Effects of transgenic methionine sulfoxide reductase A (MsrA) expression on lifespan and age-dependent changes in metabolic function in mice.
Mechanisms that preserve and maintain the cellular proteome are associated with long life and healthy aging. Oxidative damage is a significant contributor to perturbation of proteostasis and is dealt with by the cell through regulation of antioxidants, protein degradation, and repair of oxidized amino acids. Methionine sulfoxide reductase A (MsrA) repairs oxidation of free- and protein-bound methionine residues through enzymatic reduction and is found in both the cytosol and the mitochondria. Previous studies in Drosophila have shown that increasing expression of MsrA can extend longevity. Here we test the effects of increasing MsrA on longevity and healthy aging in two transgenic mouse models. We show that elevated expression of MsrA targeted specifically to the cytosol reduces the rate of age-related death in female mice when assessed by Gompertz analysis. However, neither cytosolic nor mitochondrial MsrA overexpression extends lifespan when measured by log-rank analysis. In mice with MsrA overexpression targeted to the mitochondria, we see evidence for improved insulin sensitivity in aged female mice. With these and our previous data, we conclude that the increasing MsrA expression in mice has differential effects on aging and healthy aging that are dependent on the target of its subcellular localization.
Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA; The Sam and Ann Barshop Institute for Longevity and Aging Studies and Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. Electronic address: salmona@uthscsa.edu.
Adam B
AB
Salmon
Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
Geumsoo
G
Kim
Transgenic Core, National Heart, Lung and Blood Institute, Bethesda, MD, USA.
Chengyu
C
Liu
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Jonathan D
JD
Wren
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Constantin
C
Georgescu
Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center and Oklahoma City VA Medical Center, Oklahoma, OK, USA.
Arlan
A
Richardson
Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, Bethesda, MD, USA. Electronic address: rlevine@nih.gov.
Rodney L
RL
Levine
D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003600:Cytosol / Q000378:metabolism*; D005260:Female; D007333:Insulin Resistance / Q000235:genetics*; D008136:Longevity; D008297:Male; D008715:Methionine / Q000378:metabolism; D051150:Methionine Sulfoxide Reductases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D023421:Models, Animal; D018384:Oxidative Stress
D008715:Methionine; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase
Longevity; Metabolism; Oxidative stress; Proteostasis; Redox