title: A new role for oxidative stress in aging: The accelerated aging phenotype in Sod1-/-mice is correlated to increased cellular senescence.
abstract: In contrast to other mouse models that are deficient in antioxidant enzymes, mice null for Cu/Zn-superoxide dismutase (Sod1-/-mice) show a major decrease in lifespan and several accelerated aging phenotypes. The goal of this study was to determine if cell senescence might be a contributing factor in the accelerated aging phenotype observed in the Sod1-/-mice. We focused on kidney because it is a tissue that has been shown to a significant increase in senescent cells with age. The Sod1-/-mice are characterized by high levels of DNA oxidation in the kidney, which is attenuated by DR. The kidney of the Sod1-/-mice also have higher levels of double strand DNA breaks than wild type (WT) mice. Expression (mRNA and protein) of p16 and p21, two of the markers of cellular senescence, which increased with age, are increased significantly in the kidney of Sod1-/-mice as is β-gal staining cells. In addition, the senescence associated secretory phenotype was also increased significantly in the kidney of Sod1-/-mice compared to WT mice as measured by the expression of transcripts for IL-6 and IL-1β. Dietary restriction of the Sod1-/-mice attenuated the increase in DNA damage, cellular senescence, and expression of IL-6 and IL-1β. Interestingly, the Sod1-/-mice showed higher levels of circulating cytokines than WT mice, suggesting that the accelerated aging phenotype shown by the Sod1-/-mice could result from increased inflammation arising from an accelerated accumulation of senescent cells. Based on our data with Sod1-/-mice, we propose that various bouts of increased oxidative stress over the lifespan of an animal leads to the accumulation of senescent cells. The accumulation of senescent cells in turn leads to increased inflammation, which plays a major role in the loss of function and increased pathology that are hallmark features of aging.
authors.affiliation: Greehy Children's Cancer Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Geriatric Medicine and the Reynolds Oklahoma Center on Aging, Oklahoma University Health Science Center, Oklahoma City, OK, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Unnikrishnan
authors.affiliation: Department of Geriatric Medicine and the Reynolds Oklahoma Center on Aging, Oklahoma University Health Science Center, Oklahoma City, OK, USA.
authors.forename: Sathyaseelan S
authors.initials: SS
authors.lastname: Deepa
authors.affiliation: Departments of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Departments of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Departments of Pathology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Geriatric Research, Education and Clinical Center (GRECC), South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikeno
authors.affiliation: Department of Geriatric Medicine and the Reynolds Oklahoma Center on Aging, Oklahoma University Health Science Center, Oklahoma City, OK, USA.
authors.forename: Danuta
authors.initials: D
authors.lastname: Sosnowska
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Oklahoma City VA Medical Center, Oklahoma City, OK, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Van Remmen
authors.affiliation: Department of Geriatric Medicine and the Reynolds Oklahoma Center on Aging, Oklahoma University Health Science Center, Oklahoma City, OK, USA; Oklahoma City VA Medical Center, Oklahoma City, OK, USA. Electronic address: Arlan-richardson@ouhsc.edu.
authors.forename: Arlan
authors.initials: A
authors.lastname: Richardson
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology; D000818:Animals; D016922:Cellular Senescence / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D000072105:Superoxide Dismutase-1 / Q000235:genetics*; D054462:p21-Activated Kinases / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; C577686:interleukin-6, mouse; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases
keywords: Aging; Cellular senescence; DNA damage; Dietary restriction; Inflammation; Oxidative stress; Superoxide dismutase