The Paul F. Glenn/Afar Conference on the Biology of Aging the 31St Annual Afar Grantee Conference

THE PAUL F. GLENN/AFAR CONFERENCE ON THE BIOLOGY OF AGING THE 31ST ANNUAL AFAR GRANTEE CONFERENCE

JUNE 4 – 6, 2018 Four Seasons Resort The Biltmore Santa Barbara, CA

#AFAR2018 @AFARorg

MONDAY, JUNE 4

3:30 - 4:00 p.m. Registration/reception Alto

4:00 – 4:10 p.m. Welcome El Mar Stephanie Lederman Executive Director American Federation for Aging Research

David Sinclair, PhD (2000 AFAR Grantee) Board Member, American Federation for Aging Research Professor, Department of Genetics Co-director, Paul F. Glenn Center for Biology of Aging Research Harvard Medical School

4:10 – 5:10 p.m. Breakthroughs in Gerontology (BIG) and Midcareer Presentations Targeting Mitochondrial Redox Stress to Improve In Vivo Energetics and Exercise Performance with Age David Marcinek, PhD (2015 BIG Awardee) Associate Professor of Radiology University of Washington

Cellular Recycling: Role of Autophagy in Aging and Disease. Malene Hansen, PhD (2014 Midcareer Awardee, 2005 Ellison/AFAR Postdoc, 2010 AFAR Grantee) Associate Dean of Student Affairs, SBP Graduate School Faculty Advisor for Postdoctoral Training Professor, Program of Development, Aging and Regeneration Sanford Burnham Prebys Medical Discovery Institute, La Jolla 5:10 – 5:30 p.m. Break

5:30 – 6:00 p.m. Mitochondrial Energetics and Aging: Lessons From Serendipity in Science Peter Rabinovitch, MD, PhD (2010 BIG Awardee) Professor and Vice Chair of Research University of Washington

6:00 – 6:30 p.m. Targeting Healthspan: Functional Genetic Variation in Human Aging and Longevity Yousin Suh, PhD Professor of Genetics and Medicine Albert Einstein College of Medicine

6:30 – 7:00 p.m. Questioning the Immutability of Aging David Sinclair, PhD (2000 AFAR Grantee) Professor, Department of Genetics Co-director, Paul F. Glenn Center for Biology of Aging Research Harvard Medical School

7:00 – 8:30 p.m. Dinner El Mar

8:30 – 9:30 p.m. Social gathering, with dessert, coffee and wine Alto

TUESDAY, JUNE 5 THE NINTH ANNUAL GLENN WORKSHOP ON THE BIOLOGY OF AGING BACK TO BASICS: EXPLAINING THE OBVIOUS Joint meeting with the AFAR Grantee Conference and Glenn Workshop participants

Moderator: Kevin Lee, PhD

7:30 – 8:15 a.m. Breakfast La Marina

8:30 – 8:40 a.m. Welcome and Opening Remarks La Veranda Kevin Lee, PhD Senior Scientiﬁ c & Programmatic Advisor Glenn Foundation for Medical Research

8:40 – 9:00 a.m. How Do You Explain Aging? Mark Collins (Longest Serving AFAR Board Member) President Glenn Foundation for Medical Research

9:00 – 9:40 a.m. Primary Prevention With a Captial P Jay Olshansky, PhD Professor, School of Public Health University of Illinois at Chicago

9:40 – 10:20 a.m. Sex Differences as an Investigative Tool in Aging Research Steven Austad, PhD Distinguished Professor, Department Chair Department of Biology Director, Nathan Shock Center of Excellence in the Basic Biology of Aging University of Alabama, Birmingham 10:20 – 10:50 a.m. Break

10:50 – 11:30 a.m. Dissecting Sex Differences in Aging and Neurodegenerative Disease Dena Dubal, MD, PhD (2015 AFAR Grantee, 1998 Glenn Scholar, 2009 Beeson Scholar) Associate Professor, David A. Coulter Endowed Chair in Aging and Neurological Disease Department of Neurology and Weill Institute for Neurosciences University of California, San Francisco

11:30 a.m.– 12:10 p.m. Aging: Sex Differences in Vulnerability To and Resilience Against Alzheimer’s Disease Roberta Diaz Brinton, PhD Director, UA Center for Innovation in Brain Science, Professor, Department of Pharmocology and Neurology Professor Psychology and Evelyn F. McKnight Brain Institute University of Arizona Health Sciences

12:10 – 1:10 p.m. Lunch Palmera Garden

1:10 – 1:50 p.m. Is “Time-Restricted Eating” a Practical Framework Integrating Circadian Rhythms, Nutrient Sensing, and Energy Homeostasis to Increase Healthy Lifespan? Satchindananda Panda, PhD (2014 Midcareer Awardee) Professor, Regulatory Biological Laboratory Salk Institute for Biological Studies

1:50 – 2:30 p.m. Systems Genetics Identiﬁ es Resilience Factors in Normal Cognitive Aging and Alzheimer’s Catherine Kaczorowski, PhD (2014 New Investigator In Alzheimer’s Disease) Associate Professor Evnin Family Endowed Chair in Alzheimer’s Research The Jackson Laboratory

2:30 – 2:50 a.m. Break

2:50 – 3:30 p.m. Cholesterol Homeostasis in Aging and Disease Raj Apte, MD, PhD (2005 AFAR Grantee, 2012 BIG Awardee) Paul A. Cibis Distinguished Professor of Ophthalmology Professor of Developmental Biology and Medicine Director of Translational Research and Jeffrey Fort Innovation Fund Washington University School of Medicine

3:30 – 5:30 p.m. Poster Session Loggia Ballroom Kindly remove your poster at the conclusion of the session.

6:00 – 7:00 p.m. Reception La Pacifi ca Terrace 7:00 – 9:00 p.m. Dinner La Pacifi ca Science in the Age of Celebrity Timothy Caulfi eld, LLM, FRSC, FCAHS Canada Research Chair in Health Law & Policy Trudeau Fellow and Professor, Faculty of Law and School of Public Health Research Director, Health Law Institute University of Alberta

WEDNESDAY, JUNE 6

7:30 – 9:00 a.m. Breakfast La Marina

ADJOURN

PAUL F. GLENN

Founded by Paul F. Glenn in 1965, the mission of the Glenn Founda- tion For Medical Research is to extend the healthy years of life through research on mechanisms of biology that govern normal human aging and its related physiological decline, with the objective of translating research into interventions that will extend healthspan with lifespan.

2017 Major Sponsors of AFAR Grant Programs The Glenn Foundation for Medical Research The Rosalinde and Arthur Gilbert Foundation The AFAR Board of Directors Proceeds from AFAR’s 2017 Luncheon Anonymous The James A. and Dorothy R. Brunn Foundation David W. Gore The Hearst Foundation, Inc. Diana Jacobs Kalman Neurosciences Education Research Foundation Diane Nixon The Irving S. Wright Endowment

Research Abstracts Table of Contents

Poster Grantee Grant Title

1 Zid, B. A RNA-binding protein phase transitions during yeast aging.

2 Zhang, H. PD Acute SS-31 treatment reverses mitochondrial dysfunction in aged cardiomyocytes

3 Xiao, R. A An essential role of the iron-sulfur cluster assembly enzyme isu-1 in aging and stress response

4 Wey, H. AD Epigenetic Dysregulation in Alzheimer’s Disease Revealed by Human Histone Deacetylase PET Imaging

5 Vermulst, M. AD Transcription errors in aging and disease

6 Unnikrishnan, A. A Effect of Dietary Restriction on Insulin Sensitivity and Metabolic Memory

7 Ucar, D. NSC The chromatin accessibility signature of aging in human blood leukocytes stems from CD8+ T cells

8 Sun, L. NSC The Generation of a Novel GH mutant Mouse Model Using the CRISPR/cas9 System

9 Sumien, N. NSC Chronic glutathione deficiency: implications for lifespan and healthspan

10 Stout, M. NSC 17α-estradiol acts through Hypothalamic Pro-opiomelanocortin Neurons to Reduce Feeding Behaviour

11 Sharma, R. NSC Caspase-2 maintains bone homeostasis by regulating osteoclast number and function

12 Sebastiano, V. A Transient non-integrative nuclear reprogramming promotes multifaceted reversal of aging in human cells

A = AFAR Research Grant for Junior Faculty AD = New Investigtor Award in Alzheimer’s Disease PD = Glenn/AFAR Postdoctoral Fellowship Program NSC = Nathan Shock Center Pilot Award AR = Arthritis and Aging Research Grant Research Abstracts Table of Contents

13 Schafer, M. PD Cellular senescence mediates fibrotic pulmonary disease

14 Saurat, N. PD Identifying novel strategies to induce age-associated damage in human pluripotent stem cell models of Alzheimer's disease

15 Rodriguez, K. NSC The influence of HSP25 overexpression on lifespan and neurodegenerative disease

16 Riddle, N. NSC Using the Loligo system to measure respiration rates in Drosophila melanogaster

17 Prahlah, V. NSC Rethinking protein homeostasis in a metazoan: A Case of Nerves?

18 Pickering, A. NSC Proteasome dysfunction, a key downstream driver of Alzheimer’s disease symptoms and progression.

19 Oddo, S. AD Necroptosis Activation in Alzheimer's Disease

20 Moussaieff, A. AD Exploring the role and regulation of phospholipids in the AD brain

21 Logan, S. NSC Astrocytic IGF-1 signaling regulates working memory, mitochondrial metabolism and amyloid-β uptake

22 Li, M. PD Uncoupling of Metabolic Health from Longevity through Genetic Alteration of Adipose Tissue Lipid-Binding Proteins

23 Leiser, S. A Serotonin signaling in stress perception and longevity

24 Lee, C. A Intergenomic Basis of Mitonuclear Regulation

25 Lamming, D. NSC Ovariectomy uncouples lifespan from metabolic health

26 Labunskyy, V. A A genetic screen identifies adaptive aneuploidy as a key mediator of ER stress resistance in yeast 27 Jergovic, M. PD Inflammatory cytokines restore the age related impairment of cytotoxic T cell priming in Listeria monocytogenes infected mice

28 Greer, E. A Transgenerational effects of hypoxia in C. elegans

29 Garratt, M. A, NSC Acarbose has sex-dependent and independent effects on mouse aging

30 Frost, B. AD Tau-induced nuclear envelope invagination causes a toxic increase in RNA export

31 Douglas, P. A Age-dependent actin phosphorylation through heat shock factor compromises intestinal barrier and drives pathogenesis

32 Diekman, B. AR The Role Of p16INK4a Expression In Cartilage Aging And Osteoarthritis Development

33 Cuddy, L. PD A novel angiotensin converting enzyme 1 mutation is associated with increased risk for Alzheimer’s disease and reduces cell survival

34 Cortes, C. NSC Enhanced skeletal muscle proteostasis as a determinant of CNS protein quality control and neural function in the aging brain

35 Chaston, J. NSC Associated microorganisms can function as methionine sources or sinks to influence Drosophila melanogaster longevity

36 Brace, L. PD Mechanisms of sexual dimorphism and mTORC1 effectors in type 2 diabetes, non-alcoholic fatty liver disease, and aging

37 Biga, P. NSC Improved Metabolic Rate by Teneurin C-terminal Associated Peptide (TCAP)-3: A Comparative Approach Across Zebrafish Life-Stages

38 Batista, L. A Progressive telomere shortening impairs human hepatocyte development and function by down-regulation of human hepatocyte nuclear factor 4a (HNF4a) 39 Bartley, J. PD Mechanisms of influenza-induced disability with aging

40 Ashpole, N. NSC Effects of Exogenous Cannabinoids on the Aging Brain

Joonhyuk Choi, Shuhao Wang, Brian M. Zid University of California San Diego, Chemistry & Biochemistry

Loss of protein homeostasis is one of the hallmarks of aging and some neurodegenerative diseases in humans, such as amyotrophic lateral sclerosis (ALS). It often manifests as the accumulation of misfolded or aggregated proteins, many of which are RNA-binding proteins. Although the aggregation of RNA-binding proteins is ubiquitous across eukaryotic organisms, its physiological implications are poorly understood. For example, it has been shown that the RNA-binding protein FUS (fused in sarcoma) aggregates in ALS patients over time, and its ability to phase transition from a liquid-like to a solid-like state may drive pathological symptoms in ALS. However, how these solid-like FUS aggregates form and how they are detrimental to cells remains elusive. To investigate a molecular mechanism by which protein aggregation affects cell physiology during aging, we are exploring the possible causes and consequences of the aggregation of RNA-binding protein in yeast as a model system. Based on our following preliminary data, we hypothesize that a phase transition of RNA-binding protein aggregates from a liquid-like to a solid-like state is detrimental to yeast cells during aging. We found that a number of RNA-binding proteins consisting of a type of stress-induced RNA-protein aggregates called processing bodies (P-bodies) undergo a primary phase transition from diffuse localization to concentrated aggregates during aging even when no external stress is present. As yeast cells aged, the portion of cells showing the aggregation of P-body proteins increased. Furthermore, many of the protein components of P- bodies were colocalized with each other during aging, but other RNA-binding proteins, such as stress granule proteins, were not localized to these age-induced P-bodies. We initially observed these phenotypes in batch culture using the mother enrichment program (MEP). Recently, we verifiedthese results in the wild type strain without using MEP in a microfluidics device that allows us to follow the formation of RNA-binding protein aggregates at the single cell level across the entire lifespan of yeast. Intriguingly, we observed what appears to be a secondary phase transition from small liquid-like aggregates in middle age to large, potentially solid-like aggregates at later cellular ages. This phenotype appears similar to FUS aggregates in human patients as yeast cells die soon after the formation of these large RNA-binding protein aggregates. To verify this hypothesis, we are trying to understand what drives the phase transitions of these RNA-binding proteins and their consequences during aging.

Poster 2

Acute SS-31 treatment reverses mitochondrial dysfunction in aged cardiomyocytes

Huiliang Zhang1, Mariya T. Sweetwyne1, Ying Ann Chiao1, Hazel Szeto2, Peter S. Rabinovitch1 1University of Washington, 2Burke Medical Research Institute

Rationale: Aging is the greatest risk factor for cardiac disease. The mitochondrial theory of aging pinpoints mitochondria as the major reactive oxygen species (ROS) production site and target of oxidative stress during aging. Previously, studies from our lab have shown that systemic 8-week treatment of aged mice with SS-31 (elamipretide), a mitochondrial targeted small peptide, improves cardiac diastolic function and myocardial performance (ms. in preparation, Chiao et al.). This study aims to investigate the mitochondrial mechanism of cardiac aging and how SS-31 protects the aging heart, especially to determine whether SS-31 is directly effective to the aged cardiomyocytes.

Methods and Results: By using Seahorse Assay on intact primary isolated cardiomyocytes, we found mitochondrial basal respiration in cells from old (24 month) mice was higher than that in young (6 month) mouse cells, however, the maximal respiration rate was without significant difference. The increased basal respiration was attributed to a higher proton leak in old cardiomyocytes (131 ± 14 in 24 month vs 94 ± 11 in young, pmol/min/800cells, n=17-35, p<0.05). Isolated cardiomyocytes from SS-31 8-week in vivo treatment (3mg/kg) mice showed that SS-31 shifted respiration to the young pattern with a decreased mitochondrial proton leak. Interestingly, acute (2 hours) in vitro treatment of the old cardiomyocytes with SS-31 in a logarithmic dose curve from 1 nM to 10 μM showed SS-31 improved mitochondrial respiration by decreased proton leak in a dose-dependent manner, starting from 10 nM and plateauing at 100 nm. Moreover, SS-31 (100 nM, 12 hrs) decreased the superoxide production as measured by ratio of MitoSOX Red to MitoTrackerGreen fluorescence by confocal imaging.

Conclusion: These results indicate that SS-31 directly protects cardiac aging through rapid rejuvenation of mitochondrial respiration in cardiomyocytes, and in particular, by reducing the proton leak. This study helps to uncover the mechanism of the protective effect on cardiac aging by short-term SS-31 treatment.

Funding: This study was supported by grants from NIH/NIA (P01AG001751, 1R56AG055114-01 to P.S.R.) and Glenn/AFAR Foundation Postdoctoral Fellowship for Translational Research on Aging to H.Z. Elamipretide was kindly provided by Stealth Biotherapeutics.

Poster 3

An essential role of the iron-sulfur cluster assembly enzyme isu-1 in aging and stress response

Yi Sheng1, Kaitlyn Casey1, Shayla Curry1, Wei Li2 & Rui Xiao1

1. Department of Aging & Geriatric Research, Institute on Aging, College of Medicine, University of Florida, Gainesville, FL

2. Department of Pathology, College of Medicine, University of Florida, Gainesville, FL

Iron is essential for animal cellular homeostasis by acting in the biogenesis of two important redox-reactive prosthetic groups of enzymes: iron sulfur clusters (ISC) and heme. Previous studies have indicated that the dysregulation of iron homeostasis is associated with multiple aging-related neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. However, how iron metabolism modulates aging remains largely elusive.

In the current study, we aim to reveal the roles and mechanisms of iron metabolism in the aging process of C. elegans, a well-established genetic model organism for aging research. Through our preliminary studies, we found that the iron–sulfur cluster assembly gene isu-1 plays an important role in lifespan modulation and stress resistance of C. elegans. Specifically, RNAi knocking-down of isu-1 caused a significantly upregulated mitochondrial unfolded protein response (mitoUPR). Furthermore, isu-1 RNAi-treated worms were significantly more resistant to heat shock and oxidative stress. Lastly, isu-1 RNAi significantly extended lifespan.

Currently, we are examining the transcription factors downstream of isu-1 in regulating aging and stress response. Surprisingly, the isu-1 RNAi-triggered lifespan extension appears to be independent of insulin and IGF pathway, an evolutionarily conserved master regulator of animal growth and aging. We plan to characterize the mechanisms underlying the effects of iron-sulfur cluster in animal aging and stress response using various genetic and biochemical approaches.

Poster 4

Epigenetic Dysregulation in Alzheimer’s Disease Revealed by Human Histone Deacetylase PET Imaging

Hsiao-Ying Wey1, Frederick A. Schroeder1, Jonathan M. DuBois1, Daniel B. Chonde1, Nicole R. Zürcher1, Tonya M. Gilbert1, Baileigh G. Hightower1, Sara J. Makaretz2, Bradford Dickerson2, Jacob M. Hooker1

1Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, 2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA

Introduction: Histone deacetylases (HDACs) are enzymes that modulate DNA expression and have emerged as an important target in understanding brain disorders. HDAC expression has been measured in postmortem brain tissue samples from healthy and Alzheimer’s disease (AD) brain. In addition, genetic manipulations or pharmacologic inhibition of HDAC2 and HDAC3 activity rescued behavioral defects in rodent models of AD. Collectively, these studies implicate a direct relationship between the levels of HDACs and neuronal function. In this study, we use a novel PET imaging agent, [11C]Martinostat, that selectively binds to a subset of HDAC enzymes, to quantify the availability of [11C]Martinostat in AD patients and compared to matched healthy controls.

Materials and Methods: Subjects with AD (n=9) and matched healthy controls (n=13) were recruited in this study. All subjects were administered the mini mental state exam (MMSE) and Logical Memory IIa, and clinical dementia rating (CDR). Images were acquired on a 3T Siemens TIM Trio with a BrainPET insert. A T1-MPRAGE sequence was collected and reconstructed with FreeSurfer v6.0. Dynamic PET image acquisition was initiated with IV bolus injection of ~5 mCi [11C]Martinostat (controls 5.22 ± 0.27; AD 5.18 ± 0.26) and binned into 6, 5min frames spanning 60-90min post-injection. PET data were reconstructed using the 3D OP-OSEM algorithm in the units of SUV, motion- corrected, and processed with FreeSurfer and FSL. SUV images were normalized to the SUV of pons (SUVR60-90min) and spatially smoothed at 8mm. A priori ROI analysis of the hippocampus and whole-brain voxelwise analysis using FSL's FEAT with OLS mixed- effects modeling (Z> 2.3, Pcluster< 0.05) were performed.

