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A Role for Sirtuins in Maintaining Mammalian Lifespan and Healthspan

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A Role for Sirtuins in Maintaining Mammalian Lifespan and Healthspan A Role for Sirtuins in Maintaining Mammalian Lifespan and Healthspan by William J. Giblin, Jr. A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Human Genetics) in the University of Michigan 2017 Doctoral Committee: Associate Professor David B. Lombard, Co-Chair Associate Professor JoAnn M. Sekiguchi, Co-Chair Associate Professor Yali Dou Assistant Professor Shigeki Iwase Associate Professor Sundeep Kalantry William J. Giblin, Jr. [email protected] ORCID iD: 0000-0001-5247-7802 © William J. Giblin, Jr. 2017 DEDICATION I dedicate this thesis to Sgt. Timothy R. Giblin and Roy E. Wareham. Thank you for your strength and sacrifice. ii ACKNOWLEDGEMENTS I have many people to thank who have helped and supported me during my graduate career. First, I’d like to thank my thesis advisor, Dr. David Lombard. Dave is a great mentor, and I have felt he has always treated me as colleague. He has great optimism and is always excited about almost every result, big or small, positive or negative – you can learn from every experiment. This was a nice counter to my less- than-optimistic perspective on many experiments I’ve presented at lab meetings. Dave has also been invested in my career development, in that he would always arrange for me to meet, host, or lunch with the many, many speakers he has invited to the university, which allowed me to network, but also to gain outside perspective about my research. Second, I’d like to thank my second committee co-chair, Dr. JoAnn Sekiguchi. I have known JoAnn for several years, and when I’m complimented on my technical capabilities at the research bench, I often credit her, as she was my first mentor in an academic research lab. Her mentorship laid the groundwork for me to be able to become an independent research scientist. I also want to thank the other members of my thesis committee, Dr. Yali Dou, Dr. Shigeki Iwase, and Dr. Sundeep Kalantry for their useful suggestions, patience, support and at times, collaborations during these years. I would also like to acknowledge the Human Genetics faculty and administrative staff, in particular, Karen Grahl, who is the iii first point of contact when students have a problem or issue, and Susan Kellogg for all her help. I also thank Reynetta Fath, who organizes the Geriatrics Seminars and Symposia. I also must thank the entire Lombard lab, past and present for your friendship, support and tolerance. I would like to specifically thank a very talented undergraduate, Michelle Azar, who has worked with me since I started my work in the Lombard lab, and will be attending graduate school next year. I have made many, many friends during my extended stay in Michigan. I’d like to thank all of you, in no particular order: Sandy, Jennie, Cheryl, Scout, Betsy, Chris, Huira, Mary, Andrew, Carie, Brain, Lauren, Gonzalo, Matt, Adam, Heather, Nicole, Surinder, Martina, Donna, Mike, Tamar, Andrej, Kylie, Bernadette, Ali, Michelle, Jessica, Angela, Emmalee, Bebo, Haya, and probably others (sorry). Thanks for your support. I also must thank my family. I have a very large extended family, so suffice it to say, thank you for your love and support. I am grateful for my funding throughout the years as well. I have been supported by the Human Genetics Training Grant T32-GM07544, the Biomedical Research Training in the Biology of Aging Award T32-AG000114, and the Rackham Merit Fellowship. iv TABLE OF CONTENTS DEDICATION....................................................................................................................ii ACKNOWLEDGEMENTS................................................................................................iii LIST OF FIGURES..........................................................................................................vii LIST OF TABLES.............................................................................................................ix LIST OF ABBREVIATIONS..............................................................................................x ABSTRACT....................................................................................................................xiv CHAPTER 1: Sirtuins as Guardians of Mammalian Lifespan and Healthspan Abstract..................................................................................................................1 Introduction............................................................................................................1 Sirtuin-driven Lifespan Extension in Invertebrates.................................................3 Sirtuin Enzymatic Activity.......................................................................................7 Sirtuins and Mammalian Longevity......................................................................13 Sirtuins as Modulators of Responses to Caloric Restriction................................22 Roles for Sirtuins in Diverse Disease States.......................................................29 Sirtuin Activating Compounds..............................................................................45 Conclusion...........................................................................................................48 Acknowledgements..............................................................................................55 v CHAPTER 2: Age-Associated Epigenetic Dysregulation in Mouse Heart Abstract................................................................................................................56 Introduction..........................................................................................................57 Results.................................................................................................................60 Discussion............................................................................................................80 Materials and Methods.........................................................................................84 Acknowledgements..............................................................................................90 CHAPTER 3: SIRT5 is a Pro-Survival Factor in Human Melanoma Abstract................................................................................................................91 Introduction..........................................................................................................92 Results.................................................................................................................95 Discussion..........................................................................................................123 Materials and Methods.......................................................................................126 Acknowledgements............................................................................................135 CHAPTER 4: Future Directions Overview............................................................................................................137 Future Directions................................................................................................138 Summary............................................................................................................142 REFERENCES.............................................................................................................144 vi LIST OF FIGURES Figure 1.1 Sirtuins are NAD+ dependent enzymes...........................................................3 Figure 1.2 Sirtuin subcellular localization.......................................................................10 Figure 1.3 Lifespan extension in brain-specific Sirt1 transgenic mice............................16 Figure 1.4 Global SIRT6 overexpression increases the lifespan of male mice..............20 Figure 1.5 Summary of sirtuin involvement in inhibiting age-related pathology..............29 Figure 1.6 Means of sirtuin modulation...........................................................................50 Figure 2.1 MSR silencing is lost during aging in cardiac tissue......................................61 Figure 2.2 MSR expression is increased specifically in the aged myocardium..............62 Figure 2.3 MSR expression is restricted to the heart in 30-month-old mice...................63 Figure 2.4 Loss of SUV39H-mediated MSR silencing is molecularly distinct from age- associated MSR derepression........................................................................................66 Figure 2.5 5-Hydroxymethylcytosine is increased in aged heart tissue..........................69 Figure 2.6 Loss of SIRT1, but not other nuclear sirtuins, promotes MSR expression....71 Figure 2.7 SIRT1 and SUV39H1 protein levels remain constant with age.....................72 Figure 2.8 Calorie restriction suppresses MSR expression in aged heart......................74 Figure 2.9 NAMPT overexpression does not alleviate MSR derepression.....................75 Figure 2.10 NMN supplementation does not silence MSR expression...........................76 Figure 2.11 SIRT1 overexpression partially rescues MSR derepression in aged heart................................................................................................................................78 vii Figure 2.12 Analysis of global histone PTMs in aged mouse myocardium....................79 Figure 3.1 SIRT5 is amplified in human melanoma........................................................95 Figure 3.2 Reduced survival when SIRT5 is amplified
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