Mitochondrial-targeted catalase is good for the old mouse proteome, but not for the young: 'reverse' antagonistic pleiotropy?

Nathan Basisty,Arni Gagnidze,Dao‐Fu Dai,Peter S Rabinovitch,Edward J Hsieh,Mary J Emond,George M Martin,Yvonne Maina,Michael J Maccoss,Richard P Beyer,Lemuel Gitari,Jeanne Fredrickson

doi:10.1111/acel.12472

Abstract

SummaryReactive 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.

Highlights

Reactive oxygen species (ROS) are associated with the progression of a broad spectrum of pathologies including aging (Harman, 1956), neurodegeneration, metabolic syndrome (Fisher-Wellman & Neufer, 2012; Dodson et al, 2013), heart disease (Dai et al, 2013; Wohlgemuth et al, 2014), cancer, and others (Brieger et al, 2012)
Given that oxidative modifications can impair the activity of macromolecules, and the well-documented correlation between oxidative damage and aging reported in almost all models studied, it has been tempting to conclude that this is a likely mechanism for aging (Bokov et al, 2004)
While mtDNA mutations increase with age, the characteristic mutations created by ROS are not among those most seen by the new method of duplex sequencing, suggesting that ROS may not be a driver of somatic mutations in aging (Itsara et al, 2014)

Summary

Introduction

Reactive oxygen species (ROS) are associated with the progression of a broad spectrum of pathologies including aging (Harman, 1956), neurodegeneration, metabolic syndrome (Fisher-Wellman & Neufer, 2012; Dodson et al, 2013), heart disease (Dai et al, 2013; Wohlgemuth et al, 2014), cancer, and others (Brieger et al, 2012) This has largely been attributed to oxidative modification of cellular macromolecules, including lipids (Arai, 2014), DNA (Lee et al, 2010a), and proteins (Forman et al, 2014). In C elegans, an invertebrate model of aging, several strains deficient in respiratory proteins that produce excess reactive oxygen species are longer lived than WT controls (Lee et al, 2010b), and ROS has been shown to be indispensable for the increased lifespan of glycolysis-deficient worms or worms on glucose restriction (Schulz et al, 2007)

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