Results, Discussions and Conclusion: Our quantitative results indicate areas of known AD disease pathology may also exhibit abnormal HDAC expression (e.g., bilateral hippocampus, precuneus, parietal and temporal cortex, hippocampus). Interestingly, no region was found to show a higher HDAC availability in AD patients than controls. The SUVR analysis is based on brain region(s) of interest defined by individual subject’s anatomical MR images, which counts for potential inter-subject variations in brain atrophy. We have an active and evolving workflow to process not only utilize structural MR images for ROI delineation but also performed MR-based attenuation correction, motion correction, and partial volume correction on the simultaneously acquired PET data. Post- hoc analysis was also performed to obtain regional SUV values from individual subjects. No group difference was found in the SUVs of pons between patients and controls suggesting that using pons as a pseudo-reference tissue for normalization is valid. Poster 5

Marc Vermulst, Children's Hospital of Philadelphia

Poster title: Transcription errors in aging and disease

Accurate transcription is required for the faithful expression of genetic information. However, the molecular mechanisms that control the fidelity of transcription are largely unknown. We used a novel, massively parallel sequencing approach to determine how genetic and environmental factors impact transcriptional fidelity in multicellular organisms. By analyzing the transcriptome of Saccharomyces Cerevisiae, Caenorhabditis elegans and Drosophila melanogaster, we found that key components of the RNA polymerase II holoenzyme are vital to the fidelity of gene expression, and that this fidelity is directly challenged by natural aging and the exposure to mutagenic compounds. These observations suggest that in multicellular organisms, aging, the environment, and our genetic composition control the accuracy with which genetic information is conveyed to the cytoplasm. Because transcription errors give rise to misfolded proteins and shorten cellular lifespan, these findings provide a novel, mechanistic link between the environment and natural aging to various aspects of age- related pathology, including protein aggregation and cellular lifespan.

Poster 6

Effect of Dietary Restriction on Insulin Sensitivity and Metabolic Memory

Stephanie Matyi1, Jordan Jackson1, Michelle Ranjo-Bishop1, Karla Garrett1, and Archana Unnikrishnan1, 2 1University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 2Member of Harold Hamm Diabetes Center, Oklahoma City, Oklahoma

DR has been shown to increase lifespan and delay the onset and progression of most age- related diseases. Many mechanisms have been proposed for the life-extending action of DR; however, it is still unclear as to the molecular basis of DR’s action. One consistent observation in mammals is that DR has a dramatic effect on insulin sensitivity, and it has been argued that improved insulin sensitivity plays a role in DR’s life-extending action. An important aspect of DR that has been largely overlooked is that DR can have early effects that create a cellular memory, which persists throughout life, e.g., DR implemented only early in life can increase lifespan of rodents fed ad libitum (AL) the rest of their life. This has also been observed with respect to the effect of DR on insulin sensitivity, e.g., insulin sensitivity is improved within a month after implementation of DR and persists after DR is discontinued. These studies suggest that DR could be acting through a novel mechanism that involves a molecular signal(s) that arises shortly after the implementation of DR that has an impact on the animal over its lifespan even after DR is discontinued, e.g., DNA methylation, by which the transcriptional capability of cells can be altered, potentially, for the life of an organism. Recent research showing that alterations in DNA methylation levels can be used to predict the chronological age in humans suggests that DNA methylation plays a role in aging. In addition, studies indicate that DNA methylation changes with age and that DNA methylation changes play a role in age-related diseases. Although there are essentially no data on the effect of DR on both DNA methylation and insulin sensitivity combined, recent studies suggest that alterations in DNA methylation are involved in insulin resistance, e.g., hypermethylation of specific genes have been observed in insulin resistance. Therefore, I hypothesize that DR induces metabolic memory by altering DNA methylation (5mC) at specific sites that regulate insulin sensitivity. To test this hypothesis, whole genome bisulfite sequencing is being used to measure the genome-wide changes in specific 5mC and 5hmC sequences in CpG islands, shores, and shelves as well as the promoter and intragenic regions of genes. Four insulin responsive tissues involved in glucoregulation are being studied: adipose tissue, liver, skeletal muscle, and hypothalamus. DR is a well-known modifier of adipose tissue which in turn is involved in the regulation of blood glucose and insulin sensitivity. In addition, both liver and skeletal muscles are well known regulators of glucose homeostasis and impaired functioning of these tissues results in insulin resistance. Finally, the hypothalamus, a key tissue in the life-extending action of DR has been reported to receive signals from insulin and promote glucose homeostasis. Here I present preliminary data showing DR’s effect on metabolic memory and basal 5mC and 5hmC levels in all four glucose responsive tissues. Our data shows that 40% DR not only has an early effect on glucose tolerance but also maintains it after DR was discontinued for 2 months. In addition, DR implemented just during the pre-weaning period, by enlargement of litter size (crowded litter), also significantly improved insulin sensitivity even after animals were fed ad-libitum post- weaning for about 15 months. Poster 7

The chromatin accessibility signature of aging in human blood leukocytes stems from CD8+ T cells

Authors: Duygu Ucar1†*, Eladio J. Márquez1†, Cheng-han Chung1,3†, Radu Marches1, Robert J. Rossi1, Asli Uyar1, Te-Chia Wu1, Joshy George1, Michael Stitzel1, Karolina Palucka1, George A Kuchel2*, and Jacques Banchereau1*

Affiliations: 1The Jackson Laboratory for Genomic Medicine, Farmington, CT.

2University of Connecticut Center on Aging, University of Connecticut, Farmington, CT.

3Department of Biomedical Studies, Baylor University, Waco, TX.

*To whom correspondence should be addressed: [email protected], [email protected], [email protected]

†Co-first authors

Abstract: Aging is linked to deficiencies in immune responses and increased systemic inflammation. To unravel regulatory programs behind these changes, we applied systems immunology approaches and profiled chromatin accessibility and transcriptome in peripheral blood mononuclear cells (PBMCs), and purified monocytes, B and T cells. Analysis of samples from 77 young and elderly donors revealed a novel and robust aging signature in PBMCs with simultaneous systematic chromatin closing at promoters and enhancers associated with T cell signaling, and, a potentially stochastic, chromatin opening mostly found at quiescent and repressed sites. Combined analyses of chromatin accessibility and transcriptome uncovered immune molecules activated/inactivated with aging, and identified the silencing of IL7R gene and the IL-7 signaling pathway genes as potential biomarkers. This signature is borne by memory CD8+ T cells, which exhibited an aging- related loss in binding of NF-κB and STAT factors. Thus, our study provides a unique and comprehensive approach to identify candidate biomarkers as well as mechanistic insights into aging associated immunodeficiency.

Poster 8

The Generation of a Novel GH mutant Mouse Model Using the CRISPR/cas9 System

Michael Paul Fitch, Anil Kumar Challa, Liou Y. Sun

Department of Biology, University of Alabama at Birmingham

Growth hormone (GH) is naturally produced by somatotropic cells in the anterior pituitary gland and plays an important role in growth and development. In the mouse, the hormone is produced as a 216 amino acid precursor protein with an N-terminal signal peptide (26 amino acids) essential for hormone secretion. The signal peptide is cleaved during the secretion process resulting in a 191 amino acid mature form of GH. Loss of function mutation in the growth hormone (GH) signaling in mouse has been attributed to an increased life span and increased insulin sensitivity. To further study the effects of the loss of GH gene on aging and health, we used the CRISPR/Cas9 system and identified a novel mutation of the mouse GH gene. Here we report a small deletion (14 bp) in exon 3 that results in a frame shift allele, causing an early truncation of the predicted protein sequence and includes 79 mutant amino acids. In the homozygous state, this deletion allele causes embryonic lethality in a C57BL/6 and in a mixed C57BL/6 X BALBc background. Timed mating and analysis of harvested embryos show that homozygous mutant embryos are conceived and develop at least until E14; no live homozygous mutant pups were found in all the litters. This suggests that GH is likely to be critical for embryonic development during the last week of gestation. Also, the mutant allele might produce a non-functional protein or be toxic to embryonic development.

Poster 9

TITLE: Chronic glutathione deficiency: implications for lifespan and healthspan

Authors: J. Thomas Mock, Delaney Davis, Philip Vann, Jessica Wong and Nathalie Sumien

Affiliation: Department of Pharmacology & Neuroscience, UNT Health Science Center, Fort Worth

ABSTRACT:

Redox state has been implicated as a potential factor in human and rodent aging, and can be manipulated by altering levels of glutathione (GSH). A pro-oxidizing shift in the ratio of reduced to oxidized GSH is expected to disrupt cellular signaling and function leading to impairments. Chronic glutathione deficiency is achieved by knockout of glutamate cysteine ligase modifier (gclm) subunit, an enzyme that is rate-limiting during glutathione synthesis. Glutathione levels in these mice (gclm-/-) are ~80% decreased in brain and peripheral tissues when compared with gclm+/+ mice. We subjected gclm+/+ and gclm-/- male and female mice (n = 15-23 / sex / age / genotype) to a functional test battery at 5, 10, or 20 months of age, and we some were followed for survivorship. Results indicated an increase in median lifespan for both male and female mice. The deficiency was associated with improved motor performance in young females and adult males. In old mice, glutathione derangement improved balance in males but accelerated motor declines in females. There was no major effect on cognitive function, except in fear conditioning in young mice. These data imply that (i) motor and cognitive domains appear to be differentially affected by chronic glutathione deficiency, (ii) older females were more susceptible to glutathione depletion leading to further motor impairments. Cerebellum, skeletal muscles, cortex and striatum were sent to the Redox Biology Core in Oklahoma to determine whether redox and energy balance across the lifespan contributed to the effects observed in behavioral and survival studies.

Poster 10

17α-estradiol acts through Hypothalamic Pro-opiomelanocortin Neurons to Reduce Feeding Behaviour

1 1 2 3 Frederik J. Steyn , Shyuan T. Ngo , Shivani N. Mann , Derek M. Huffman , Willard M. 4-6 7 2,5,6 Freeman , Malcolm J. Low , Michael B. Stout

1 2 School of Biomedical Sciences, University of Queensland, AUS; Department of 3 Nutritional Sciences, University of Oklahoma, USA; Department of Molecular 4 Pharmacology, Albert Einstein College of Medicine, USA; Department of Physiology, 5 University of Oklahoma; Reynolds Oklahoma Center on Aging, University of Oklahoma; 6 7 Harold Hamm Diabetes Center, University of Oklahoma; Department of Molecular and Integrative Physiology, University of Michigan, USA

Dietary restriction (DR) is the most effective intervention for diminishing disease burden and increasing lifespan in model organisms. Pharmacological interventions that elicit responses similar to DR may offer effective strategies to emulate the benefits of DR without adversely affecting quality of life. We previously reported that dietary 17α-estradiol (17α-E2) administration elicits beneficial effects on metabolism and inflammation in old male mice (Stout et al. 2017). These observations were associated with reduced calorie consumption, although the mechanisms of action were unresolved. In the current set of studies, we sought to determine if 17α-E2 would elicit similar effects in mouse models of diet-induced obesity, genetically-induced hyperphagia (leading to obesity), and rats receiving localized infusion of 17α-E2. Moreover, we sought to determine if the beneficial metabolic effects of 17α-E2 are primarily in response to changes in food intake via hypothalamic actions or poor palatability of diets containing 17α-E2. We found that 17α- E2 does indeed reduce food intake and improve metabolic parameters when administered both orally or through subcutaneous pellets. Interestingly, 17α-E2-mediated effects on food intake, body mass, and adiposity were completely ablated in mice lacking functional Pomc expression, confirming that 17α-E2 modulates appetite through selective interactions within hypothalamic anorexigenic pathways. Interestingly, peripheral markers of metabolic homeostasis were also improved in animals with near complete loss of ARC Pomc transcription, suggesting 17α-E2-mediated effects on metabolism may not be completely dependent on reductions in food intake. Supporting this contention was our finding that acute infusions of 17α-E2 in the brain or periphery improved insulin-sensitivity in rats during a hyperinsulinemic-euglycemic clamp. Collectively, these data suggest 17α- E2 likely has synergistic central and peripheral actions that beneficially alter metabolic homeostasis.

Poster 11

Caspase-2 maintains bone homeostasis by regulating osteoclast number and function Ramaswamy Sharma1, Michelle Bendele1, Teja Guda2 and Brian Herman3 1University of Texas Health Science Center at San Antonio, 2University of Texas at San Antonio and 3University of Minnesota

Background/Objectives: Osteoporosis is a worldwide health problem leading to painful fractures that increase morbidity and mortality with aging. With 10 million osteoporotic patients, 34 million osteopenic individuals and 2 million osteoporosis-based fractures every year, the societal and financial burden accounts for acute and rehabilitative medical costs of more than $20 billion in USA alone. However, molecular mechanisms contributing to bone loss are yet to be fully elucidated. We find that genetic ablation of caspase-2, a cysteine aspartate protease involved in oxidative stress homeostasis, results in significant bone loss in both male and female Casp2-/- mice with aging. Loss of caspase-2 significantly decreases cortical bone thickness, trabecular bone volume and trabecular number, resulting in significantly increased bone porosity. Bone loss is characterized by decreased bone mineral density (BMD; upto 20%) and increased bone fragility (upto 30% decrease in fracture strength) that correlates with an increase in bone resorption markers and an increase in the number and function of the bone-resorbing cells, osteoclasts. Therefore, our central hypothesis is that Casp2 maintains bone quality by regulating osteoclast numbers and function. Methods: We generated novel transgenic mice selectively overexpressing full-length Casp2 in osteoclasts (Casp2tg). We analyzed bone using dual X-ray absorptiometry (DXA), micro-CT, 3- point bending and microindentation. Results: Strikingly, longitudinal DXA and micro-CT analysis indicate a significant and consistent increase in BMD and trabecular thickness in Casp2 transgenic male and female mice (2-month onwards) as compared to wild type (WT) mice. Importantly, DXA analysis also indicate that transgenic mice continue to maintain higher BMD with aging. Conclusions: Overall, our data point to a critical role for caspase-2 in maintaining bone homeostasis and identify a novel target for the treatment of osteoporosis. Poster 12

Title Transient non‐integrative nuclear reprogramming promotes multifaceted reversal of aging in human cells

Author Vittorio Sebastiano

Institution Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305. Department of Obstetrics and Gynecology, Stanford School of Medicine, Stanford, CA 94305.

Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels. At the chromatin level, aging is associated with the progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis. The technology of nuclear reprogramming to pluripotency, through over‐expression of a small number of transcription factors, can revert both the age and the identity of any cell to that of an embryonic cell by promoting epigenetic reprogramming. Recent evidence has shown that transient transgenic reprogramming can ameliorate age‐associated hallmarks and extend lifespan in progeroid mice. However, it is unknown how this form of ‘epigenetic rejuvenation’ would apply to physiologically aged cells and, importantly, how it might translate to human cells. Here we show that transient reprogramming based on non‐integrative mRNA technologies reverses hallmarks of physiological aging of human fibroblasts and endothelial cells, ameliorates disease phenotypes in osteoarthritis, and restores youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity. Our method of transient cell reprogramming paves the way to a novel, potentially translatable strategy for ex vivo cell rejuvenation treatment. In addition, this approach holds promise for in vivo tissue rejuvenation therapies to reverse the physiological manifestations of aging and the risk for the development of age‐related diseases. Poster 13

Title: Cellular senescence mediates fibrotic pulmonary disease

Authors: Marissa J. Schafer1,2, Thomas A. White1, Koji Iijima3, Andrew J. Haak4, Giovanni Ligresti4, Elizabeth J. Atkinson5, Ann L. Oberg5, Jodie Birch9, Hanna Salmonowicz9, Yi Zhu1, Daniel L. Mazula1, Robert W. Brooks10, Heike Fuhrmann‐Stroissnigg10, Tamar Pirtskhalava1, Y.S. Prakash4,6, Tamara Tchkonia1, Paul D. Robbins10, Marie Christine Aubry7, João F. Passos9, James L. Kirkland1,4,8, Daniel J. Tschumperlin4, Hirohito Kita3, Nathan K. LeBrasseur1 ,2,4

Author Affiliations: 1Robert and Arlene Kogod Center on Aging; 2Department of Physical Medicine and Rehabilitation; 3Division of Allergic Diseases, Department of Internal Medicine; 4Department of Physiology and Biomedical Engineering; 5Division of Biomedical Statistics and Informatics, Department of Health Sciences Research; 6Department of Anesthesiology; 7Department of Laboratory Medicine and Pathology, 8Department of Internal Medicine; Mayo Clinic College of Medicine, Rochester, MN, 55905, USA 9Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing NE4 5PL Newcastle upon Tyne, UK 10Department of Metabolism and Aging; The Scripps Research Institute, Jupiter, FL, 33458, USA

Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease characterized by interstitial remodeling, leading to severely compromised lung structure and function. Cellular senescence, a stress‐ induced state of stable replicative arrest, is causally implicated in numerous age‐related diseases. Markers of senescence are detectable within parenchyma of chronologically aged and IPF lung tissue. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. We demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing concordantly with disease severity. We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic in vitro. Leveraging intratracheal administration of bleomycin to replicate aspects of IPF, we demonstrate that early‐intervention suicide‐gene‐mediated ablation of p16Ink4a‐expressing senescent cells in Ink‐Attac mice improves pulmonary function and physical health. Senolytic DQ treatment replicates benefits of transgenic clearance. Thus, our findings demonstrate that fibrotic pulmonary disease is mediated in part by senescent cells, which can be pharmacologically targeted to improve physical health and function. Published at: Schafer et al. Nat Commun. 2017;8:14532. PMID: 28230051.

Poster 14

Identifying novel strategies to induce age-associated damage in human pluripotent stem cell models of Alzheimer's disease Nathalie Saurat1, Gabriele Ciceri1, Dylan Kwart2, Dominique Paquet2, Marc Tessier-Lavigne2 and Lorenz Studer1 1The Center for Stem Cell Biology and Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA. 2 Laboratory of Brain Development and Repair, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.

Despite being formulated over 25 years ago, the amyloid hypothesis has not resulted in interventions that can slow or cure the progression of Alzheimer’s disease. One of the challenges in studying this devastating disease and identifying effective drug candidates is the long prodromal phase of the disease: despite having disordered Aβ production since birth, patients with autosomal dominant forms of Alzheimer’s disease don’t develop dementia or show significant neuronal loss until midlife. This is consistent with sporadic forms Alzheimer’s disease whereby age is the biggest risk factor for neurodegeneration. In light of this, I aim to identify regulators of age in human neurons and investigate their impact on Alzheimer’s disease neurodegeneration.

To address this question I am carrying out a whole genome CRISPR/Cas9 screen using cortical neurons derived from human pluripotent stem cells. This approach has several distinct advantages: the neurons generated are human, patient specific and can be made in virtually unlimited quantities whereas traditional cell and animal models have had poor predictive value when putative AD drugs are tested in humans. Published AD-iPSC models have reproducibly captured the altered APP processing typical of the early stages of Alzheimer’s disease but don’t recapitulate the late onset neurodegenerative phenotypes. I hypothesize that the lack of late- stage pathologies in in vitro AD-iPSC models occurs because there is an age component missing from existing cellular models. This is supported by previous work from the Studer Laboratory whereby the incorporation of Progerin, a truncated form of the Lamin A responsible for the premature aging syndrome HGPS, into midbrain dopaminergic neurons was successful in inducing cellular hallmarks of age and late stage neurodegenerative disease phenotypes in stem cell models of Parkinson’s disease.

Using a whole genome CRISPR/Cas9 screen I will identify genes whose loss of function selectively compromises the viability of AD but not isogenic control neurons. Following my hypothesis, loss of viability in these neurons would result from the synergistic action of genetic susceptibility and age-related vulnerability and thus allow me to identify genes and cellular pathways involved in neuronal aging. I have successfully engineered a cellular system to complete this screen including: generating isogenic pluripotent stem cell lines with the APPSwe mutation and inducible Cas9 protein in the AVS1 safe harbor locus, developing a scalable method to generate highly pure cortical neurons from the engineered cells, documenting the amyloid and Tau changes in each genotype over the 90 days of culture required for this screen and validating assays for cellular age. I am now ready to begin the screen. It is anticipated that, when completed, this screen will generate new insights into the biology of aging in human neurons and provide a novel platform to study and test drugs for AD-neurodegeneration.

Poster 15

The influence of HSP25 overexpression on lifespan and neurodegenerative disease

Courtney M. Carroll1,2, Tamara Fraker1, Aliyah Encarnacion1, Maruf Khan3, Alfred Fisher1,3,4,5, and Karl A. Rodriguez1,2

1Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center San Antonio (UTHSCSA), San Antonio, TX 78229; 2Department of Cell Systems and Anatomy, UTHSCSA; 3Department of Pharmacology, UTHSCSA ; 4Center for Healthy Aging, UTHSCSA; 5GRECC, South Texas VA Healthcare System, San Antonio, TX 78229

Both aging and neurodegenerative disorders are characterized by protein aggregates, which may arise or are exacerbated by a failure of the protein homeostasis network. Small heat shock proteins (sHSP’s) are molecular chaperones that function not only in protein folding, but also improve the degradation activity of the proteasome and autolysosome, potentially decreasing disease-associated aggregates. Previous work from our lab has shown that the expression level of small heat shock protein 25 (HSP25) in muscle and liver tissue correlates best with maximum lifespan potential in rodents, yet how this chaperone improves lifespan and the effect it may have on protein aggregation is unknown.

