & redox signaling.

[46]  Jake Jacobson,et al.  Intracellular distribution of the fluorescent dye nonyl acridine orange responds to the mitochondrial membrane potential: implications for assays of cardiolipin and mitochondrial mass , 2002, Journal of neurochemistry.

[47]  S. Minucci,et al.  Electron Transfer between Cytochrome c and p66Shc Generates Reactive Oxygen Species that Trigger Mitochondrial Apoptosis , 2005, Cell.

[48]  Amy N Holland,et al.  Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. , 2003, Endocrinology.

[49]  A. Girotti.  Lipid hydroperoxide generation, turnover, and effector action in biological systems. , 1998, Journal of lipid research.

[50]  M. Lutter,et al.  Biochemical pathways of caspase activation during apoptosis. , 1999, Annual review of cell and developmental biology.

[51]  R. Brigelius-Flohé,et al.  Overexpression of PHGPx inhibits hydroperoxide-induced oxidation, NFkappaB activation and apoptosis and affects oxLDL-mediated proliferation of rabbit aortic smooth muscle cells. , 2000, Atherosclerosis.

[52]  W. Bradley,et al.  Cytochrome c Association with the Inner Mitochondrial Membrane Is Impaired in the CNS of G93A-SOD1 Mice , 2005, The Journal of Neuroscience.

[53]  Animesh Nandi,et al.  Suppression of Aging in Mice by the Hormone Klotho , 2005, Science.

[54]  Pier Paolo Pandolfi,et al.  The p66shc adaptor protein controls oxidative stress response and life span in mammals , 1999, Nature.

[55]  F. V. van Kuijk,et al.  Consecutive action of phospholipase A2 and glutathione peroxidase is required for reduction of phospholipid hydroperoxides and provides a convenient method to determine peroxide values in membranes. , 1985, Journal of free radicals in biology & medicine.

[56]  Arlan Richardson,et al.  Genetic mouse models of extended lifespan , 2003, Experimental Gerontology.

[57]  H. Warner.  Apoptosis: a two-edged sword in aging. , 1999, Anticancer research.

[58]  G. Paradies,et al.  Role of Reactive Oxygen Species and Cardiolipin in the Release of Cytochrome C from Mitochondria , 2022 .

[59]  T. Prolla,et al.  Embryonic fibroblasts from Gpx4+/- mice: a novel model for studying the role of membrane peroxidation in biological processes. , 2003, Free radical biology & medicine.

[60]  A Turturro,et al.  Normal mouse and rat strains as models for age-related cataract and the effect of caloric restriction on its development. , 2000, Experimental eye research.

[61]  R. Weinberg,et al.  Tumor spectrum analysis in p53-mutant mice , 1994, Current Biology.

[62]  J. Nelson,et al.  Housing density does not influence the longevity effect of calorie restriction. , 2005, The journals of gerontology. Series A, Biological sciences and medical sciences.

[63]  H. Warner,et al.  Superoxide dismutase, aging, and degenerative disease. , 1994, Free radical biology & medicine.

[64]  A. Richardson,et al.  Transgenic Mice Overexpressing Glutathione Peroxidase 4 Are Protected against Oxidative Stress-induced Apoptosis* , 2004, Journal of Biological Chemistry.