title: Mitochondrial-targeted catalase is good for the old mouse proteome, but not for the young: 'reverse' antagonistic pleiotropy?
abstract: Reactive oxygen species (ROS) are highly reactive oxygen-containing molecules associated with aging and a broad spectrum of pathologies. We have previously shown that transgenic expression of the antioxidant enzyme catalase targeted to the mitochondria (mCAT) in mice reduces ROS, attenuates age-related disease, and increases lifespan. However, it has been increasingly recognized that ROS also has beneficial roles in signaling, hormesis, stress response, and immunity. We therefore hypothesized that mCAT might be beneficial only when ROS approaches pathological levels in older age and might not be advantageous at a younger age when basal ROS is low. We analyzed abundance and turnover of the global proteome in hearts and livers of young (4 month) and old (20 month) mCAT and wild-type (WT) mice. In old hearts and livers of WT mice, protein half-lives were reduced compared to young, while in mCAT mice the reverse was observed; the longest half-lives were seen in old mCAT mice and the shortest in young mCAT. Protein abundance of old mCAT hearts recapitulated a more youthful proteomic expression profile (P-value < 0.01). However, young mCAT mice partially phenocopied the older wild-type proteome (P-value < 0.01). Age strongly interacts with mCAT, consistent with antagonistic pleiotropy in the reverse of the typical direction. These findings underscore the contrasting roles of ROS in young vs. old mice and indicate the need for better understanding of the interaction between dose and age in assessing the efficacy of therapeutic interventions in aging, including mitochondrial antioxidants.
authors.affiliation: Department of Pathology, University of Washington, 1959 NE Pacific Ave, Seattle, WA, 98195, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Basisty
authors.affiliation: Department of Pathology, University of Washington, 1959 NE Pacific Ave, Seattle, WA, 98195, USA.
authors.forename: Dao-Fu
authors.initials: DF
authors.lastname: Dai
authors.affiliation: Department of Pathology, University of Washington, 1959 NE Pacific Ave, Seattle, WA, 98195, USA.
authors.forename: Arni
authors.initials: A
authors.lastname: Gagnidze
authors.affiliation: Department of Pathology, University of Washington, 1959 NE Pacific Ave, Seattle, WA, 98195, USA.
authors.forename: Lemuel
authors.initials: L
authors.lastname: Gitari
authors.affiliation: Department of Pathology, University of Washington, 1959 NE Pacific Ave, Seattle, WA, 98195, USA.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Fredrickson
authors.affiliation: Department of Pathology, University of Washington, 1959 NE Pacific Ave, Seattle, WA, 98195, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Maina
authors.affiliation: Department of Environmental Health, University of Washington, 1959 NE Pacific Ave, Seattle, WA, 98195, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Beyer
authors.affiliation: Department of Biostatistics, University of Washington, 1959 NE Pacific Ave, Seattle, WA, 98195, USA.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Emond
authors.affiliation: Department of Genome Sciences, University of Washington, 1959 NE Pacific Ave, Seattle, WA, 98195, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hsieh
authors.affiliation: Department of Genome Sciences, University of Washington, 1959 NE Pacific Ave, Seattle, WA, 98195, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: MacCoss
authors.affiliation: Department of Pathology, University of Washington, 1959 NE Pacific Ave, Seattle, WA, 98195, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Martin
authors.affiliation: Department of Pathology, University of Washington, 1959 NE Pacific Ave, Seattle, WA, 98195, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002374:Catalase / Q000378:metabolism*; D058685:Genetic Pleiotropy; D006207:Half-Life; D008099:Liver / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D020543:Proteome / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D020543:Proteome; C108078:catalase I; D002374:Catalase
keywords: aging; antagonistic pleiotropy; catalase; mitochondria; protein turnover; reactive oxygen species