To explore the role of HSP25 in longevity, we created a nematode overexpressing HSP25 from the naked-mole rat, and found that HSP25 improves lifespan potential and heat resistance in C. elegans. RNAi experiments suggest that the lifespan extension is dependent on hsf-1 and skn- 1, but independent of daf-16. RNAseq from HSP25 overexpressing worms show enrichment in several skn-1 associated pathways, such as collagen proteins and the innate immune response. HSP25 overexpression also has a beneficial effect on proteostasis in a C. elegans model of neurodegeneration. Notably, there is an increase in lifespan and heat resistance and a decrease in heat-associated protein aggregation when the HSP25 overexpression worm is crossed with a worm model of tauopathy. We are currently working to mechanistically define the effect of HSP25 overexpression in these models.

Poster 16

Using the Loligo system to measure respiration rates in Drosophila melanogaster

R. Colton Ritchie1, Louis P. Watanabe1, Maria S. Johnson2, Tim R. Nagy2,3, and Nicole C. Riddle1,3

1 Department of Biology, University of Alabama at Birmingham, Birmingham, AL 2 Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 3 Nathan Shock Center of Excellence in the Basic Biology of Aging, UAB, Birmingham, AL

Respirometry assesses an organism’s metabolism by measuring either an increase in carbon dioxide (CO2) or a decrease in oxygen (O2) due to respiration of the organism. Changes in metabolism such as those precipitated by increased physical activity/exercise or due to the aging process – lead to changes in respiration rates over time. Thus, an organism’s energy expenditures can be estimated using respirometry. Measurement of CO2 and/or O2 concentration requires specialized sensors, and often, the equipment necessary is both expensive and highly specific to a particular study organism. At UAB, systems for respirometry studies are available for rodents and aquatic animals, but were lacking for our animal model, the fruit fly Drosophila melanogaster. For our research on exercise biology and aging, we need to determine how respiration changes in Drosophila a) in response to exercise and b) with increased age, and how these two factors, age and exercise, interact. We collaborated with the Comparative Organismal Energetics Core of the UAB Nathan Shock Center of Excellence in the Basic Biology of Aging to adapt the Loligo system owned by the core facility for respirometry studies in Drosophila melanogaster. To date, the Loligo system has been used mostly for aquatic organisms. We succeeded in developing a protocol for Drosophila, and our pilot experiments demonstrates that respirometry analysis with the Loligo system is feasible for terrestrial organisms. Our pilot study was successful in detecting an impact of sex and age on respiration rates. By expanding the species range assayed by the Loligo system, the protocol we developed will enable greater access to respirometry analysis for researchers working with a variety of organisms.

Poster 17

“Rethinking protein homeostasis in a metazoan: A Case of Nerves?”

Veena Prahlad, Felicia Ooi and Srijit Das Department of Biology, Aging Mind and Brain Initiative, University of Iowa, Iowa City

Protein misfolding is central to the pathology of neurodegenerative diseases. Cells possess natural defense mechanisms to counteract protein misfolding. One such mechanism is the activation of a conserved gene expression program, the so‐called heat‐ shock response, which increases the cellular protein quality control (QC) capacity to help refold and/or degrade misfolded proteins. Experimentally activating this response ameliorates disease pathology, making it a prime target for medical intervention. Yet, in neurodegenerative diseases, cells accumulate misfolded and aggregated proteins but fail to naturally activate this response. Our work over the past years has shown that as in human disease, cells of the metazoan Caenorhabditis elegans do not activate their protein QC machinery upon protein misfolding. This is because in the absence of an external stressor, neuronal activity inhibits the cells’ natural defense against misfolding. However, upon a sensed threat in the environment, the nervous system systemically activates this response even in the absence of protein misfolding through neuromodulators such as serotonin. Serotonin (5‐hydroxytryptamine, 5‐HT) plays a central role in the neuronal mechanisms of learning and memory that allows organisms to synthesize information from their surroundings to predict danger. We find that olfactory learning in C. elegans mediated by the serotonergic system not only enhances avoidance behaviors to potential threats, but also induces neuronal and non‐neuronal cells throughout the organism to increase expression of their molecular chaperones if they subsequently encounter this threat. Specifically, neurosensory training promotes DNA binding HSF‐1 in anticipation of the actual encounter with the stressor. This binding does not in itself result in an increase in transcription of target genes, but potentiates the subsequent activity of HSF‐1 only if and when the animals encounters the threat. In addition, not only is HSF‐1 transcriptional activity enhanced by the serotonergic learning circuitry, but HSF1 is required for the ‘learnt’ avoidance behavior itself. Thus, serotonergic control of HSF‐1 equips C. elegans to better survive environmental dangers by pre‐emptively and specifically enhancing cellular homeostasis using the neuronal circuitry underlying memory and learning. These studies provide a mechanism for the protective role of environmental enrichment in disease. We are currently investigating which genes are upregulated upon a sudden increase in exogenous serotonin levels, the mechanisms by which serotonin primes protective transcription, and are testing whether mammalian cells of neuronal origin (N2A cells and mouse primary cortical neurons) also respond similarly to exposure to serotonin.

Poster 18

Proteasome dysfunction, a key downstream driver of Alzheimer’s disease symptoms and progression. Andrew M. Pickering Ph.D.*

Barshop institute for Aging Studies and Longevity Department of Molecular Medicine University of Texas Health Science Center At San Antonio

Alzheimer’s disease represents the single greatest pharmacologic challenge of the 21st century. An aging and progressively longer-lived population has resulted in an escalating disease rate. There are 35 million cases at present with 115 million expected by 2050. No new drugs for Alzheimer’s disease have been approved since 2003, while those drugs available tend not to be highly effective and provide relief only at early stages. The majority of recent trials have focused on interventions which reduce β-amyloid formation/aggregation or enhance β-amyloid clearance. These trials have met repeatedly with failure. This is likely because later stages of the disease are driven by pathways independent of β-amyloid. Here β-amyloid triggers disruption of a host of different pathways but it is the continued dysfunction in these pathways that has made Aβ targeting interventions so ineffective. Clinical trials are beginning against Tau however it is too early to determine if these will be any more effective. For this reason an important direction of research is the development of interventions that target non-β-amyloid aspects of Alzheimer’s disease.

An understudied aspect of Alzheimer’s disease is proteasome dysfunction. The proteasome has key roles in neuronal proteostasis, including protein turnover, removal of misfolded or oxidized proteins, presynaptic protein turnover, synaptic efficacy, and synaptic plasticity. Patients as well as animal models of Alzheimer’s disease have a pronounced decline in proteasome function. The proteasome has critical roles in the nervous system loss of proteasome has been shown to recapitulate many aspects of Alzheimer’s disease.

We show both in cell culture and invertebrate models of Alzheimer’s disease that proteasome function is a strong determinant of the rate of Alzheimer’s disease progression. Proteasome knockdown or inhibition accelerates Alzheimer’s disease progression while proteasome overexpression delays Alzheimer’s disease progression. We also show novel proteasome targeting pharmacologics to delay cognitive and neurodegenerative symptoms of Alzheimer’s disease. Proteasome manipulation does not alter β-amyloid synthesis, deposition of stability but reduces β-amyloid toxicity. We present proteasome manipulation as a novel downstream intervention to slow Alzheimer’s disease progression.

Poster 19

NECROPTOSIS ACTIVATION IN ALZHEIMER’S DISEASE

Salvatore Oddo

The Arizona State University-Banner Neurodegenerative Disease Research Center at the Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, Arizona, 85287

Alzheimer’s disease (AD), the most common neurodegenerative disorder, is characterized by severe neuronal loss. However, the mechanisms by which neurons die remain elusive. Necroptosis, a programmed form of necrosis, is executed by the mixed lineage kinase domain- like (MLKL) protein, which is triggered by receptor-interactive protein kinases (RIPK) 1 and 3. We used human and mouse tissue and applied complementary genetic and pharmacological approaches to dissect the role of necroptosis in AD. We show that necroptosis is activated in postmortem human AD brains, where it positively correlates with Braak stage and inversely correlates with brain weight and cognitive scores. Notably, in a gene regulatory network built from post-mortem brain tissue, the set of genes regulated by RIPK1 overlap significantly with multiple, independent AD transcriptomic signatures, indicating that RIPK1 activity could explain a significant portion of described transcriptomic changes in AD. We further show that reducing necroptosis activation with a RIPK1 inhibitor reduces cell loss in 5xFAD mice, a mouse model of AD. Our results provide compelling evidence that necroptosis is activated in AD and thus may contribute to neurodegeneration in this insidious disorder. We anticipate that our findings will spur a new area of research in the AD field focused on further detailing the role of necroptosis in AD and developing new therapeutic strategies aimed at blocking RIPK1 and/or MLKL activation.

Poster 20

Exploring the role and regulation of phospholipids in the AD brain

Saidemberg D1, Bennet E2, Zucker A1, Greenberg D2, Soreq H2, Moussaieff

1. Institute for Drug Research, The Hebrew University of Jerusalem, Israel.

2. Department of Biological Chemistry, The Edmond and Lily Safra Center for Brain

Sciences,, The Hebrew University of Jerusalem, Israel.

Dysregulation of lipid metabolism in the brain has been strongly associated with AD, but its functional implications remain largely unknown. Membrane phospholipid (PL) contents determine the physicochemical properties of the membrane, suggesting a critical role in the progression of AD neuropathology.

However, little is known on the detailed composition and regulation of PLs in

AD brain. We aim to decipher the regulation of PLs in the context of the AD pathology and cognitive decline. Previous work indicates involvement of PLs in AD pathogenesis, while suggesting unchanged total contents of PLs in the

AD brain. Here, we report mapping of the shifts in the phospholipid network in the brains of several AD patients vs. healthy volunteers (5/5). In line with previous studies, our analyses demonstrate selective changes in the PL composition representing the most discriminative metabolic shift in the AD brain. Surprisingly, the observed change in PL metabolism is specific, occurring in less than 10% of the 496 PLs that were tentatively identified.

Also, these changes could not be explained by shifts in the transcriptome.

Given the recent revelations on the roles of non-coding (nc)RNAs, we are exploring ncRNA association with PLs accumulation in a much bigger cohort of over 100 brain samples. Poster 21

Astrocytic IGF-1 signaling regulates working memory, mitochondrial metabolism and amyloid-β uptake Sreemathi Logan1, Gavin Pharaoh2,3, Matthew C Marlin6, Dustin R Masser1,2, Satoshi Matsuzaki3,4, Benjamin Wronowski1,2, Alexander Yeganeh1,5, Eileen Parks1,5, Pavithra Premkumar3, Julie Farley1, Daniel Owen1, Kenneth Humphries3,4, Michael Kinter3, Willard Freeman1,2,5, Luke Szweda3,4, Holly Van Remmen2,3,5, William E. Sonntag1,2,5.

1Reynold’s Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center 2Department of Physiology, University of Oklahoma Health Sciences Center; 3Aging & Metabolism Research Program, Oklahoma Medical Research Foundation; 4Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center 5Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center 6Graduate College, University of Oklahoma Health Sciences Center

ABSTRACT

Objective: A decline in mitochondrial function and biogenesis as well as increased reactive oxygen species (ROS) are important determinants of aging. With advancing age, there is a concomitant reduction in circulating levels of insulin-like growth factor-1 (IGF-1) that is closely associated with neuronal aging and neurodegeneration. In this study, we investigated the effect of the decline in IGF-1 signaling with age on astrocyte mitochondrial metabolism and astrocyte function and its association with learning and memory. Methods: Learning and memory was assessed using the radial arm water maze in young and old mice as well as tamoxifen-inducible astrocyte-specific knockout of IGFR (GFAP-CreTAM/igfrf/f). The impact of IGF-1 signaling on mitochondrial function was evaluated using primary astrocyte cultures from igfrf/f mice using AAV-Cre mediated knockdown using Oroboros respirometry and Seahorse assays. Results: Our results indicate that a reduction in IGF-1 receptor (IGFR) expression with age is associated with decline in hippocampal-dependent learning and increased gliosis. Astrocyte- specific knockout of IGFR also induced impairments in working memory. Using primary astrocyte cultures, we show that reducing IGF-1 signaling via a 30-50% reduction IGFR expression, comparable to the physiological changes in IGF-1 that occur with age, significantly impaired ATP synthesis. IGFR deficient astrocytes also displayed altered mitochondrial structure and function and increased mitochondrial ROS production associated with the induction of an antioxidant response. However, IGFR deficient astrocytes were more sensitive to H2O2-induced cytotoxicity. Moreover, IGFR deficient astrocytes also showed significantly impaired glucose and Aβ uptake, both critical functions of astrocytes in the brain. Conclusions: Regulation of astrocytic mitochondrial function and redox status by IGF-1 is essential to maintain astrocytic function and coordinate hippocampal-dependent spatial learning. Age-related astrocytic dysfunction caused by diminished IGF-1 signaling may contribute to the pathogenesis of Alzheimer’s disease and other age-associated cognitive pathologies.

Poster 22

Uncoupling of Metabolic Health from Longevity through Genetic Alteration of Adipose Tissue Lipid-Binding Proteins

Khanichi N. Charles1,#, Min-Dian Li1,#, Feyza Engin1, Ana Paula Arruda1, Karen Inouye1, Gokhan S. Hotamisligil1,2,*

1Department of Genetics and Complex Diseases and Sabri Ulker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA 2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA

#These authors contributed equally *Corresponding author

Deterioration of metabolic health is a hallmark of aging and generally assumed to be detrimental to longevity. Exposure to a high-calorie diet impairs metabolism and accelerates aging; conversely, calorie restriction (CR) prevents age-related metabolic diseases and extends lifespan. However, it is unclearwhether preservation of metabolic health is sufficient to extend lifespan. We utilized a genetic mouse model lacking Fabp4/5 that confers protection against metabolic diseases and shares molecular and lipidomic features with CR to address this question. Fabp-deficient mice exhibit extended metabolic healthspan, with protection against insulin resistance and glucose intolerance, inflammation, deterioration of adipose tissue integrity, and fatty liver disease. Surprisingly, however, Fabp-deficient mice did not exhibit any extension of lifespan. These data indicate that extension of metabolic healthspan in the absence of CR can be uncoupled from lifespan, indicating the potential for independent drivers of these pathways, at least in laboratory mice.

Poster 23

Serotonin signaling in stress perception and longevity

Hillary A. Miller1, Safa Beydoun2, Shijiao Huang2, Michael J. Murphy2, and Scott F. Leiser2,3

1 Cellular and Molecular Biology Department, University of Michigan 2 Molecular & Integrative Physiology Department, University of Michigan 3 Department of Internal Medicine, University of Michigan

Recent studies in model organisms identify pathways that link the perception of stress with changes in long‐term health. These pathways often originate in the nervous system with distinct signaling networks and downstream effectors that modify health and longevity. Several of these cell non‐autonomous pathways are reported to utilize the monoamine neurotransmitter serotonin as a key signaling molecule, suggesting that serotonergic signaling may play a critical role in regulating aging. Our previous work identified a key role for serotonin signaling in the induction of flavin‐containing monooxygenase‐2 (fmo‐2) downstream of the hypoxic response. This fmo‐2 expression is necessary and sufficient to promote health and longevity downstream of multiple genetic pathways. To address how biogenic amine signaling leads to improved health and longevity in nematodes, we utilized a transcriptional reporter for fmo‐2 and tested whether small molecules related to serotonergic signaling could induce fmo‐2 and subsequently increase lifespan. Our resulting data show that fmo‐2 is induced by the atypical antidepressant and serotonin antagonist, mianserin. Our data also show that mianserin, which was previously reported to increase lifespan in C. elegans, fully requires fmo‐2 for this effect, and suggest that mianserin acts as a dietary restriction mimetic by blocking the perception of food. Our data support a model where mianserin blocks a serotonin‐mediated signal when food is perceived, leading to a downstream signaling cascade that induces fmo‐2 and extends lifespan. These findings highlight the critical role of serotonergic signaling in longevity regulation and further define the mechanism of a clinically relevant drug. Poster 24

Intergenomic Basis of Mitonuclear Regulation Kyung Hwa Kim1§, Jyung Mean Son1, Bérénice A. Benayoun1,2,3, and Changhan Lee1,2,4*

Affiliations: 1 Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089. 2 USC Norris Comprehensive Cancer Center, Los Angeles, CA 90089. 3 USC Stem Cell Initiative, Los Angeles, CA 90089. 4 Biomedical Science, Graduate School, Ajou University, Suwon 16499, Korea.

Abstract Cellular homeostasis is coordinated through communication between mitochondria and the nucleus, organelles that each possess their own genomes. Whereas the mitochondrial genome is regulated by factors encoded in the nucleus, the nuclear genome is currently not known to be actively controlled by factors encoded in the mitochondrial DNA. We previously identified a peptide encoded in the mitochondrial DNA, named MOTS-c (mitochondrial open-reading-frame of the twelve S rRNA -c). MOTS-c regulates insulin sensitivity and metabolic homeostasis in an AMPK- and SIRT1-dependent manner. In mice, MOTS-c expression is age- and tissue- dependent. Further, MOTS-c treatment reversed age-dependent insulin resistance. Our recent studies show that MOTS-c rapidly and dynamically translocates to the nucleus to regulate the nuclear genome in response to cellular stress. Our data suggest the integration of mitochondrial and the nucleus at the genetic level and that the close intergenomic communication regulates adaptive stress response and aging metabolism.

Poster 25

Ovariectomy uncouples lifespan from metabolic health

Sebastian I. Arriola Apelo1,2, Jacqueline A. Brinkman2,3, Mark Morrison2,3, Emma Meyer1,2, Cassidy P. Pumper2,3, Amy Lin1,2, Nicole E. Cummings2,3,4, Emma L. Baar2,3, and Dudley W. Lamming2,3,4.

1Department of Dairy Science, University of Wisconsin-Madison, Madison, WI 2William S. Middleton Memorial Veterans Hospital, Madison, WI 3Department of Medicine, University of Wisconsin-Madison, Madison, WI 4Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI Rapamycin is an immunosuppressant and anticancer drug that extends lifespan in model organisms including mice by inhibiting the activity of a protein kinase, the mechanistic Target Of Rapamycin Complex 1 (mTORC1). Rapamycin induces hepatic insulin resistance through “off- target” disruption of a second complex, the mechanistic Target Of Rapamycin complex 2 (mTORC2), an effector of insulin/PI3K signaling. Genetic disruption of hepatic mTORC2 via liver- specific deletion of the mTORC2 subunit Rictor causes hepatic insulin resistance in both sexes and decreases male, but not female, lifespan.

Here, we investigate how sex hormones and hepatic mTORC2 interact to control metabolic health and lifespan. We gonadectomized or performed sham surgery on pre-pubertal male and female mice in which Rictor is specifically deleted in the liver (L-RKO) and their wild-type littermates. Deletion of Rictor strongly impaired glucose and pyruvate tolerance in male mice, regardless of surgery treatment, while Rictor deletion impaired glucose and pyruvate tolerance in intact female mice, but had no further effect on ovariectomized mice. Gonadectomy also promoted adiposity in both males and females, but had minimal effects on frailty. While our lifespan study is still ongoing, our results suggest that ovariectomy extends lifespan in both wild-type and L-RKO mice, while castration has minimal, possibly negative, effects on longevity. These finding align with previous findings that germline ablation (in C. elegans) and ovariectomy (in R. microptera) extends longevity, and suggests that the control of aging by the germline is conserved from nematodes and insects to mammals.

