1 3 Q1 Obesity-induced oxidative stress, accelerated functional decline with age 4 and increased mortality in mice 5 6 7 Yiqiang Zhang a,b Q2 , Kathleen E. Fischer e , Vanessa Soto a , Yuhong Liu a , Danuta Sosnowska f , 8 Arlan Richardson f , Adam B. Salmon a,c,d,⇑ 9 a The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Q3 10 b Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA 11 c Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA 12 d Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA 13 e Department of Biology, University of Alabama at Birmingham, Birmingham, AL, USA 14 f Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center and Oklahoma City VA Medical Center, Oklahoma, OK, USA 15 16 18 article info 19 Article history: 20 Received 10 September 2014 21 and in revised form 5 December 2014 22 Available online xxxx 23 Keywords: 24 Obesity 25 Rotarod 26 Longevity 27 Oxidation 28 Grip strength 29 Respirometry 30 Gait 31 32 abstract 33 Obesity is a serious chronic disease that increases the risk of numerous co-morbidities including meta- 34 bolic syndrome, cardiovascular disease and cancer as well as increases risk of mortality leading some 35 to suggest this represents accelerated aging. Obesity is associated with significant increases in oxidative 36 stress in vivo and, despite the well-explored relationship between oxidative stress and aging, the role this 37 plays in the increased mortality of obese subjects remains an unanswered question. Here, we addressed 38 this by undertaking a comprehensive, longitudinal study of a group of high fat-fed obese mice and 39 assessed both their changes in oxidative stress and in their performance in physiological assays known 40 to decline with aging. In female C57BL/6J mice fed a high-fat diet starting in adulthood, mortality was 41 significantly increased in high fat-fed mice as was oxidative damage in vivo. High fat-feeding significantly 42 accelerated the decline in performance in several assays, including activity, gait, and rotarod. However, 43 we also found that obesity had little effect on other markers and actually improved performance in grip 44 strength, a marker of muscular function. Together, this first comprehensive assessment of longitudinal 45 functional changes in high fat-fed mice suggests that obesity may induce segmental acceleration of some 46 of the aging process. 47 Ó 2015 Published by Elsevier Inc. 48 49 50 51 Introduction 52 The prevalence of obesity among all age groups in the US pop- 53 ulation has risen dramatically over the last few decades due in part 54 to increased sedentary behavior and availability of high calorie 55 food choices [1,2]. Without intervention, a large proportion of this 56 population will be obese (defined as BMI P30) for a significant 57 proportion of their lives. That is, people are living longer with obes- 58 ity and are thus subject to increased incidences of the numerous 59 co-morbidities associated with this condition. Obese subjects are 60 at an elevated risk of early mortality likely due to dramatic 61 increases in the occurrence and severity of chronic illnesses such 62 as cardiovascular disease, diabetes, and cancer among this group 63 [3–5]. Interestingly, the spectrum of diseases that are exacerbated 64 by obesity are relatively similar to those that increase in preva- 65 lence with normal aging. Further, the deterioration and pathology 66 of organs that occurs with chronic obesity is in many ways similar 67 to that which occurs in normal aging leading some to suggest that 68 chronic obesity accelerates the aging process. 69 There is substantial evidence that elevated oxidative stress 70 mediates the progression of many of the comorbidities associated 71 with obesity. The expansion of adipose tissue is linked with an 72 increased production of reactive oxygen species (ROS) 1 in both 73 human and rodent models through various mechanisms [6,7]. More- 74 over, the production and secretion of inflammatory adipokines from 75 adipose tissue under metabolic stress promotes a positive feedback 76 loop further exacerbating oxidative stress both in this tissue and 77 throughout the body [8,9]. The accumulation of oxidative stress is http://dx.doi.org/10.1016/j.abb.2014.12.018 0003-9861/Ó 2015 Published by Elsevier Inc. ⇑ Corresponding author at: 15355 Lambda Drive, San Antonio, TX 78245-3207, USA. Fax: +1 (210) 562 6110. E-mail address: salmona@uthscsa.edu (A.B. Salmon). 1 Abbreviations used: ROS, reactive oxygen species; QMRi, Quantitative Magnetic Resonance imaging; 4-HNE, 4-hydroxynonenal; RQ, respiratory quotient; RMR, resting metabolic rate. Archives of Biochemistry and Biophysics xxx (2015) xxx–xxx Contents lists available at ScienceDirect Archives of Biochemistry and Biophysics journal homepage: www.elsevier.com/locate/yabbi YABBI 6857 No. of Pages 10, Model 5G 3 January 2015 Please cite this article in press as: Y. Zhang et al., Arch. Biochem. Biophys. (2015), http://dx.doi.org/10.1016/j.abb.2014.12.018