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. 2016 Dec;10:251-256.
doi: 10.1016/j.redox.2016.10.012. Epub 2016 Oct 25.

Effects of Transgenic Methionine Sulfoxide Reductase A (MsrA) Expression on Lifespan and Age-Dependent Changes in Metabolic Function in Mice

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Free PMC article

Effects of Transgenic Methionine Sulfoxide Reductase A (MsrA) Expression on Lifespan and Age-Dependent Changes in Metabolic Function in Mice

Adam B Salmon et al. Redox Biol. .
Free PMC article

Abstract

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.

Keywords: Longevity; Metabolism; Oxidative stress; Proteostasis; Redox.

Figures

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Fig. 1
Fig. 1
Increased MsrA in the cytosol slows the rate of aging A. Gompertz slopes calculated across lifespan for Control (solid line), TgCyto MsrA (dashed line) and TgMito MsrA (dotted line). For each line, (slope, x-intercept) are as follows: control (0.01, −13.93), TgCyto MsrA (0.0062, −10.51), TgMito MsrA (0.0092, −13.22). B. Log Rank survival curve for Control (closed circle), TgCyto MsrA (open square) and TgMito MsrA (open triangle) female mice. Each symbol represents the natural death of an individual mouse.
Fig. 2
Fig. 2
MsrA and MsrB1 expression changes with age and transgenic expression. A. Representative immunoblot of kidney and muscle of young (6–9 months) and old (24–30 months) control (Co), TgCyto MsrA (TgC) and TgMito MsrA (TgM) mice. B. Quantification of proteins measure in A. Bars indicated mean protein level for indicated group; error bars indicated standard error.
Fig. 3
Fig. 3
Age, but not transgenic MsrA expression, alters body composition. Body weight, fat mass and fat-free mass from young (6–9 months) and old (24–30 months) control, TgCyto MsrA and TgMito MsrA mice. Bars indicate mean values (±standard error) for indicated measurements. Asterisks indicate significant effect of age.
Fig. 4
Fig. 4
Mitochondrial-, but not cytosolic-, targeted MsrA overexpression improves insulin sensitivity in old mice. A. Insulin tolerance tests and calculated areas under curves. B. Glucose tolerance tests and calculated areas under curve. For both, each symbol represents mean value (±standard error) for Control (closed circle), TgCyto MsrA (open square) and TgMito MsrA (open triangle) female mice for indicated tests. Bars indicate mean values (±standard error) for indicated measurements. Asterisk indicates significant effect of genotype.
Fig. 5
Fig. 5
Scheme of the major conclusions from this study.

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