Poster 26

A genetic screen identifies adaptive aneuploidy as a key mediator of ER stress resistance in yeast

Carine Beaupere1, Leticia Dinatto1, Brian Wasko2, Rosalyn B. Chen1, Lauren VanValkenburg1, Michael G. Kiflezghi2, Mitchell B. Lee2, Daniel E. L. Promislow2, Weiwei Dang3, Matt Kaeberlein2, and Vyacheslav M. Labunskyy1

1Department of Dermatology, Boston University School of Medicine, Boston, MA 2Department of Pathology, University of Washington, Seattle, WA 3Department of Molecular and Human Genetics, Baylor College of Medicine, Huston, TX

The yeast genome becomes unstable during stress, which often results in adaptive aneuploidy allowing rapid activation of protective mechanisms that restore cellular homeostasis. In this study, we performed a genetic screen in Saccharomyces cerevisiae to identify genome adaptations that confer resistance to tunicamycin-induced endoplasmic reticulum (ER) stress. Whole-genome sequencing of tunicamycin-resistant mutants revealed that ER stress resistance correlated significantly with gains of chromosomes II and XIII. We found that chromosome duplications are acquired in response to acute but not chronic ER stress, and that the gain of an extra copy of chromosome II alone is sufficient to induce protection from tunicamycin. We demonstrate that the protective effect of disomic chromosomes can be recapitulated by overexpression of several genes located on chromosome II. Among these genes, overexpression of UDP-N-acetylglucosamine-1-P transferase (ALG7), a subunit of the 20S proteasome (PRE7), and YBR085C-A induced tunicamycin-resistance in wild-type cells, whereas deletion of all three genes completely reversed the tunicamycin resistance phenotype. Together, our data provide evidence that aneuploidy plays a critical role in adaptation to ER stress by increasing copy number of ER stress protective genes and identifies new genes involved in maintaining ER protein homeostasis. Such genes may represent useful targets for therapeutic interventions against age-related diseases associated with protein misfolding. Poster 27

Inflammatory cytokines restore the age related impairment of cytotoxic T cell priming in Listeria monocytogenes infected mice

Mladen Jergovic1, Jennifer Uhrlaub1, Megan Smithey1, Heather Thompson1 and Janko Nikolich- Zugich1

Author Affiliation(s): 1. Department of Immunobiology and the Arizona Center on Aging, University of Arizona College of Medicine, Tucson, Arizona, USA.

In response to infection with intracellular microorganisms, old mice mobilize decreased numbers of antigen-specific CD8 T cells with reduced production of effector molecules including granzyme B and IFN-, decreased polyfunctionality (ability to produce multiple effector molecules), and impaired cytolytic activity. However, the naïve CD8 T cell-intrinsic vs. extrinsic contribution to, and molecular mechanisms behind, these defects remain unclear. To address this question, we performed reciprocal transfer experiments with T cells from adult and old transgenic OT-1 mice. Our data shows that naïve adult OT-1 T cells fail to expand well in the old organism infected with Listeria-OVA. This defect is preceded by an impaired glycolytic switch when T cells are primed in the old organism, which is essential for effector function and proliferative burst. On the other hand, naïve CD8 T cells isolated from adult and old C57BL/6 mice proliferated and produced effector molecules to a similar extent when stimulated in vitro with polyclonal stimuli. Together these data indicate that old priming environment fails to efficiently prime and metabolically license cytotoxic T cells for massive proliferation and acquisition of effector function. Early after infection (d1) with Lm old mice exhibited lower expression of costimulatory molecules on DCs and a decrease in multiple inflammatory cytokines (IL-12, IFN-γ, IL-6, IL-1b) while basal levels of IL-2 were reduced irrespective of infection. These results point to a broad array of cellular defects in innate immunity that might be contributing to CD8 T cells receiving suboptimal signals during their recruitment in to the response. Here we show that these priming defects can be ameliorated by treatment of mice with inflammatory cytokines. Administration of high doses of IL-2 and IL-12 on days 4-6 of Listeria infection resulted in the reconstitution of the cytotoxic T cell response of aged mice to the level of adult. Poster 28

Transgenerational effects of hypoxia in C. elegans

Zach K. O’Brown, Yuan Wang, Eric L. Greer

1 Division of Newborn Medicine, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA 2 Department of Pediatrics, Harvard Medical School, Boston MA 02115, USA

Longevity has long been shown to be regulated by genetic and environmental factors. We and others have recently shown that longevity can also be regulated by the transmission of epigenetic information. We have shown that several chromatin modifying enzymes have a transgenerational non-Mendellian effect in worms on the longevity of their descendants. Others have shown that starvation of ancestral C. elegans can lead to a transgenerational extension in descendant lifespan. However, how epigenetic information is transmitted across generations to regulate descendant lifespan is still unknown. Hypoxia, the reduction of available oxygen, is a well characterized environmental regulator of longevity across a variety of species. Previous work has found that brief exposure of C. elegans to hypoxia can extend lifespan. We have found that acute parental hypoxia exposure leads to an extension in descendant lifespan in the nematode C. elegans. This hypoxia exposure also causes a transgenerational reduction in fertility and a reduction of heritable histone methylation. This data suggests that early life stress, in the form of acute hypoxia exposure, can induce an epigenetic change which extends longevity and reduces fertility. This work also provides us with a new epigenetic paradigm for studying how non-genetic information can be transmitted across generations in an experimentally manipulatable system. Poster 29

Acarbose has sex‐dependent and independent effects on mouse aging

Garratt M1, Herrera JJ 2 Louzon SD2, Leander DC1, Pifer KR1, Day SM2,3, Miller RA1

Departments of Pathology1, Molecular and Integrative Physiology2, and Internal Medicine3, University of Michigan, Ann Arbor, Michigan, USA

Abstract

With an expanding aging population burdened with comorbidities, there is considerable need to discover treatments that optimize health in later life. Treatment of mice with Acarbose (ACA), a Type 2 diabetic oral drug, has recently been shown to extend mouse lifespan, although life‐ extension was greater in males than females. Accordingly, approved pharmacological agents already used in the treatment of chronic diseases in humans might also protect against the consequences of aging. Utilizing genetically heterogeneous mice, we tested whether ACA could ameliorate functional, pathological and biochemical changes that occur during aging, and whether any observed effects were sex‐dependent or independent. We found that ACA had anti‐aging effects on a variety of different parameters. ACA improves grip strength and motor function later in life, and in contrast to the sex‐specific lifespan effects, functional improvements occur equally in both sexes. In both sexes, ACA maintains body weight during aging, although age‐associated muscle atrophy was slowed preferentially in males. Male mice also demonstrated characteristic age‐related cardiac hypertrophy, which was attenuated by ACA and was associated with reduced activation of cardiac growth promoting pathways. We further tested whether these beneficial effects could be conferred by a shorter (five month) treatment duration starting in middle‐age. Remarkably, the functional benefits of ACA are recapitulated even by late life treatment. Our results demonstrate that ACA has broad‐ranging anti‐aging effects in different tissues, with potential to increase physical function later in life in both sexes.

Poster 30

Tau-induced nuclear envelope invagination causes a toxic increase in RNA export

Bess Frost, UTHSCSA

The nucleus is a spherical dual-membrane bound organelle that encapsulates the genome. In eukaryotes, messenger RNAs (mRNA) are transcribed in the nucleus and transported through nuclear pores into the cytoplasm for translation into protein. In certain cell types and pathological conditions, nuclei harbor tubular invaginations of the nuclear envelope known as the “nucleoplasmic reticulum.” Nucleoplasmic reticulum expansion has recently been established as a mediator of neurodegeneration in tauopathies, including Alzheimer’s disease. While the presence of a pore lined, cytoplasm-filled, nuclear envelope invagination in the deep nuclear interior could facilitate the rapid export of RNAs from the nucleus to the cytoplasm, the functional significance of nuclear envelope invaginations in regard to RNA export in any disorder is currently unknown. We have found that polyadenylated RNAs accumulate within and adjacent to tau- induced nuclear envelope invaginations. Genetic or pharmacologic inhibition of RNA export machinery reduces accumulation of polyadenylated RNA within and adjacent to nuclear envelope invaginations, and reduces tau-induced neuronal death. These data point toward a central role for increased RNA export as a driver of neurodegeneration in tauopathy, and suggest that RNA export machinery may serve as a novel class of therapeutic targets for the treatment of tauopathies.

Poster 31

Age-dependent actin phosphorylation through heat shock factor compromises intestinal barrier and drives pathogenesis

Pauline Wales1, Charles Savelle1, Ian Gonzalez, Atossa Ghorashi1, Sonja L. Arneaud1, Sivaramakrishna Yadavalli2, Hamid Mirzaei2 and Peter M. Douglas 1,3,*

1. UT Southwestern Medical Center, Dallas, TX, USA. Department of Molecular Biology 2. UT Southwestern Medical Center, Dallas, TX, USA. Department of Biochemistry 3. Hamon Center for Regenerative Science and Medicine, Dallas, TX, USA. * Corresponding author

The heat shock transcription factor, HSF1, is a cytoprotective modulator of thermotolerance, age determination, neurodegeneration and oncogenesis. Originally thought to act predominately through protein folding mechanisms, emerging evidence implicates its alternative role as a regulator of the actin cytoskeleton. We have identified an intestinal-specific, actin variant (ACT- 5) as an essential age determinant under HSF1 regulation in C. elegans. Compromising HSF-1 expression impairs activity of the Protein Phosphatase I and causes aberrant mislocalization and accumulation of the ACT-5 protein through its increased phosphorylation. This activity accelerates decay of the sub-apical terminal web within the intestine and decreases its ability to bind adherens junction proteins. Subsequent loss of cell-cell junctional integrity drives intestinal barrier dysfunction, accelerates pathogenesis and promotes early death. Thus, we provide mechanistic explanation for HSF-mediated age-regulation, which entails a novel phosphatase and an uncharacterized post-translational modification on a low abundant variant of actin.

Poster 32

The Role Of p16INK4a Expression In Cartilage Aging And Osteoarthritis Development Presenting author: Brian O. Diekman1,2, [email protected] Co-authors: Garrett A. Sessions1, John A. Collins1, Cathy S. Carlson3, Richard F. Loeser1, Norman E. Sharpless4 1University of North Carolina School of Medicine, Chapel Hill, NC, 2North Carolina State University, Raleigh, NC, 3University of Minnesota, St. Paul, MN, 4Current affiliation: National Cancer Institute, Bethesda, MD

INTRODUCTION: Aging is the greatest risk factor for the development of osteoarthritis (OA), and the increased presence of senescent cells with aging may drive OA through the production of matrix-degrading and pro- inflammatory factors known as the senescence associated secretory phenotype (SASP)1. Increased expression of the cell cycle inhibitor p16INK4a (p16) serves as a biomarker of senescence and excess p16 can play a functional role by preventing necessary proliferation and reinforcing the senescent state2. We hypothesized that p16 expression increases with age in primary human chondrocytes and that in vivo genetic deletion of p16 in murine chondrocytes would limit the development of OA with aging and in response to joint instability. METHODS: All animal experiments were approved by the Institutional Animal Care and Use Committee. For OA studies, cohorts of male mice were injected with tamoxifen at skeletal maturity to induce cartilage-specific loss of p16INK4a (p16 loss, AggrecanCreERT2:p16flox/flox) alongside controls (p16 intact, AggrecanCreERT2:p16wt/wt). Age-related OA was assessed at 18 months and injury-induced OA was assessed 8 weeks after destabilization of the medial meniscus (DMM) performed on 12 month-old mice. The severity of OA was analyzed by an established histological scoring system. For gene expression studies, murine cartilage was isolated using dissection of femoral cap cartilage and primary human chondrocytes were isolated with collagenase digestion from cadaveric ankle tissue. RESULTS: Gene expression of p16 was increased in murine cartilage at 18 months and 22-27 months of age as compared to 4 month old mice (Fig. 1A). p16 also showed a strong correlation to age in primary human chondrocytes (Fig. 1B). The expression of Aggrecan and matrix metalloproteinase (MMP-1) did not correlate to age (Fig. 2A), but donors with high p16 levels had significantly decreased Aggrecan expression and significantly increased MMP-1 expression (Fig. 2B). The genetic loss of p16 was insufficient to protect mice from age-related OA (Fig. 3A) or injury-induced OA (Fig. 3B). In both aging and injury cohorts, we noted an increased rate of bone marrow neoplasia associated with intramedullary bone formation in the p16 loss mice. DISCUSSION: This work establishes that p16 gene expression increases with age in both murine and human cartilage. Furthermore, high p16 expression was found to correlate with other markers of chondrocyte dysfunction independent of age (lower Aggrecan expression and higher MMP-1 expression), which suggests that p16 levels may represent the molecular age of cartilage. Our finding that cartilage-specific p16 loss was insufficient to prevent OA is interesting in the context of recent work showing that specifically killing senescent cells in the joint with “senolytics” reduced the development of post-traumatic OA3. Together, these studies suggest that p16 may be a biomarker of dysfunction but not functionally required for chondrocyte senescence, or that senescence of other cell types in the joint such as the synovium may play a more central role in mediating OA. REFERENCES: This work is in press at Aging Cell (doi: 10.1111/acel.12771). 1) Loeser RF, Collins JA, Diekman BO, 2016, Nat Rev Rheumatol. 12, 412-420. 2) He S & Sharpless NE, 2017, Cell. 169, 1000-1011. 3) Jeon OH et al, 2017, Nat Med. 23, 775-781. This work was conducted while Brian Diekman was an Arthritis and Aging Research Grant recipient from the Arthritis National Research Foundation and American Federation for Aging Research. Additional funding provided by the National Institutes of Health.

Poster 33

A novel angiotensin converting enzyme 1 mutation is associated with increased risk for Alzheimer’s disease and reduces cell survival Leah K Cuddy1, Rudolph E Tanzi2, Robert Vassar1 1Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. 2MassGeneral Institute for Neurodegenerative disease, Charlestown, MA, USA,

Background The Cure Alzheimer’s Fund Genome Project identified a novel, highly penetrant mutation in the angiotensin converting enzyme 1 (ACE1) gene that is associated with increased risk for Alzheimer’s disease (AD). ACE1 is best known for its role in blood pressure control and ACE1 inhibitors (ACEIs) are widely prescribed blood pressure-lowering drugs. Mutant ACE1 could cause AD pathogenesis by raising blood pressure, since midlife hypertension has been associated AD. However, ACE1 is expressed in all tissues including brain and can cleave many substrates. Therefore, any of the myriad of ACE1 functions in the brain or periphery could have a role in AD pathogenesis. The goal of this study is to determine how this mutation increases the risk of AD.

Materials and Methods The role of mutant ACE1 in AD was investigated in cultured forebrain neurons from wild-type (WT) and knock-in (KI) mice and in human SH-SY5Y cells stably expressing either WT ACE1 or mutant ACE1 and in vivo in aged cohorts of WT and KI mice. 6 month old WT and KI mice were treated with captopril, a brain penetrant ACEI, and analyzed at 14 m. To determine the effect of ACE1 KI on amyloid pathology, rAAV1- BRI2-Aβ-42 and control rAAV1- BRI2-ΔKR were stereotaxically injected into the brains of WT or KI mice and ACE1 KI crosses with 5XFAD amyloid mice were analyzed.

Results Blood pressure is unchanged in KI mice, but KI mice show higher functional ACE1 enzyme levels in cortical and cerebellar brain regions and in cultured forebrain neurons compared to WT mice. Unexpectedly, mutant ACE1 reduces cell survival in SH-SY5Y cells, cultured mouse forebrain neurons and in mouse brains. Interestingly, neurodegeneration occurs in ACE1 KI mouse brains primarily in granular neurons of the cerebellum, hippocampus and olfactory bulb. Neurodegeneration observed in KI mice is accelerated by Aβ. Increased cell death is related to a toxic gain-of-function of mutant ACE1.

Discussion These studies will provide novel information about the physiological function ACE1 in the brain, and how altered ACE1 function may cause AD. The results of this study could eventually lead to the use of ACEIs as a treatment or prevention of AD, or alternatively suggest that only ACEIs that do not enter the brain should be prescribed to control blood pressure. Moreover, understanding the role of the ACE1 mutation in AD may identify novel drug targets that could be exploited for the prevention or treatment of AD or other age-related neurodegenerative disorders.

Conclusions Mutant ACE1 increases the risk of AD at least in part by increasing neuronal cell death.

Poster 34

Enhanced skeletal muscle proteostasis as a determinant of CNS protein quality control and neural function in the aging brain

Cortes CJ1, Tucker HA1, Gromova A1‐4, LA Spada AR1‐3.

Departments of Neurology1, Neurobiology2, Cell Biology3, Duke University School of Medicine, Biomedical Sciences Graduate Program4, University of California San Diego

Proteostasis is essential for cell health and viability, and involves complex and highly conserved networks that regulate protein translation, protein folding, and protein degradation. A decline in proteostasis function is one of the features of aging tissues, particularly of the central nervous system (CNS). Indeed, the aging brain is particularly sensitive to proteotoxic stress, as demonstrated by the high number of age‐associated neurodegenerative disorders characterized by protein misfolding and aggregation, including Alzheimer’s disease (AD). The regulation of non‐cell autonomous proteostasis has recently arisen as a novel mechanism for the modulation of systemic homeostasis in worms and flies, and is postulated to have important organismal effects on metabolism and aging. However, to date, there are no studies addressing the existence and activity of these pathways in mammals, and their potential effects on the aging brain. Transcription Factor E‐B (TFEB) is a powerful master transcription factor regulator of proteostasis, integrating autophagy and bioenergetics. We recently derived transgenic mice that moderately overexpress TFEB in skeletal muscle, and discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity in the CNS and also improve cognition and memory in aging mice. We have also uncovered changes in soluble TFEB muscle‐secreted factors (myokines), suggesting a potential modulation of the observed neuroprotective effects. Identification of pathways regulating cross‐talk between skeletal muscle and CNS may yield targets with high therapeutic potential for diseases of the aging CNS. Poster 35

Associated microorganisms can function as methionine sources or sinks to influence Drosophila melanogaster longevity Melinda K. Matthews, Hailey Wilcox, Rachel Hughes, Austin Hammer, Corinne E. Sexton, John M. Chaston Department of Plant and Wildlife Sciences, Brigham Young University, Provo, UT 84602 Animal-associated microbes (‘microbiota’) exert substantial influence on animal aging. To better understand the genetic relationship between animal aging and the microbiota we identified lifespan-influencing bacterial genes and confirmed their influence on animal metabolism using comparative genomic and metabolomic approaches. We used Drosophila melanogaster, a key model in aging research and a developing model for host-microbiota interactions, in this work. As a surrogate genetic screen we used metagenome-wide association (MGWA) to identify bacterial genes that influenced D. melanogaster longevity. First, we measured the individual influence of 41 genome-sequenced bacterial strains on D. melanogaster lifespan in flies that were reared on a nutrient rich diet. To prevent poor diet conditions and introduction of contaminating microbes, flies were transferred to fresh, sterile diets in a biosafety cabinet every 2-3 days, and contamination of the flies was monitored in spent vials (contaminated vials were discarded). Separately, the bacterial genes from the 41 bacteria were clustered using the OrthoMCL software. Bacterial gene presence was associated with variation in D. melanogaster lifespan by MGWA using the MAGNAMWAR R package. A KEGG analysis identified methionine metabolism genes were enriched among the top MGWA predictions, predicting a key role for bacterial methionine metabolism in D. melanogaster lifespan. We confirmed that bacterial methionine metabolism genes influence D. melanogaster lifespan through mutant analysis. In flies reared from sterile embryos with different E. coli methionine cycle mutants we observed both lifespan extension or shortening relative to flies inoculated with wild-type bacteria, confirming a role for bacterial methionine metabolism genes in fruit fly lifespan. To begin to understand how the bacterial influence is mediated, we initially focused on 2 bacterial vitamin B6 mutants that shortened mean fly lifespan by ~ 20%. When we measured the metabolomes of flies and their diets that were inoculated with the bacterial vitamin B6 mutants, there were no changes in the flies’ vitamin B6 content but a significant increase in D. melanogaster methionine content. We tentatively explain the increased levels of methionine as a consequence of bacterial B6 auxotrophy, which may limit conversion of methionine to other metabolites (i.e. cysteine), and propose the vitamin B6 mutants act as a methionine source opposite the lifespan-extending consequences of methionine restriction. To provide additional support for the hypothesis that bacteria alter D. melanogaster aging by functioning as methionine sources or sinks we are collecting targeted metabolomic data for aging flies inoculated with other lifespan-influencing methionine-cycle bacterial mutants. Preliminary findings suggest that the age-dependent influences of methionine are a key factor in the analysis. In the future we hope to provide additional support for this hypothesis through other approaches, including tracking the source of the increased methionine via radiolabeling experiments; and testing if other biologically-relevant aspects of aging (i.e. healthspan) are also affected by the bacteria. Taken together, we anticipate that this work will help to reveal patterns by which animal-associated microorganisms influence animal aging. Poster 36

Mechanisms of sexual dimorphism and mTORC1 effectors in type 2 diabetes, non‐alcoholic fatty liver disease, and aging.

Lear E. Brace,1 Stuart S. Adamson,1 Kaitlyn Vitangcol,1 Koby Ashizawa,1 Emily Klein,1 Bailey Crocker,1 Kallie Ziegler Alkatib,1 and Brian K. Kennedy1,2

1Buck Institute for Research on Aging 2Yong Loo Lin School of Medicine, National University of Singapore.

Age and sex are major risk factors for numerous metabolic diseases that afflict developed countries, including obesity and insulin resistance, which contribute to the progression of Type 2 Diabetes (T2D). The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has long been associated with T2D progression and the Kennedy lab has previously demonstrated that mTORC1 signaling differs in female and male mice and leads to worse progression of obesity and insulin resistance in males. The lab determined that male mice fed a high fat diet (HFD) lose metabolic tissue expression of 4E‐BP1, a downstream effector of mTORC1, leading to a pro‐inflammatory state, obesity, and insulin resistance, whereas females fed a HFD retain 4E‐BP1 expression and have far lesser diabetic phenotypes. Overexpression of 4E‐BP1 in muscle (4E‐BP1mt) protected male mice from T2D, potentially through FGF21 signaling. We aim to determine if FGF21 is a key player in the protection from diabetes progression with 4E‐BP1mt upon a HFD by generating animals that also lack FGF21 to determine if the protection is lost. We also investigate whether contributions of sex chromosomes or gonadal hormone secretions drive sex differences in response to overnutrition and age using mice of the “Four Core Genotypes” (FCG), generating XX‐females, XY‐males, XX‐males, and XY‐females by moving the testes‐determining gene to an autosome. Lastly, we examine another disease that displays sexual dimorphism, non‐alcoholic fatty liver disease (NAFLD), and determine the role FGF21 plays in insulin resistance. We seek to disseminate the molecular mechanisms driving sex‐specificity in diabetes, NAFLD, and aging using novel mouse models and an expertise in biological research.

Poster 37

Improved Metabolic Rate by Teneurin C‐terminal Associated Peptide (TCAP)‐3: A Comparative Approach Across Zebrafish Life‐Stages.

Ross M. Reid1, Andrea D’Aquila2, David Lovejoy2, Peggy R. Biga1 1Department of Biology, University of Alabama at Birmingham, 1300 University Blvd, CH 464, Birmingham, AL 35294 USA 2Cell & Systems Biology Department, University of Toronto, 25 Harbord St., Toronto, ON Canada

Exercise rewards its host with improved skeletal muscle health and increased metabolism, which improves overall energy regulation. Recent research demonstrates that regular exercise can defy the aging process by decreasing age‐related physiological changes including in muscle mass. Recent studies have shown teneurin C‐terminal associated peptide (TCAP)‐1, a bioactive peptide, increases glucose uptake in skeletal muscle, both in vitro and in vivo, as well as skeletal muscle hypertrophy and kinetics, in vivo, in rodent models. Here we investigate the role of TCAP‐3, a closely ‐related paralogue, as a novel activator of muscle metabolism in zebrafish skeletal muscle. To demonstrate TCAP functional conservation, glucose uptake was measured in response to TCAP‐3 treatment in a zebrafish primary myoblast cell culture system. Similar to insulin, TCAP‐3 increased glucose uptake in zebrafish primary myoblasts after 60 minutes of treatment. To assess metabolic rate, oxygen consumption was measured in both larval and adult zebrafish using Loligo systems respirometry chambers and a less labor intensive resazurin metabolic assay. TCAP‐3 treatment increased maximum oxygen consumption rates (~1.8 fold) in adult zebrafish. In addition, TCAP‐3 treatment in increased cumulative NADH2 production (~2‐fold), seen up to 48 hours after treatment, in larval fish. Collectively, these assays demonstrate the conserved effect of TCAP‐3 across life stages in zebrafish. Thus, this project provides insights into the roles of TCAP‐ 3 as a novel regulator of muscle metabolism and may have practical applications in the prevention of metabolism‐associated muscle diseases, such as aging.

Poster 38

Progressive telomere shortening impairs human hepatocyte development and function by down-regulation of human hepatocyte nuclear factor 4a (HNF4a)

Evandro Niero, Alexandre Vessoni, Kirsten Brenner and Luis Batista Department of Medicine, Washington University in St. Louis, St Louis, MO, 63110

Telomere attrition represents a significant risk factor for end-stage liver disease. However, due to a lack of adequate models and intrinsic difficulties in studying telomerase in physiologically relevant cells, the molecular mechanisms responsible for liver disease in settings of dysfunctional telomeres remains elusive. To circumvent that, we used genome editing to generate isogenic human embryonic stem cell lines (hESCs) harboring liver-disease associated mutations (including the common DKC1_A353V mutation) and subjected them to an in vitro, stage-specific hepatocyte differentiation protocol, that resembles hepatocyte development in vivo. Accordingly, we observed that while telomerase is highly expressed in hESCs, it is quickly silenced, due to TERT down- regulation, after endoderm differentiation, and completely absent in in vitro derived hepatocytes, similarly to what is observed in primary hepatocytes. Interestingly, while endoderm derivation is not impacted by telomere shortening, progressive telomere dysfunction significantly impaired hepatic endoderm formation. Consequently, hepatocyte-derivation, as measured by AFP, albumin, FGA and FGG expression, is severely compromised in DKC1_A353V cells. Interestingly, this phenotype was not caused by cell death induction or reduced proliferation. Rather, we determined that telomere shortening induces the down regulation of the human hepatocyte nuclear factor 4 (HNF4), in a p53 dependent manner. Telomerase reactivation, as well as p53 silencing, rescued hepatocyte formation in DKC1_A353V cells. Likewise, conditional expression of HNF4even in cells that retained short telomeres, could successfully restore hepatocyte formation from DKC1_A353V hESCs. Combined, our data shows that telomere dysfunction impairs a major regulator of hepatocyte biology, pointing to a novel target in telomerase dysfunction-induced hepatocyte failure.

Poster 39

Mechanisms of influenza-induced disability with aging Jenna M. Bartley1,2, Spencer R. Keilich1,2, George A. Kuchel1, and Laura Haynes1,2 1Center on Aging, University of Connecticut Health Center, Farmington, CT 2Department of Immunology, University of Connecticut Health Center, Farmington, CT

The elderly have increased susceptibility and severity of infection with influenza (flu) being a top killer. In addition to a greater risk of hospitalization and death, older adults are also more likely to develop disability following flu infection. Utilizing a well-established murine model of flu infection and aging, we have previously shown that despite being a respiratory infection, flu has dramatic effects on skeletal muscle both from a functional and molecular perspective. During flu infection, both young and aged mice have altered gait kinematics, reduced voluntary mobility, and decreased grip strength with more prolonged deficits in the aged mice. Molecularly, there is an upregulation of skeletal muscle atrophy genes (Atrogin1, MuRF-1, UBB, UBC) and a downregulation of positive muscle regulators (IGF1, Pax7, MyoD, MyoG). These effects are prolonged with aging, suggesting a direct link between flu infection and increased risk of disability in the elderly. Here, we aimed to further interrogate the mechanism behind this interaction. We found that there was no direct viral infection of skeletal muscle, however there was alterations in the muscle inflammatory milieu. Flu infection caused upregulation of IL-6 and IL6-RA gene expression in both young and aged mice at day 7, however remained elevated later in infection in aged mice only. Additionally, there was dramatic upregulation of CXCL10 gene expression and protein levels in the gastrocnemius muscle of aged mice only, while anti-inflammatory cytokines such as IL-4 and IL-10 were only elevated in young mice later in infection. This suggests that aged mice have continued inflammation that likely contributes to greater muscle atrophy/degradation, while young mice resolve to an anti-inflammatory and potentially muscle regeneration phenotype. Supporting this thought, immunohistochemistry of murine gastrocnemius muscle revealed higher numbers of leukocytes (CD45+) during flu infection in young and aged mice with a prolonged elevation in the aged mice only. Interestingly, an influx of T lymphocytes (CD45+CD3+) only occurred in aged muscle later in infection likely due to increased muscle-localized CXCL10 causing increased infiltration of CXCR3 expressing T cells into skeletal muscle. It is possible that infiltrating T cells are causing increased muscle atrophy and degradation in the aged mice resulting in increased functional decline and overall disability following flu infection. Ongoing analyses in the lab are focused on better understanding the phenotype and function of infiltrating T cells in skeletal muscle post flu infection, as well as determining the role the CXCL10/CXCR3 axis plays within skeletal muscle during flu infection to better understand the exact mechanism of flu-induced muscle atrophy with aging.

Poster 40

Effects of Exogenous Cannabinoids on the Aging Brain Erik L. Hodges, Jessica Posey, Katherine Blackburn, and Nicole M. Ashpole Department of BioMolecular Sciences, University of Mississippi School of Pharmacy

Age-related reduction in the ability to learn, remember, and perform mental tasks can drastically decrease an individual’s independence and negatively affect their quality of life. Studies suggest that age-related cognitive decline is potentially reversible, yet there are no effective therapeutics available for slowing or reversing these age-related impairments. Our lab is particularly interested in exploring the therapeutic potential of cannabinoids and the endocannabinoid system. Current societal trends indicate that cannabis use, both medicinal and recreational, is increasing. However, there are still gaps in our scientific understanding of this substance’s effects on the brain. It was long-thought that cannabinoids like ∆9-tetrahydrocannabinol (THC) were detrimental to physiological function. Indeed, consumption of high amounts of cannabis is associated with memory loss. However, many studies now tout the therapeutic potential of THC and other cannabinoids in treating disorders of nociception, anxiety, and epilepsy. Increased availability of cannabis and surging societal prevalence necessitate the elucidation of the effects of these substances on the aging system. Recently, studies have implied that THC may have benefits in the aging brain as well. Mice lacking the prototypical receptor for THC (cannabinoid-1 receptor) display age-associated behavioral disturbances earlier than wild-type mice. Furthermore, two new reports indicated that low doses of THC may boost learning and memory in mice. Unfortunately, these studies had considerably different experimental designs, one with a single dose of 0.002mg/kg THC treatment in female mice and one with a chronic treatment of 3mg/kg THC in male mice. Further characterization of the effects elicited by low and high doses of THC at multiple stages of life in both sexes is needed to determine the extent to which cannabinoids might be used to treat age-related functional deficits. The goal of our project is to evaluate whether novel cannabinoids are able to protect neurons from oxidative stress, inflammation, and excitotoxic stress- insults commonly seen in the aging brain. Moreover, we are examining the effects of chronic administration of varying doses of THC in young, middle-aged, and old mice, in order to better understand the potential therapeutic value of THC on the brain. Thus far, we have identified six cannabinoid derivatives that confer neuroprotection in a concentration-dependent manner. While our long-term in vivo studies have just initiated, we have new evidence suggesting that aged mice show increased behavioral responsiveness to cannabinoid analogs, compared to their younger counterparts which highlights the importance of examining these compounds in both young and old animals. 2018 AFAR Grantee Conference Contact Information FIRST LAST INSTITUTION/ORGANIZATION E-MAIL

Christopher Ackerson Colorado State University [email protected] Raj Apte Washington University [email protected] Nicole Ashpole University of Mississippi School of Pharmacy [email protected] Steven Austad University of Alabama at Birmingham [email protected] Jenna Bartley University of Connecticut [email protected] Luis Batista Washington University in St. Louis [email protected] Carolyn Bertozzi Stanford University [email protected] Peggy Biga University of Alabama at Birmingham [email protected] Nancy Bonini University of Pennsylvania [email protected] Lear Brace Buck Institute for Research on Aging [email protected] Roberta Diaz Brinton University of Arizona [email protected] Timothy Caulfield Univeristy of Alberta [email protected] John Chaston Brigham and Young University [email protected] Todd Cohen University of North Carolina at Chapel Hill [email protected] Mark Collins Glenn Foundation for Medical Research www.glennfoundation.org Ray Copeland Glenn Foundation for Medical Research www.glennfoundation.org Constanza Cortes Duke University [email protected] Leah Cuddy Northwestern University [email protected] Brian Diekman University of North Carolina at Chapel Hill [email protected] Andrew Dillin University of California, Berkeley [email protected] Peter Douglas University of Texas Southwestern Medical Center [email protected] Dena Dubal University of California, San Francisco [email protected] Roberto Fernandez-Romero The University of Tennessee Medical Center [email protected] Bess Frost University of Texas Health Science Center at San Antonio [email protected] Michael Garratt University of Michigan [email protected] 2018 AFAR Grantee Conference Contact Information FIRST LAST INSTITUTION/ORGANIZATION E-MAIL

Eric Greer Harvard Medical School [email protected] Leonard Guarente Massachusetts Institute of Technology [email protected] Malene Hansen Sanford Burnham Prebys Medical Discovery Institute, La Jolla [email protected] Hattie Herman AFAR [email protected] Jason Hinman University of California, Los Angeles [email protected] Mladen Jergovic University of Arizona [email protected] Leonard Judson The Glenn Foundation for Medical Research www.glennfoundation.org Catherine Kaczorowski The Jackson Laboratory [email protected] Daniel Kaganovich Hebrew University of Jerusalem [email protected] Itamar Kahn Technion - Israel Institute of Technology [email protected] Jan Karlseder The Salk Institute for Biological Studies [email protected] Vyacheslav Labunskyy Boston University School of Medicine [email protected] Dudley Lamming University of Wisconsin-Madison [email protected] Stephanie Lederman AFAR [email protected] Changhan Lee University of Southern California [email protected] Kevin Lee Glenn Foundation for Medical Research [email protected] Scott Leiser University of Michigan [email protected] Min-Dian Li Harvard Medical School [email protected] Sreemathi Logan University of Oklahoma Health Science Center [email protected] David Marcinek University of Washington Medical Center [email protected] George Martin University of Washington School of Medicine [email protected] Richard Miller University of Michigan [email protected] Arieh Moussaieff The Hebrew University of Jerusalem [email protected] Coleen Murphy Princeton University [email protected] Salvatore Oddo Arizona State University School of Life Sciences [email protected] 2018 AFAR Grantee Conference Contact Information FIRST LAST INSTITUTION/ORGANIZATION E-MAIL

Jay Olshansky University of Illinois at Chicago [email protected] Satchin Panda The Salk Institute for Biological Studies [email protected] Vinay Parikh Temple University [email protected] Andrew Pickering University of Texas Health Science Center at San Antonio [email protected] Veena Prahlad University of Iowa [email protected] Elizabeth Pritchett-Montavon AFAR [email protected] Ling Qi The University of Michigan Medical School [email protected] Peter Rabinovitch University of Washington [email protected] John Reynolds The Salk Institute for Biological Studies [email protected] Nicole Riddle University of Alabama at Birmingham [email protected] Karl Rodriguez University of Texas Health Science Center at San Antonio [email protected] Subhojit Roy University of Wisconsin, Madison [email protected] Jack Rudel Glenn Foundation for Medical Research www.glennfoundation.org Gary Ruvkun Massachusetts General Hospital [email protected] Nathalie Saurat Memorial Sloan Kettering Cancer Center [email protected] Yonatan Savir Technion [email protected] Marissa Schafer Mayo Clinic [email protected] Vittorio Sebastiano Stanford School of Medicine [email protected] Ramaswamy Sharma UTHSCSA [email protected] Yin Shen University of California, San Francisco [email protected] Nina Silverberg National Institute on Aging, National Institutes of Health [email protected] David Sinclair Harvard Medical School [email protected] Michael Stout University of Oklahoma Health Sciences Center [email protected] Beth Stutzmann Rosalind Franklin University [email protected] Yousin Suh Albert Einstein College of Medicine [email protected] 2018 AFAR Grantee Conference Contact Information FIRST LAST INSTITUTION/ORGANIZATION E-MAIL

Nathalie Sumien University of North Texas Health Science Center [email protected] Liou Sun The University of Alabama at Birmingham [email protected] Jacki Trotter Copeland, Hild & Trotter, P.C. www.glennfoundation.org Duygu Ucar Jackson Laborary for Genomic Medicine [email protected] Archana Unnikrishnan University of Oklahoma Health Science Center [email protected] Odette Van Der Willik AFAR [email protected] Jan Van Deursen Mayo Clinic [email protected] Eric Verdin Buck Institute for Research on Aging [email protected] Marc Vermulst Children's Hospital of Philadelphia [email protected] Hsiao-Ying Wey Massachusetts General Hospital [email protected] Tony Wyss-Corey Stanford University School of Medicine [email protected] Rui Xiao University of Florida [email protected] Bruce Yankner Harvard Medical School [email protected] Huiliang Zhang University of Washington [email protected] Brian Zid University of California, San Diego [email protected]

300 dpi photograph

Rajendra S. Apte, MD, PhD Paul A. Cibis Distinguished Professor, Department of Ophthalmology & Visual Science Professor, Department of Developmental Biology Professor of Medicine Director of Translational Research Director, Jeffrey Fort Innovation Fund Fellowship Director, Medical & Surgical Vitreo-Retinal Diseases Washington University School of Medicine

660 S. Euclid Ave, Campus Box 8096, St. Louis, MO 63110 [email protected]

Dr. Rajendra S. Apte is the Paul A. Cibis Distinguished Professor at Washington University School of Medicine in St. Louis, Missouri, where he serves as the Director of Translational Research in the Department of Ophthalmology and Visual Sciences, and is a Professor in the Department of Developmental Biology and Medicine. Dr. Apte received his medical degree from the University of Bombay and joined Washington University School of Medicine after obtaining a Ph.D. in Immunology at the University of Texas Southwestern Medical Center in Dallas, Texas, completing a residency at Parkland Hospital, and a retinal vascular and vitreo-retinal surgery fellowship at The Johns Hopkins University School of Medicine in Baltimore, Maryland. Dr. Apte was recruited to Washington University in 2003 and became a tenured professor at the School of Medicine in less than ten years. Dr. Apte is a vitreoretinal surgeon and clinician scientist. His basic research is focused on inflammation, aging, neurodegeneration and angiogenesis. His clinical research spans the translational spectrum from drug discovery and development to clinical trials. Dr. Apte has published extensively in basic and clinical peer reviewed journals and has participated as a principal investigator in numerous clinical trials.

Dr. Apte has won numerous awards, honors, and educational scholarships, and some recent highlights are as follows: 2018 European Vision and Eye Research Certificate of Honour and Keynote Lecture, 2017 J. Wayne Streilein Distinguished Alumnus Award Lecture in Immunology, 2017 Macula Society W. Richard Green Award, 2016 Research to Prevent Blindness Nelson Trust Award, 2014 Research to Prevent Blindness Sybil B. Harrington Physician-Scientist Award for Age-Related Macular Degeneration, 2014 ASRS Presidents’ Award, 2013/2014 Carl Camras Translational Research Award, the Macula Society Young Investigator Award in 2013, Julie Martin Mid- Career Award in Aging Research from AFAR in 2012, the Macula Society Retina Research Foundation Cox Research Award in 2010, the American Retina Foundation Research Award in 2008, the Washington University Nominee for the Ellison Foundation New Scholars Award in Aging in 2005, and the Research to Prevent Blindness Career Development Award in 2004. These awards accompany his 115+ peer-reviewed publications. His entrepreneurial activities include starting four life sciences companies.

His research has been published in several high impact journals including Nature, Cell, Cell Metabolism, the JCI, Nature Communications, PLoS Medicine, PNAS, among others.

Additionally, Dr. Apte has professional associations with the American Society for Clinical Investigation, American Academy of Ophthalmology, the American Society of Retina Specialists, the Association for Research in Visual Ophthalmology, Club Jules Gonin, the Macula Society, and the Retina Society.

OMB No. 0925-0001 and 0002 (Rev. 11/16 Approved Through 10/31/2018)

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: Austad, Steven Nels eRA COMMONS USER NAME (credential, e.g., agency login): austad POSITION TITLE: Distinguished Professor and Chair of Biology

University of California, Los Angeles (Los Angeles, B.A. 06/1969 English Literature CA) California State University, Northridge (Northridge, B.S. 06/1976 Biology CA) Purdue University, West Lafayette, IN PhD 06/1981 Biological Sciences A. Personal Statement

I have been centrally involved in aging research since the late 1980’s. My work has won both national and international awards (see below). My interests in health- and life-span are thus long-standing as well as wide- ranging. I have published on aging- and health-related topics from cellular to population processes, including nutritional and pharmacological interventions. Indicative of my involvement in many aspects of health- and aging-related topics, I serve on the editorial boards of 8 journals in the field [Aging Cell, Journal of Population Aging, Annual Review of Gerontology & Geriatrics, Journals of Gerontology: Biological Sciences, Geroscience (formerly AGE) Biogerontology, Evolutionary Medicine and Public Health, Longevity & Healthspan and Mechanisms of Aging and Development]. I co-edited with Edward Masoro three editions of the Handbook of the Biology of Aging (2001, 2006, 2011). Therefore I feel that I am highly qualified to participate in this research project. I currently serve as Director of the UAB Nathan Shock Center, one of six such Centers in the US. The focus of this Shock Center is on energetics, health, and aging. I am also one of two PI’s of the multi-PI Nathan Shock Centers Coordinating Center along with Stephanie Lederman of the American Federation for Aging Research (AFAR), an organization for which I am Scientific Director. AFAR is a philanthropic foundation that solicits, reviews, and issues research grants on aging-related topics to a wide range of investigators. I am also the Associate Director of UAB’s Comprehensive Center for Healthy Aging as well as a Senior Scientist at UAB’s Nutrition Obesity Research Center and Center for Exercise Medicine. I previously directed a research core in the Nathan Shock Center of University of Texas Health Science Center San Antonio as well as serving on the External Advisory Board of the Jackson Laboratory Nathan Shock Center. I am currently on the external advisory committee of the Mayo Clinic’s Kogod Center on Aging and the Duke Lemur Center.

B. Positions and Honors

Positions and Employment 1986-1990 Assistant Professor, Department of Organismic & Evolutionary Biology, Harvard University, Cambridge, MA 1990-1992 Associate Professor, Department of Organismic & Evolutionary Biology, Harvard University, Cambridge, MA 1993-1997 Associate Professor, Department of Biological Sciences, University of Idaho, Moscow, ID 1997-2004 Professor, Department of Biological Sciences, University of Idaho, Moscow, ID 2004-2013 Professor, Department of Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, San Antonio, TX

2012-2013 Interim Director, Barshop Institute for Longevity & Aging Studies, University of Texas Health Science Center, San Antonio, San Antonio, TX 2014- present Distinguished Professor & Chair. Department of Biology, University of Alabama at Birmingham, Birmingham, AL 2014- present Scientific Director, American Federation for Aging Research, New York City, NY

Selected Other Positions and Professional Memberships 1992-1997 Science Advisory Board, National Public Radio, Washington, DC 1993-2013 Affiliate Professor, Department of Pathology, University of Washington, Seattle, WA 2000-2006 Executive Scientific Advisory Board, Science of Aging Knowledge Environment, American Association of Science & High Wire Press. 2001-2002 Chair, Biological Sciences Section, Gerontological Society of America, Washington, DC 2001-2013 Initiial Review Board: Aging. Ellison Medical Foundation, Bethesda, MD 2003-2004 Charter Member, NIH Study Section: Cellular Mechanisms of Aging & Development, Bethesda, MD 2004-2012 Co-director (with Gary Ruvkun, Harvard University) Molecular Biology of Aging Training Course, Marine Biological Laboratory, Woods Hole, MA 2006-2011 External Advisory Committee. Jackson Laboratory Aging Center, Bar Harbor, ME 2007-2013 Director, Biology of Aging Training Grant, Barshop Institute for Longevity & Aging Studies, UT Health Science Center, San Antonio, San Antonio, TX 2008-2010 Publications Committee, Gerontological Society of America, Washington, DC 2008-2009 Chair, Ellison/AFAR Postdoctoral Research Grant Review Committee, American Federation for Aging Research, New York, NY 2009-2013 National Scientific Advisory Board, Texas Biomedical Research Institute, San Antonio, TX 2010-2013 Deputy Scientific Director, American Federation for Aging Research, New York, NY 2007 - Board of Directors, American Federation for Aging Research, New York, NY 2009 - External Advisory Committee, Mayo Clinic Kogod Center on Aging, Rochester, MN 2012 - Steering Committee Member. National Institation on Aging Interventions Testing Program, Bethesda, MD 2013 - External Scientific Advisory Committee, Duke Lemur Center, Durham, NC

Selected Honors & Awards

1993 Elected Fellow, Gerontological Society of American, Washington, DC 1993 Elected Member, New York Academy of Sciences 1994 Winner (with John P. Phelan) Geron Corporation-Samuel Goldstein Distinguished Publication Award, Gerontological Society of America, Biology Sciences Section 1997 Phi Kappa Phi/University of Idaho Alumni Association Distinguished Faculty Award 1999 Ellison Medical Foundation Senior Scholar Award 2003 Robert W. Kleemeier Award for Outstanding Research, Gerontological Society of America 2008 Outstanding Alumnus Award, Purdue University, Department of Biological Sciences 2011 Irving S. Wright Award of Distinction, American Federation for Aging Research 2015 Fondation IPSEN Longevity Prize. Boulogne-Billancourt, France 2016 Fellow, American Association for the Advancement of Science

C. Contributions to Science

1. Some of my earliest contributions to the biology of aging field had to do with the interpretation and phenomenology of the life extending effects of dietary restriction. A common interpretation prior to my work was that laboratory animals are grossly overfed and by restricting their diets, we were simply returning them to the healthy level of food intake to which they had evolved. I did the first experiment that combined field observations on food intake with laboratory feeding (in a spider) to show that animals fed much less than they ate in the field lived considerably longer than those fed their “natural” dietary level. I later followed the up by showing from the 24 hour metabolic expenditures of mice living in nature, that mice in the field ate at least as much as ad lib-fed mice in the laboratory. However as a corollary to this work, I began to think that wild mice might not respond to dietary restriction in the same way as did laboratory mice, so I performed a

dietary restriction experiment in wild-derived mice and found that average longevity was not changed under dietary restriction. This was the first finding to indicate that not all genotypes of mice would live longer with a restricted diet – something that has been supported by subsequent work by others. a. Austad, S.N. 1989. Life extension by dietary restriction in the bowl and doily spider, Frontinella pyramitela. Experimental Gerontology 24: 83-92. b. Austad, SN; Kristan, DM. 2003. Are mice calorically-restricted in nature? Aging Cell 2: 209-218. c. Harper, JM, Leathers, CW, Austad, SN. 2006. Does caloric restriction extend life in wild mice? Aging Cell 5, 441-449. PMCID: PMC2923404.

2. I was also the first person to validate an evolutionary theory of aging using a natural field experiment. That theory was that animals that had evolved in an environment with low hazards should exhibit slower aging than animals evolving in a high hazard environment. I critically evaluated this idea by comparing aging in the field in mainland versus island populations of opossums, measuring aging by a combination of field demography, offspring growth rate from mothers of different ages, and tail tendon breaking time. This study is now widely cited in textbooks and the idea is now ensconced as one of the major truths about aging in the natural world. In passing I also discovered in passing during that work that animals really do age in nature, it is not an artifact of captivity as had previously been thought. a. Austad, S.N. 1993. Retarded aging rate in an insular population of opossums. Journal of Zoology 229: 695-708. b. Nussey DH, Froy H, Lemaitre J-F, Gaillard J-M, Austad SN (2013) Senescence in natural populations of animals: widespread evidence and its implications for biogerontology. Aging Research Reviews. 12, 214-225. PMCID: PMC4246505.

3. A third contribution was to use comparative analyses to convincingly debunk several widely-accepted rate- of-living theories of aging and show how large patterns of longevity across the animal world could be explained much better by evolutionary theory. The first of these was rate-of-living theory, the idea that the rate of metabolism dictated longevity. This idea had achieved wide acceptance from previous comparative and experimental work and was even thought by many to explain the dietary restriction effect. I showed that a more refined look at species patterns, in particular marsupials and bats compared with other mammals, showed that metabolic rate did not determine longevity but that the hazardousness of the environment was more important. I also showed that the popular idea that brain size had a major impact on species longevity was also flawed except in the primates. The rate-of-living theory and the brain size theories of aging died peaceful deaths not long thereafter. a. Austad SN, Fischer KE. 1991. Mammalian aging, metabolism, and ecology: evidence from the bats and marsupials. Journal of Gerontology 46:B47-B53. b. Austad SN & Fischer KE. 1992. Primate longevity: its place in the mammalian scheme. American Journal of Primatology 28: 251-261. c. Kirkwood TBL, Austad SN. 2000. Why do we age? Nature 408, 233-238.

4. A fourth contribution has been to illustrate the utility of nontraditional, exceptionally long-lived species for elucidating mechanisms of aging. Specifically, I have introduced into the aging literature, studies of potential cellular mechanisms of aging in birds, where I showed fibroblasts isolated from long-lived wild species have exceptional resistance to a variety of stressors and that that stress resistance is due to actively transcribed genes. I have shown the generality of stress resistance either in cultured cells or in whole animals as a contributor to slow aging in species from bats to bivalve mollusks. A major mechanism of this stress resistance appears to be enhanced proteome homeostasis in divergent species. a. Ogburn CE, Martin GM, Ottinger MA, Holmes DJ, Carlberg K, Austad SN (2001). Exceptional cellular resistance to oxidative damage in long-lived birds requires active gene expression. Journal of Gerontology: Biological Sciences 56A:B468-B474. b. Lambert AJ, Boysen HM, Buckingham JA, Yang T, Podlutsky A, Austad SN, Kunz TH, Buffenstein R, Brand MD. 2007. Low rates of hydrogen peroxide production by isolated heart mitochondria associate with long maximum lifespan in vertebrate homeotherms. Aging Cell, 6: 607-618. c. Treaster SB, Ridgway ID, Richardson CA, Chaudhuri AR, Austad SN. (2014) Superior proteome stability in the world’s longest-lived animal. Age 36(3),9597. doi: 10.1007/s11357-013-9597-9. Epub 2013 Nov 20. PMC4082568.

d. Treaster SB, Chaudhuri A, Austad SN. (2015). Longevity and GAPDH stability in bivalves and mammals: a convenient marker for comparative gerontology and proteostasis. PLoS One Nov 30;10(11):e0143680. doi: 10.1371/journal.pone.0143680. PMC4664256.

5. A recent contribution has been in the development of assays for evaluating healthspan in mice and the assessment of health differences between the sexes. I have actually been a pioneer in this area having noted the importance of, and called for the development of, such metrics in the very early 2000’s. a. Fischer KE, Gelfond JAL, Soto VY, Han C, Someya S, Richardson A, Austad SN (2015). Health effects of long-term rapamycin treatment: the impact on mouse of enteric rapamycin treatment from four months of age throughout life. PloS One May 15;10(5):e0126644. doi: 10.1371/journal.pone.0126644. PMC4433347. b. Richardson A, Fischer KE, Speakman JR, de Cabo R, Mitchell SJ, Peterson CA, Rabinovitch P, Chiao YA, Taffet G, Miller RA, Renteria RC, Bower J, Ingram DK, Ladiges WC, Ikeno Y, Sierra F, Austad SN (2016). Measures of healthspan as indices of aging in mice – a recommendation. Journal of Gerontology Series A Biological and Medical Sciences. 71(4): 427-30. PMC4834833. c. Fischer KE, Hoffman JM, Sloane LB, Gelfond JAL, Soto VY, Richardson AG, Austad SN. (2016). A cross-sectional study of male and female C57BL/6Nia mice suggests lifespan and healthspan are not necessarily correlated. Aging. 8(10):2370-2391. doi: 10.18632/aging.101059. PMC5115894. d. Austad SN, Fischer KE (2016). Sex differences in lifespan. Cell Metabolism 23:1022-33. doi: 10.1016/j.cmet.2016.05.019. PMC4932837.

Selected (more extensive) List of Published Work in My Bibliography: http://www.ncbi.nlm.nih.gov/sites/myncbi/1hYwgtRDVU3Ac/bibliography/47793531/public/?sort=date&direction =ascending

D. Additional Informatin: Research Support and/or Scholastic Performance

Ongoing Research Support

5R01AG057434 Austad (PI) 9/15/17 – 5/31/22 A sex difference approach to evaluating resilience as a predictor of healthspan in mice. Goals: This project will develop resilience assays that predict mouse healthspan, evaluating the success at prediction by relaying on interventions that differentially affect mouse health between the sexes.

P30 AG 050886. Austad (PI) 7/1/15 - 6/30/20 Comparative Energetics and Aging. Nathan Shock Center of Excellence in the Basic Biology of Aging. Goals: This Center grant provides services and leadership to the basic aging research community on methods of assessing the impact of energetics, including body composition, at the cellular and whole animal level on the rate of aging in a range of species as well as providing help in analysis of complex aging, energetics and health datasets.

U24AG056053 Austad/Lederman (PI’s, multi-PI grant) 4/1/17 – 3/31/20 Nathan Shock Center Coordinating Centers. This center grant coordinates activities, including organizing meetings, pilot and feasibility grant announcements, reviews, and grant award logistics. Publicize activities of the Nathan Shock Centers, including availability and use of their Research Cores

1 R01 AG043972 Allison (PI) 09/15/12 - 5/31/17 (now on no-cost extension) Energetics, Disparities, & Lifespan A unified hypothesis. The goal of this research is to investigate the factors that lead to disparities in health, to differences in body fat levels, and to healthier aging in our increasingly older population. Role: Co-investigator

Glenn Foundation for Medical Reseach Austad (PI) 06/01/15-5/31/18 Dietary Restriction in a Short-lived Killifish. This project investigates the impact of restriction of a newly formulated diet on growth, survival, and fecundity of Nothobranchius furzeri, an exceptionally short-lived killifish.

Recently Completed Research Support

R01 AG037962 Austad (PI) 04/30/11 – 05/1/16 Hydra: New Models for Aging Research. The goal of this research was to develop several hydra species as new models for aging research. The project determined optimal conditions for assessment of hydra demography, seek to identify novel genes and pathways involved in modulating aging, and determine the extent to which genomic and proteomic stability determines aging rate in this unique animal model.

R13 AG053043-01 Austad (PI) 04/01/16 – 03/31/17 Disease Drivers of Aging. This grant partially supported the second Geroscience Summit held at the New York Academy of Sciences. The goal of the meeting was to examine the impact of various diseases (cancer, HIV, diabetes) on the aging process.

Timothy Caulfield

Timothy Caulfield is a Canada Research Chair in Health Law and Policy, a Professor in the Faculty of Law and the School of Public Health, and Research Director of the Health Law Institute at the University of Alberta. His interdisciplinary research on topics like stem cells, genetics, research ethics, the public representations of science and health policy issues has allowed him to publish over 350 academic articles. He has won numerous academic and writing awards and is a Fellow of the Royal Society of Canada, the Trudeau Foundation and the Canadian Academy of Health Sciences. He contributes frequently for the popular press and is the author of two national bestsellers: The Cure for Everything: Untangling the Twisted Messages about Health, Fitness and Happiness (Penguin 2012) and Is Gwyneth Paltrow Wrong About Everything?: When Celebrity Culture and Science Clash (Penguin 2015). Caulfield is also the host and co-producer of the documentary TV show, A User’s Guide to Cheating Death. BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: Dena B. Dubal, M.D., Ph.D. eRA COMMONS USER NAME (credential, e.g., agency login): DDUBAL POSITION TITLE: Associate Professor in Residence

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) FIELD OF STUDY INSTITUTION AND LOCATION DEGREE MM/YYYY (if applicable) University of California, Berkeley B.A. 1992–1996 Neurobiology/Anthropology University of Kentucky College of Medicine M.D., Ph.D. 1996–2003 Medicine/Neuroscience Internship 2003–2004 Internal Medicine University of California, San Francisco Residency 2004–2007 Neurology Fellowship 2007–2009 Dementias/Behavioral Neurology Gladstone Institute of Neurological Disease Fellowship 2007–2012 Neurodegenerative Disease

A. Personal Statement I am a physician-scientist, an Associate Professor in Residence in the Department of Neurology at UCSF and hold an Endowed Chair in Aging and Neurodegenerative Disease. My laboratory is focused on mechanisms of resilience in aging, with a particular focus on mechanisms of cognitive resilience through the study of female longevity and the longevity hormone klotho. My expertise in sex biology, aging, transgenic mouse models, and human clinical research provide a strong foundation for high-impact investigations. I am committed to the rigorous study of sex differences in aging, particularly in unraveling mechanisms that protect one sex or make the other more vulnerable.

In addition to my research focus on sex biology, my contributions to promoting the importance of the study of sex as a fundamental biologic variable include (1) service to the Alzheimer’s Association Think Tank on Gender, (2) participation in the Office of Research on Women's Health: Workshop for the NIH, UCSF "New Dimensions and Strategies for Women's Health Research from the NIH", (3) serving as an Associate Editor for the Biology of Sex Differences Journal.

Through my Paul Beeson Award in Aging Research (NIH/AFAR), start-up funds, foundation grants, and philanthropy, my group spearheaded, discovered, and published, in collaboration with others, a series of findings demonstrating mechanisms of brain resilience, as listed below. Our most recent findings, in review, build upon our discovery that sex chromosomes, and specifically X chromosomes, impact susceptibility to aging and deficits in disease models. As a physician-scientist, I hold a steadfast commitment to biomedical discoveries aimed at deciphering and developing strategies for increasing health-span and life-span. Examples of our work include:

1. Leon J, Moreno AJ, Garay BI, Chalkley RJ, Burlingame AL, Wang D, *Dubal DB (*corresponding author). (2017) Peripheral Elevation of a Klotho Fragment Enhances Brain Function and Resilience in Young, Aging, and α-Synuclein Transgenic Mice. Cell Reports, 20(6):1360-71. PMID: 28793260. Cited by 2 (Google Scholar)

2. *Dubal DB, Rogine C. Apolipoprotein E ε4 and Risk Factors for Alzheimer Disease—Let’s Talk About Sex (*corresponding author). (2017) JAMA neurology, 74(10):1167-8. PMID: 28846761.

1 3. *Dubal DB, Broestl L, Worden K (*corresponding author) (2012) Sex and gonadal hormones in mouse models of Alzheimer's disease: what is relevant to the human condition? Biology of Sex Differences. 3:24. PMID: 23126652, PMCID: PMC3524653. Cited by 12 (Google Scholar)

4. *Dubal DB, Yokoyama JS, Zhu L, Worden K, Broestl L, Wang D, Sturm VE, Kim D, Klein E, Yu GQ, Ho K, Eilersten KE, Yu L, Kuro-o M, De Jager P, Coppola G, Small GW, Bennett DA, Kramer JH, Abraham CR, Miller BL, Mucke L* (*co-corresponding author). Life extension factor klotho enhances cognition (2014) Cell Reports S2211-1247. PMID: 24813892, PMCID: PMC4176932. Cited by 89 (Google Scholar)

5. *Dubal DB, Zhu L, Sanchez PE, Worden K, Broestl L, Johnson E, Ho K, Yu GQ, Kim D, Betourne A, Kuro-o M, Masliah E, Abraham CR, *Mucke L (*co-corresponding author). (2015) Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice. Journal of Neuroscience, 35(6):2358-71. PMID: 25673831, PMCID: PMC4323521. Cited by 48 (Google Scholar)

Submissions: 1. Davis EJ, Lobach I, Dubal DB*. Male sex chromosome complement and testes increase mortality in aging. In review 2. Minones-Moyano E, Broestl L, Worden K, Devidze N, Kim DH, Garay B, Chang K, Yu GQ, Palop J, Wang D, Arnold A, White CC, Panning B, Bennett DA, De Jager P, Mucke L, *Dubal DB. The second X Chromosome confers resilience in Alzheimer disease. In revision

B. Positions and Honors Positions and Employment 1996–2003 MD/PhD Student; graduate work with Dr. Phyllis Wise, Integrative Neuroscience, University of Kentucky College of Medicine, Lexington, KY 2003–2004 Medical Intern, University of California, San Francisco 2004–2007 Resident and Chief Resident in Neurology, University of California, San Francisco 2007–2012 Postdoctoral Fellow and Staff Scientist, Gladstone Institute of Neurological Disease, San Francisco, CA 2012–2017 Assistant Professor in Residence, Dept of Neurology, University of California, San Francisco 2018–present Associate Professor in Residence, Dept of Neurology, University of California, San Francisco

Other Experience and Professional Memberships Advisory Committees 2001 Institutional Review Board: Sanders-Brown Center on Aging, University of Kentucky 2008–present Residency Admissions Committee, Dept of Neurology, UCSF 2010 Neurology Research Committee, Dept of Neurology, UCSF 2012–2014 Committee on Women Faculty in Neurology, Dept of Neurology, UCSF

Grant Peer Review NSF, American Federation for Aging Research (AFAR), Texas Alzheimer’s Research Care Consortium, Private foundations for Alzheimer’s disease funding, NIA (invited, not yet served)

Journal Editorship 2017–present JAMA Neurology, Associate Editor 2015–present Cell Reports, Editorial Board 2014–present Biology of Sex Differences, Associate Editor and Editorial Board

Professional Memberships American Neurological Association, Society for Neuroscience, Organization for the Study of Sex Differences, Alzheimer’s Association, American Academy of Neurology

Honors 1996–2003 Medical Scientist Training Scholarship, University of Kentucky College of Medicine

2 1997–1999 National Institutes of Health (NIH) Predoctoral Training Grant Fellowship, Molecular and Cellular Aspects of Brain Aging, University of Kentucky 1998 Glenn/American Federation for Aging Research (AFAR) Scholarship 1999 Glenn Foundation Endocrinology and Aging Award 2000 Merck/AFAR Scholarship in Geriatric Pharmacology for Medical Students 2000 Alpha Omega Alpha Research Award 2001 American Medical Association (AMA), Overall Excellence in Clinical Research Award, National Student Research Forum 2001 AMA, Center on Aging Award, National Student Research Forum 2002 Alpha Omega Alpha Member 2003 American Academy of Neurology Outstanding Neurology Award 2006 Kaiser BEST Resident Award, San Francisco Neurological Society 2006–7 Neurology Chief Resident, University of California, San Francisco 2008 Larry Hillblom Foundation Fellow 2008 Diplomate, American Board of Psychiatry and Neurology 2009–2014 NIA and AFAR Paul Beeson Career Development Award, Aging Research (K08) 2010 Elizabeth Young New Investigator Award, Organization for the Study of Sex Differences 2012–present David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease 2014 Member, American Neurological Association (ANA) 2014 Glenn Award for Research in Mechanisms of Biological Aging 2015 AFAR Award for Junior Faculty Research on Aging 2015 Grass Foundation – ANA Award in Neuroscience

C. Contribution to Science 1. My early publications examined the role of sex and gonadal hormones in models of aging and age- related neurodegenerative disease. We found that low levels of estradiol decreased the extent brain injury in rodent models through estrogen-receptor alpha–mediated mechanisms. Further, we found that estradiol modulates key players of cell death like bcl-2. This work contributed to the shift in our understanding of estrogens as effectors of the brain beyond the reproductive axis. Our findings continue to have implications for the study of sex differences, sequelae of menopause, and effects of hormone replacement in neurologic disease.

a. Dubal DB, Kashon ML, Pettigrew LC, Ren JM, Finklestein SP, Rau SW, Wise PM (1998) Estradiol Protects Against Ischemic Injury. Journal of Cerebral Blood Flow and Metabolism 18:1253-1258. PMID: 9809515. Cited by 575 (Google Scholar) b. Dubal DB, Shughrue PJ, Wilson ME, Merchenthaler I, Wise PM (1999) Estradiol Modulates bcl-2 in Cerebral Ischemia: A Potential Role for Estrogen Receptors. Journal of Neuroscience. 19(15):6385- 6393. PMID: 10414967. Cited by 556 (Google Scholar) c. Dubal DB, Zhu H, Yu J, Rau SW, Shughrue PJ, Merchenthaler I, Kindy MS, Wise PM (2001) Estrogen Receptor -, not -, is Critical in Estradiol-Mediated Neuroprotection Against Brain Injury. Proceedings of the National Academy of Sciences 98(4):1952-1957. PMID: 11172057, PMCID: PMC29363. Cited by 569 (Google Scholar)

2. My fellowship training in basic mechanisms of neurodegenerative disease focused on the pathogenesis of and potential protective targets against Alzheimer’s disease. My work using transgenic mouse models and cell culture paradigms identified a new role for collagen VI in binding to and aggregating amyloid-beta (A) in human and mouse studies. Additionally, I contributed to the discoveries of other fellows in identifying 2) EphB2 as a target of A–mediated toxicity and 2) tau as a pathogenic protein in the spread of Alzheimer toxicity from the entorhinal cortex.

a. *Cheng JC, *Dubal DB (*co-first author), Kim DH, Legleiter J, Cheng IH, Yu GQ, Tesseur I, Wyss- Coray T, Bonaldo P, Mucke L. (2009) Collagen VI Protects Neurons Against A Toxicity. Nature Neuroscience 12(2): 119-121. PMID: 19122666, PMCID: PMC2812922. Cited by 65 (Google Scholar)

3 b. Cisse M, Halabisky B, Harris J, Devidze N, Dubal DB, Lotz G, Kim DH, Hamto T, Ho K, Yu GQ, Mucke L. (2011) Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature 469(7328): 47-52. PMID: 21113149, PMCID: PMC3030448. Cited by 300 (Google Scholar) c. Harris JA, Koyama A, Maeda S, Ho K, Devidze N, Dubal DB, Yu GQ, Masliah E, Mucke L. (2013) Human P301L-Mutant Tau Expression in Mouse Entorhinal-Hippocampal Network Causes Tau Aggregation and Presynaptic Pathology but No Cognitive Deficits. PLoS One. 7(9):e45881. PMID: 23029293, PMCID: PMC3454317. Cited by 61 (Google Scholar)

3. The focus of my laboratory is to investigate sexual dimorphisms and mechanisms of neural resilience in aging and disease. To this end we study the neural actions of 1) klotho and 2) sex chromosomes in health and disease using approaches in humans and mouse models ranging from genetics to cognition to molecular pathways. In several human populations, we found that higher levels of klotho associate with better cognitive function and resilience against chronic stress. Using mouse models, we found that klotho enhances cognition through NMDA receptor-dependent mechanisms and counters effects of pathogenic proteins involved in neurodegenerative disease. We have also mapped mechanisms of disease susceptibility to sex chromosomes – and specifically the second X Chromsome – and are dissecting its genetic and epigenetic influence in aging. Collectively, our studies may lead to a new way of boosting brain function by increasing its resilience in aging, against various pathogenic proteins across the lifespan, and in a sex-dependent manner.

a. Leon J, Moreno AJ, Garay BI, Chalkley RJ, Burlingame AL, Wang D, *Dubal DB (*corresponding author). (2017) Peripheral Elevation of a Klotho Fragment Enhances Brain Function and Resilience in Young, Aging, and α-Synuclein Transgenic Mice. Cell Reports, 20(6):1360-71. PMID: 28793260. Cited by 2 (Google Scholar) b. *Dubal DB, Rogine C. Apolipoprotein E ε4 and Risk Factors for Alzheimer Disease—Let’s Talk About Sex (*corresponding author). (2017) JAMA neurology, 74(10):1167-8. PMID: 28846761. c. *Dubal DB (co-corresponding author), Yokoyama JS, Zhu L, Worden K, Broestl L, Wang D, Sturm VE, Kim D, Klein E, Yu GQ, Ho K, Eilersten KE, Yu L, Kuro-o M, De Jager P, Coppola G, Small GW, Bennett DA, Kramer JH, Abraham CR, Miller BL, Mucke L*. Life extension factor klotho enhances cognition (2014) Cell Reports S2211-1247. PMID: 24813892, PMCID: PMC4176932. Cited by 89 (Google Scholar) d. Yokoyama JS, Sturm VE, Bonham LW, Klein E, Arfanakis K, Yu L, Coppola G, Kramer JH, Bennett DA, Miller BL, *Dubal DB (corresponding author). (2015) Variation in longevity gene KLOTHO is associated with greater cortical volumes. Annals of Clinical and Translational Neurology 2(3):215- 230. PMID: 25815349, PMCID: PMC4369272. Cited by 23 (Google Scholar) e. *Dubal DB (co-corresponding author), Zhu L, Sanchez PE, Worden K, Broestl L, Johnson E, Ho K, Yu GQ, Kim D, Betourne A, Kuro-o M, Masliah E, Abraham CR, *Mucke L. (2015) Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice. Journal of Neuroscience, 35(6):2358-71. PMID: 25673831, PMCID: PMC4323521. Cited by 48 (Google Scholar) f. *Prather AA, Epel ES, Arenander J, Broestl L, Garay BI, Wang D, *Dubal DB (co-corresponding author) (2015). Longevity factor klotho and chronic psychological stress. Translational Psychiatry 5;e585: 1-6. PMID: 26080320. Cited by 14 (Google Scholar)

Complete List of Published Work in My Bibliography: http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/45874745/?sort=date&direction=ascending

D. Research Support On-going Research Support R01 NS092918-01A1 Dubal (PI) 04/2016-03/2021 Klotho and Neurodegenerative Disease

R21 AG051858-01 Okonkwa (PI) 01/2016-01/2019 Genetic and Lifestyle Determinants of Cognitive Resilience in Midlife

AFAR Junior Faculty Research Grant Dubal (PI) 07/2015–06/2018 Epigenetic changes in the X chromosome in the brain with aging.

Bakar Family Foundation Dubal (PI) 01/2015–01/2020 Cognitive aging.

Hillblom Network Kramer (PI) 01/2015–present Prevention of Age-Associated Cognitive Decline in normal human aging.

NIH/CTSI Catalyst Award Dubal (PI) 10/2017-present Development of klotho as a therapy in aging and disease.

Completed Research Support (past three years) K08 AG034531, Paul Beeson Award in Aging Research Dubal (PI) 9/01/09–9/30/2014 The goal of this project was to investigate factors in the pathogenesis and protection against Alzheimer’s Disease.

Glenn Award for Research in Mechanisms of Biological Aging Dubal (PI) 07/2014-07/2016 Mechanisms of klotho in countering chronic stress and aging

5 Malene Hansen, Ph.D. Professor Associate Dean of Student Affairs Faculty Advisor, Postdoctoral Training Sanford Burnham Prebys Medical Discovery Institute

Biographical Sketch Dr. Hansen is a Professor in the Program for Development, Aging and Regeneration at the Sanford Burnham Prebys Medical Discovery Institute (SBP), a nonprofit research institute located in San Diego, CA. She obtained a Master of Science in biochemistry in 1998, and a doctorate in molecular biology in 2001, both from Copenhagen University, Denmark. Hansen subsequently carried out postdoctoral studies in the laboratory of Cynthia Kenyon, Ph.D., at the University of California, San Francisco. She started her laboratory at SBP in the fall of 2007, and currently serves as Associate Dean for Student Affairs in SBP’s recently accredited graduate program, and as Faculty Advisor on postdoctoral training for SBP’s 150 postdoctoral scholars. In recognition of her mentoring efforts, Hansen recently received the 2017 Mentor Award from the National Postdoctoral Association.

Dr. Hansen has also received several awards for her research on the molecular mechanisms of aging, including an Ellison Medical Foundation New Scholar in Aging Award, a Glenn Award for Research in Biological Mechanisms of Aging, and a Julie Martin Mid-Career Award in Aging Research supported by the Ellison Medical Foundation and American Association for Aging Research. Her lab is currently funded by R01 grants from both the National Institute on Aging and the National Institute for General Medical Sciences. Since 2002, she has published more than 50 research articles, reviews, and book chapters. Hansen serves as an ad hoc reviewer for multiple scientific journals, and is currently a permanent member of the National Institute’s of Health’s Cellular and Molecular Mechanisms of Aging study section. Hansen is the 2018 co-organizer of Cold Spring Harbor Laboratory’s meeting on Mechanisms of Aging, and is the co-chair for the 2020 Gordon conference on Autophagy.

Research Interests/Scientific Focus Aging is a fundamental biological reality that is familiar to all of us. But how do organisms age at the molecular level? Several genes and processes have been identified that affect the rate of aging, many of which play important roles in highly conserved signaling pathways with relevance to age-related diseases like cancer and neurodegeneration. However, how these processes and conserved genes affect aging at the cellular and molecular level to influence organismal aging is not fully understood. The Hansen lab's research is directed towards understanding the molecular mechanisms that affect the process of aging, with a special focus on the role and regulation of the cellular recycling pathways called autophagy.

Dr. Catherine Kaczorowski is Associate Professor and Evnin Family Endowed Chair in Alzheimer’s Research at The Jackson Laboratory. She received a bachelor’s degree in Psychology from the University of Wisconsin in Milwaukee, a Ph.D. in Neuroscience from Northwestern University, and completed postdoctoral training in Biotechnology and Bioengineering at the Medical College of Wisconsin. She joined the faculty of The Jackson Laboratory in October 2017 to develop advanced systems biology resources for identification of genetic, molecular, cellular and neuronal network mechanisms underlying individual differences in ‘normal’ cognitive aging and resilience to AD. In addition to their utility in the discovery of novel drug targets, the approaches and tools that she recently developed are enabling rapid mouse‐to‐human translational validation on a scale that far surpasses what had been previously achievable. Her contributions to the field of neurogenetics and aging have been recognized by the International Behavioural and Neural Genetic Society Young Investigator Award and the Glenn Award for Research in Biological Mechanisms of Aging. Dr. Kaczorowski is currently the lead PI on 2 R01s focused on understanding the biology of normal cognitive aging and resilience to Alzheimer’s disease, a BrightFocus Foundation Award, and enjoys mentoring a number of pre‐doctoral and post‐doctoral fellows that have been generously supported by awards from AFAR, NIH NRSA and the Alzheimer’s Association. She credits much of her success to early support from the AFAR 2014 New Investigator Award in Alzheimer's Disease.

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors.

Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: MARCINEK, DAVID J eRA COMMONS USER NAME (agency login): MARCINEK POSITION TITLE: Associate Professor EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.) INSTITUTION AND LOCATION DEGREE Completion Date FIELD OF STUDY (if applicable) MM/YYYY Kalamazoo College, Kalamazoo, MI BA 06/1993 Biology Stanford University, Stanford, CA PHD 03/2000 Physiology University of Washington, Seattle, WA Postdoctoral Fellow 02/2003 Mitochondrial Energetics University of Washington, Seattle, WA NIH training grant 06/2005 Mitochondria in Aging

A. PERSONAL STATEMENT

I am well-suited to contribute to the scientific goals of this project because I have several years of experience mentoring high school students and undergraduates in my research laboratory. My laboratory has developed and applies techniques to measure mitochondrial function, bioenergetics, and skeletal muscle performance at multiple levels of organization. In addition, I have a broad background and over a decade of experience in biochemical analyses of mitochondria and metabolism in skeletal muscle. We focus on linking biochemical and cellular level changes in to in vivo function. We use permeabilized cells, isolated mitochondria, and state of the art in vivo spectroscopy to dissect skeletal muscle energetics. We use isolated muscles, in situ and in vivo preparations to assess contractile function and whole animal exercise training and testing to assess performance. Our laboratory has recently identified novel interactions between oxidative stress and dynamic control of mitochondrial metabolism in vivo. We are currently collaborating with several research groups to study the role of mitochondrial energetics in pathology of chronic disease and aging, including muscular dystrophy, cancer, and neurodegenerative disease. I am currently and have served as principal investigator on several significant awards from NIH and private foundations, including an R01, R21 RC2, K01 awards, and an award from the Ellison Medical Foundation.

1. Ryu D, Zhang H, Ropelle ER, Sorrentino V, Mazala DAG, Mouchiroud L, Marshall PL, Campbell MD, Ali AS, Knowels GM, Bellemin S, Iyer SR, Wang X, Gariani K, Sauve AA, Canto C, Conley KE, Ludvine W, Lovering RM, Chin ER, Jasmin BJ, Marcinek DJ, Menzies KJ, Auwerx J. 2016. NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation. Science Transl Med. 8(361):361ra139. PubMed PMID:27798264; PubMed Central PMCID: in process. 2. Siegel MP, Wilbur T, Mathis M, Shankland EG, Trieu A, Harper ME, Marcinek DJ. Impaired adaptability of in vivo mitochondrial energetics to acute oxidative insult in aged skeletal muscle. Mech Ageing Dev. 2012 Sep-Oct;133(9-10):620-8. PubMed PMID: 22935551; PubMed Central PMCID: PMC3456966. 3. Percival JM, Siegel MP, Knowels G, Marcinek DJ. Defects in mitochondrial localization and ATP synthesis in the mdx mouse model of Duchenne muscular dystrophy are not alleviated by PDE5 inhibition. Hum Mol Genet. 2013 Jan 1;22(1):153-67. PubMed PMID: 23049075; PubMed Central PMCID: PMC3522404. 4. Siegel MP, Kruse SE, Percival JM, Goh J, White CC, Hopkins HC, Kavanagh TJ, Szeto HH, Rabinovitch PS, Marcinek DJ. Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell. 2013 Oct;12(5):763-71. PubMed PMID: 23692570; PubMed Central PMCID: PMC3772966. B. POSITIONS AND HONORS Positions and Employment 2005 - 2011 Research Assistant Professor of Radiology, University of Washington 2008 - 2011 Adjunct Research Assistant Professor of Bioengineering, University of Washington 2009 - Co-Director, Translational Center for Metabolic Imaging, University of Washington 2011 - Associate Professor of Radiology, University of Washington 2011 - Adjunct Associate Professor of Bioengineering, University of Washington 2013 - Adjunct Associate Professor of Pathology, University of Washington

Other Experience and Professional Memberships 1995 - Member, American Physiological Society 1995 - 2000 Member, Society of Integrative and Comparative Biology 2002 - 2010 Member, Mitochondrial Research Society 2008 - Scientific Advisory Council, American Federation of Aging Research 2011 - Member, Society for Free Radical Biology and Medicine 2011 - 2014 Member, Faculty of 1000 2015 - Member, Career Development Committee - Society for Free Radical Biology and Medicine

Honors 1999 Arthur Geise Award for Best Experimental Research, Hopkins Marine Station 2000 Genetic Approaches to Aging Training Grant, University of Washington 2003 Nominee Burroughs Wellcome Fund Career Development Award, University of Washington 2006 New Scholar Award in Aging, Ellison Medical Foundation 2007 Early Career Award Recognition, University of Washington 2008 Participant - Summer Training Course in Aging Research, NIA 2011 Invited Lecturer NIA Summer Training Course in Aging Research, NIA 2011 Invited Participant Roundtabe on Connecting Skeletal Muscle Physiology to Common Diseases and Disorders, NIAMS 2012 Member - Special Emphasis Panel Study Section, NIA 2013 Ad hoc member SMEP CSR Study Section, NIH 2014 Invited Lecture Summer Training Course in Aging Research, NIA 2014 Chair - Ad Hoc Study Section, NIA 2015 Chair - Ad hoc Study Section, NIA 2015 Glenn Foundation Award for Biological Mechanisms of Aging 2016 Ad hoc member CMAD CSR Study Section, NIH

C. Contribution to Science

1. New in vivo tools. I developed an approach that combines NMR and optical spectroscopy to measure mitochondrial quality and capacity in vivo in skeletal muscle. This unique approach allows quantitative measurement of resting ATP and O2 fluxes, muscle oxygenation, maximal mitochondrial ATP production, and energy state non-invasively. These tools allowed new directions in my research program and have since been adapted for use in human muscle studies. We have adapted these tools for experiments on 4.7T, 7T,and 14T magnetic resonance scanners. The ability to non-invasively measure mitochondrial function with simultaneous MR and optical spectroscopy has allowed us to explore the effects of acute manipulation of the redox environment in muscle and has led to a new paradigm for our approach to studying oxidative stress, mitochondrial function, and aging. a. Marcinek DJ, Ciesielski WA, Conley KE, Schenkman KA. Oxygen regulation and limitation to cellular respiration in mouse skeletal muscle in vivo. Am J Physiol Heart Circ Physiol. 2003 Nov;285(5):H1900- 8. PubMed PMID: 12775561. b. Marcinek DJ, Schenkman KA, Ciesielski WA, Conley KE. Mitochondrial coupling in vivo in mouse skeletal muscle. Am J Physiol Cell Physiol. 2004 Feb;286(2):C457-63. PubMed PMID: 14522819. c. Marcinek DJ, Amara CE, Matz K, Conley KE, Schenkman KA. Wavelength shift analysis: a simple method to determine the contribution of hemoglobin and myoglobin to in vivo optical spectra. Appl Spectrosc. 2007 Jun;61(6):665-9. PubMed PMID: 17650380. d. Marcinek DJ, Kushmerick MJ, Conley KE. Lactic acidosis in vivo: testing the link between lactate generation and H+ accumulation in ischemic mouse muscle. J Appl Physiol (1985). 2010 Jun;108(6):1479-86. PubMed PMID: 20133437; PubMed Central PMCID: PMC2886682. 2. Identified reduced mitochondrial P/O as an early response to oxidative stress. Using new non- invasive tools developed by our lab we have identified reduced coupling of oxidative phosphorylation as an early response to oxidative stress that precedes structural damage to the mitochondria. This work provided the first in vivo demonstration of the ability of a redox-related signal to regulate mitochondrial energetics. This discovery laid the foundation for our later experiments examining the control of mitochondrial deficits by oxidative stress in aging skeletal muscle. a. Amara CE, Shankland EG, Jubrias SA, Marcinek DJ, Kushmerick MJ, Conley KE. Proc Natl Acad Sci USA. 2007 Jan 16;104(3):1057-62. PubMed PMID:17215370; PubMed Central PMCID: PMC1766336. b. Siegel MP, Kruse SE, Knowels G, Salmon A, Beyer R, Xie H, Van Remmen H, Smith SR, Marcinek DJ. Reduced coupling of oxidative phosphorylation in vivo precedes electron transport chain defects due to mild oxidative stress in mice. PLoS One. 2011;6(11):e26963. PubMed PMID: 22132085; PubMed Central PMCID: PMC3222658. c. Conley KE, Amara CE, Bajpeyi S, Costford SR, Murray K, Jubrias SA, Arakaki L, Marcinek DJ, Smith SR. Higher mitochondrial respiration and uncoupling with reduced electron transport chain content in vivo in muscle of sedentary versus active subjects. J Clin Endocrinol Metab. 2013 Jan;98(1):129-36. PubMed PMID: 23150693; PubMed Central PMCID: PMC3537085. d. Marcinek DJ, Siegel MP. Targeting redox biology to reverse mitochondrial dysfunction. Aging (Albany NY). 2013 Aug;5(8):588-9. PubMed PMID: 23945201; PubMed Central PMCID: PMC3796210. 3. Direct targeting of mitochondrial oxidative stress reverses the age-related decline in function. We have found that directly targeting mitochondrial oxidative stress with SS-31 treatment late in life can reverse the age-related decline in skeletal muscle and cardiac function. This work led to a new focus on the reversal of age-related deficits in our research. This presented a new paradigm for our perspective on aging compared to our previous emphasis on slowing the aging process. This work has led directly to an on going clinical trial to test whether acute treatment with SS-31 can improve skeletal muscle function in the elderly. a. Dai DF, Chen T, Wanagat J, Laflamme M, Marcinek DJ, Emond MJ, Ngo CP, Prolla TA, Rabinovitch PS. Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria. Aging Cell. 2010 Aug;9(4):536-44. PubMed PMID: 20456298; PubMed Central PMCID: PMC3265170. b. Marcinek DJ, Siegel MP. Targeting redox biology to reverse mitochondrial dysfunction. Aging (Albany NY). 2013 Aug;5(8):588-9. PubMed PMID: 23945201; PubMed Central PMCID: PMC3796210. c. Siegel MP, Kruse SE, Percival JM, Goh J, White CC, Hopkins HC, Kavanagh TJ, Szeto HH, Rabinovitch PS, Marcinek DJ. Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell. 2013 Oct;12(5):763-71. PubMed PMID: 23692570; PubMed Central PMCID: PMC3772966. d. Marcinek DJ, Conley KE. In vivo metabolic spectroscopy identifies deficits in mitochondrial quality and capacity in aging skeletal muscle. Clin Pharmacol Ther. 2014 Dec;96(6):669-71. PubMed PMID: 25207702. PubMed Central PMCID:PMC4707046. 4. Interaction between mitochondria and cell environment regulates energetics in health and disease. The application of in vivo tools to measure mitochondrial energetics has demonstrated that under stressful conditions the cell environment plays an important role in regulating mitochondrial energetics. The impact of this contribution is that under some conditions in vivo mitochondrial deficits will not be reflected in traditional ex vivo assays of mitochondrial function where the mitochondria are separated from the in vivo physiological environment. One such condition is the reversible redox regulation of mitochondrial energetics. Under redox stress multiple aspects of mitochondrial oxidative phosphorylation can be reversible inhibited by redox modification. This inhibition will be lost in isolated mitochondria or permeabilized cells where the mitochondria are assayed in standard media. Thus the combination of in vivo and ex vivo tools provides an important strategy for understanding the role of redox biology in mitochondrial deficits in aging and disease. a. Siegel MP, Wilbur T, Mathis M, Shankland EG, Trieu A, Harper ME, Marcinek DJ. Impaired adaptability of in vivo mitochondrial energetics to acute oxidative insult in aged skeletal muscle. Mech Ageing Dev. 2012 Sep-Oct;133(9-10):620-8. PubMed PMID: 22935551; PubMed Central PMCID: PMC3456966. b. Dai DF, Chiao YA, Marcinek DJ, Szeto HH, Rabinovitch PS. Mitochondrial oxidative stress in aging and healthspan. Longev Healthspan. 2014;3:6. PubMed PMID: 24860647; PubMed Central PMCID: PMC4013820. c. Marcinek DJ, Conley KE. In vivo metabolic spectroscopy identifies deficits in mitochondrial quality and capacity in aging skeletal muscle. Clin Pharmacol Ther. 2014 Dec;96(6):669-71. PubMed PMID: 25207702. PubMed Central PMCID:PMC4707046. 5. Mitochondrial dysfunction is a fundamental aspect of multiple pathological conditions. We have identified an important role for mitochondrial dysfunction in multiple disease models. Studies in rodent models of muscular dystrophy, neurodegenerative disease, cardiac disease, chronic exposure to environmental toxins, in addition to our work in aging have identified an important contribution of mitochondrial dysfunction to the pathological process. This has been an important insight because it has reinforced the idea that developing an effective intervention to reverse mitochondrial deficits could have far ranging translational benefits. a. Kruse SE, Watt WC, Marcinek DJ, Kapur RP, Schenkman KA, Palmiter RD. Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy. Cell Metab. 2008 Apr;7(4):312-20. PubMed PMID: 18396137; PubMed Central PMCID: PMC2593686. b. Dai DF, Johnson SC, Villarin JJ, Chin MT, Nieves-Cintrón M, Chen T, Marcinek DJ, Dorn GW 2nd, Kang YJ, Prolla TA, Santana LF, Rabinovitch PS. Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ Res. 2011 Apr 1;108(7):837-46. PubMed PMID: 21311045; PubMed Central PMCID: PMC3785241. c. Percival JM, Siegel MP, Knowels G, Marcinek DJ. Defects in mitochondrial localization and ATP synthesis in the mdx mouse model of Duchenne muscular dystrophy are not alleviated by PDE5 inhibition. Hum Mol Genet. 2013 Jan 1;22(1):153-67. PubMed PMID: 23049075; PubMed Central PMCID: PMC3522404. d. Yeh A, Kruse SE, Marcinek DJ, Gallagher EP. Effect of omega-3 fatty acid oxidation products on the cellular and mitochondrial toxicity of BDE 47. Toxicol In Vitro. 2015 Jun;29(4):672-80. PubMed PMID: 25659769. PubMed Central PMCID: PMC4479582.

Complete List of Published Work in My Bibliography: http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/41149634/ D. RESEARCH SUPPORT Ongoing Research Support 2015/07/01-2018/06/30 AFAR Breakthrough in Gerontology Award Mitochondrial oxidative stress alters aged muscle function through oxidation of the thiol proteome MARCINEK, DAVID J (PI) Role: PI

2012/09/24-2018/07/31 - NCE R01 ES021930-03S1, National Institute of Environmental Health Sciences (NIEHS) MARCINEK, DAVID J (PI) A novel antibody based biomarker for toxicity of chronic domoic acid exposure Role: PI

2/1/2013-1/31/2018 OCE-1314088, NSF (joint funding with R01 ES021930 above) MARCINEK, DAVID J (PI) A novel antibody based biomarker for toxicity after chronic domoic acid exposure Role: PI

2017/02/01-2022/01/31 P01 AG01751, NIH/NIA Rabinovitch, Peter (PI) Mitochondrial Antioxidants, Aging, and Healthspan Role: Co-Investigator

2018/07/01-2020/06/30 R01 DK109199– NIH to Thomas Jefferson University MARCINEK, DAVID J (PI) – UW subcontract Regulation of substrate metabolism in skeletal muscle by mitochondrial thioesterases Role: Sub contract PI

2017/09/01-2022/08/31 U24 – NIH to Pacific Northwest National Laboratory (PNNL) MARCINEK, DAVID J (PI) – UW subcontract ProMoTr: A Proteomics Center for MoTrPAC Role: PI-UW subcontract

2017/09/01-2018/08/31 R56 AG055594, NIH Myocardial Infarct in Aging Animals and dATP Therapy Role: Co-Investigator

2017/09/01-2018/08/31 R56 AG055114, NIH/NIA Preventing cardiac and skeletal muscle aging by restoring mitochondrial function Role: Multi-PI (Rabinovitch and Marcinek) Completed Research Support 12/1/14-05/30/16 AstaReal, Inc. (P.I. Marcinek) Astaxanthin Treatment Improves Exercise Performance and Mitochondrial Function in Aged Mice

12/1/12-11/30/15 R21 AG042637-01A1 (P.I. Marcinek) NIH/NIA SS peptides: A New Approach to Improve Mitochondrial and Skeletal Muscle Function with Age

05/01/10 – 03/31/14 R01 HL101186-01 (P.I. Rabinovitch; Co-Inv Marcinek) NIH/NHLBI Cardiomyocyte Mitochondria and mtROS in Cardiac Aging, Hypertrophy and Failure

7/1/12 – 6/30/13 Nathan Shock Center Pilot Award. (P.I. Marcinek) UW Nathan Shock Center Restoration of Mitochondrial Redox by SS Peptides Reverses Mitochondrial Deficits S. Jay Olshansky received his Ph.D. in Sociology at the University of Chicago in 1984. He is currently a Professor in the School of Public Health at the University of Illinois at Chicago, Research Associate at the Center on Aging at the University of Chicago and at the London School of Hygiene and Tropical Medicine, and Chief Scientist at Lapetus Solutions, Inc. The focus of his research to date has been on estimates of the upper limits to human longevity, exploring the health and public policy implications associated with individual and population aging, forecasts of the size, survival, and age structure of the population, pursuit of the scientific means to slow aging in people (The Longevity Dividend), and global implications of the re-emergence of infectious and parasitic diseases. Dr. Olshansky is on the Board of Directors of the American Federation of Aging Research; he is the first author of The Quest for Immortality: Science at the Frontiers of Aging (Norton, 2001) and A Measured Breath of Life (2013); and co-edited Aging: The Longevity Dividend (Cold Spring Harbor Laboratory Press, 2015). In 2016, Dr. Olshansky was honored with the Donald P. Kent Award from the Gerontological Society of America, the Irving S. Wright Award from the American Federation for Aging Research, and he was named one of Next Street’s Influencer in Aging.

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: Panda, Satchidananda eRA COMMONS USER NAME (credential, e.g., agency login): SATCHINPANDA POSITION TITLE: Associate Professor

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) Completion DEGREE FIELD OF STUDY INSTITUTION AND LOCATION Date (if applicable) MM/YYYY Orissa University of Ag. & Tech., India B.Sc. 12/1991 Genetics Tamilnadu Ag. Univ., India M.Sc. 04/1994 Biotechnology The Scripps Research Institute, La Jolla, CA Ph.D. 05/2001 Molecular Biology Genomics Institute of the Novartis Research Postdoctoral 11/2004 Genomics, Neurosci. Foundation, San Diego, CA

A. Personal Statement

B. Positions and Honors.

1996-2001 Graduate Student, The Scripps Research Institute, La Jolla, California 2001-2004 Postdoctoral Fellow, Genomics Institute of Novartis Research Foundation, San Diego, CA 2003 Finalist for Science-Eppendorf Prize in Neurobiology 2004-2011 Assistant Professor, The Salk Institute for Biological Studies, La Jolla, CA 2006 Pew Scholar in Biomedical Research 2011- 2016 Associate Professor, The Salk Institute for Biological Studies, La Jolla, CA 2014 The Julie Martin Mid-Career Award in Aging Research 2016- present Professor, The Salk Institute for Biological Studies, La Jolla, CA

C. Contribution to Science. 1. My research into the genome-wide circadian gene expression pattern revealed nearly the entire genome is circadianly expressed in a tissue specific manner. I laid the experimental framework and data analyses pipeline that illustrated how circadian gene expression of key regulators is timed to different times of the day. These discoveries identified key nodes through which circadian oscillator modulates physiology, behavior and metabolism to optimize adaptation to the ambient condition. These findings attracted a new wave of scientists from different fields of cell biology, metabolism, neuroscience and physiology to circadian rhythm research to understand how circadian disruption contributes to chronic diseases. a. Panda S, Antoch MP, Miller BH, Su AI, Schook AB, Straume M, Schultz PG, Kay SA, Takahashi JS, Hogenesch JB (2002) Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109: 307-320. b. Hughes ME, DiTacchio L, Hayes KR, Vollmers C, Pulivarthy S, Baggs JE, Panda S, Hogenesch JB (2009) Harmonics of circadian gene transcription in mammals. PLoS Genet 5: e1000442. c. Vollmers C, Gill S, DiTacchio L, Pulivarthy SR, Le HD, Panda S (2009) Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proc Natl Acad Sci U S A 106: 21453-21458.

d. Vollmers C, Schmitz RJ, Nathanson J, Yeo G, Ecker JR, Panda S (2012) Circadian Oscillations of Protein-Coding and Regulatory RNAs in a Highly Dynamic Mammalian Liver Epigenome. Cell Metab 16: 833-845. e. Mure LS, Le HD, Benegiamo G, Chang MW, Rios L, Jillani N, Maini N, Kariuki T, Dkhissi- Benyahya O, Cooper HM, Panda S (2018) Diurnal transcriptome atlas of a primate across major neural and peripheral tissues. Science (advance online publication on 08 Feb. 2018) 2. I have made seminal discoveries in the area of how light entrains the circadian clock to the ambient lighting condition. Rodents and humans with outer retina degeneration can still entrain to ambient light, thus indicating a novel non-rod, non-cone photoreceptor entrains the clock. Using mouse genetics I discovered that melanopsin, expressed in a small number of retinal ganglion cells, plays a dominant role in circadian photoentrainment. I also established that rod/cone and melanopsin account for all ocular photoresponses in the visible spectrum of light in mammals. Subsequent elucidation of the signaling pathways, spectral sensitivity of melanopsin, and discovery of a non-retinoid antagonist of melanopsin has wide impact in multiple disciplines of science including neuroscience, vision science, circaidan biology, behavioral science, architecture, and lighting industry. a. Panda S, Sato TK, Castrucci AM, Rollag MD, DeGrip WJ, Hogenesch JB, Provencio I, Kay SA (2002) Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science 298: 2213-2216. b. Panda S, Provencio I, Tu DC, Pires SS, Rollag MD, Castrucci AM, Pletcher MT, Sato TK, Wiltshire T, Andahazy M, Kay SA, Van Gelder RN, Hogenesch JB (2003) Melanopsin is required for non-image-forming photic responses in blind mice. Science 301: 525-527. c. Panda S, Nayak SK, Campo B, Walker JR, Hogenesch JB, Jegla T (2005) Illumination of the melanopsin signaling pathway. Science 307: 600-604. d. Jones KA, Hatori M, Mure LS, Bramley JR, Artymyshyn R, Hong SP, Marzabadi M, Zhong H, Sprouse J, Zhu Q, Hartwick AT, Sollars PJ, Pickard GE, Panda S (2013) Small-molecule antagonists of melanopsin-mediated phototransduction. Nat Chem Biol 9: 630-635. 3. My research has identified how small molecule metabolites reciprocally interact with circadian clock components and use this information to treat diseases. By forward genetics approach I identified a key regulator of NAD metabolism affecting the core circadian clock in plants. This relation between circadian clock and NAD metabolism is conserved across species and forms a reciprocal regulatory mechanism between clock and cellular metabolism. Using a novel functional genomics approach, we identified ROR group of nuclear hormone receptors as key positive regulators of the circadian oscillator, which offered a direct connection between circadian clock and metabolism. Subsequently, my lab has been instrumental in the discovery of Jumonji class of chromatin regulators as conserved components of the circadian clock from plants to mammals. Jumonji class or proteins intimately regulate the function of mitochondria, which intimately regulates redox state of the cell. Redox metabolism is linked to circadian clock through heme binding and activating the circadian clock components REV-ERBs. We have used pharmacological activation of REV-ERB as a novel method to repress autophagy and fatty acid synthesis in cancer cells to kill tumors. I have recently summarized the intimate reciprocal regulation between clock and metabolism in a unique review. a. Panda S, Poirier GG, Kay SA (2002) tej defines a role for poly(ADP-ribosyl)ation in establishing period length of the arabidopsis circadian oscillator. Dev Cell 3: 51-61. b. Sato TK, Panda S, Miraglia LJ, Reyes TM, Rudic RD, McNamara P, Naik KA, FitzGerald GA, Kay SA, Hogenesch JB (2004) A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 43: 527-537. c. DiTacchio L, Le HD, Vollmers C, Hatori M, Witcher M, Secombe J, Panda S (2011) Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock. Science 333: 1881-1885. d. Panda S (2016). Circadian physiology of metabolism. Science 354(6315): 1008-1015. e. Sulli G, Rommel A, Wang X, Kolar MJ, Puca F, Saghatelian A, Plikus MV, Verma IM, Panda S. (2018) Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature. 2018 Jan 18;553(7688):351-355. 4. My pioneering work on transcriptome regulation by circadian clock and time of food intake has led to the discovery that eating pattern can profoundly affect diurnal gene expression. We have leveraged this knowledge to devise time-restricted-feeding or eating (TRF or TRE) in which animals have access to food for a defined

period of time that ranges between 8 h and 12 h every day. TRF does not restrict caloric intake and hence is not caloric restriction, yet it imparts beneficial pleiotropic effects on prevention and prognosis of metabolic diseases. Surprisingly, TRF also improves sleep and neuromuscular function, thus offering novel entry point to understanding how metabolism can affect CNS function. TRF also changes the gut microbiome composition and their function leading to changes in nutrient digestion, absorption and excretion. a. Hatori M, Vollmers C, Zarrinpar A, Ditacchio L, Bushong EA, Gill S, Leblanc M, Chaix A, Joens M, Fitzpatrick JA, Ellisman MH, Panda S (2012) Time-Restricted Feeding without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed a High-Fat Diet. Cell Metab 15: 848- 860. b. Chaix A, Zarrinpar A, Miu P, Panda S (2014) Time-Restricted Feeding Is a Preventative and Therapeutic Intervention against Diverse Nutritional Challenges. Cell Metab 20: 991-1005. c. Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. Zarrinpar A, Chaix A, Yooseph S, Panda S (2014). Cell Metab 20(6): 1006-1017. d. Gill S, Le HD, Melkani GC, Panda S (2015) Time-restricted feeding attenuates age-related cardiac decline in Drosophila. Science 347: 1265-1269. e. Gill, S., Panda, S. (2015) A Smartphone App Reveals Erratic Diurnal Eating Patterns in Humans that Can Be Modulated for Health Benefits. Cell Metab. 2015 Nov 3;22(5):789-98. Complete List of Published Work in MyBibliography: http://www.ncbi.nlm.nih.gov/pubmed/?term=satchidananda+panda

Google Scholar page https://scholar.google.com/citations?user=6VZfvlIAAAAJ&hl=en&oi=ao

Citation indices All Since 2013 Citations 14441 7732 h-index 48 41 i10-index 70 67

D. Research Support

OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018)

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors.

Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: Rabinovitch, Peter eRA COMMONS USER NAME (agency login): PETERSR POSITION TITLE: Professor, Department of Pathology EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.) INSTITUTION AND LOCATION DEGREE Completion Date FIELD OF STUDY (if applicable) MM/YYYY University of Washington, Seattle, WA BS 07/1972 Physics University of Washington , Seattle, WA MD 12/1979 Medicine University of Washington , Seattle, WA PHD 08/1980 Genetics

A. PERSONAL STATEMENT I have been an active investigator in the field of the biology of aging for over 30 years, the author of over 270 peer-reviewed publications and have been the Director of the University of Washington Nathan Shock Center of Excellence in the Basic Biology of Aging since its inception in 1995, as well as the director of the University of Washington’s Biology of Aging Training Grant (T32 AG00057) since 1995. Over the past 8 years my research has had a special focus on healthspan and longevity extension by interventions that enhance mitochondrial function. The decline in cardiac function with age has proven to be an especially interesting phenotype in this work. The transgenic model of catalase targeted to mitochondria (mCAT), developed here, has been a useful and effective component of these studies, as mCAT mice show reduced cardiac aging and are resistant to models of cardiac hypertrophy and failure. The healthspan benefits of mCAT have more recently been translated to pharmacotherapy by showing that the peptide drug SS-31 confers similar cardiac and skeletal muscle benefits. A second focus of study of cardiac health has derived from studies of modulation of the mTOR pathway by genetic and drug (rapamycin) treatments. Both of these avenues of study have now converged by demonstrating the benefits to the aging heart of improving mitochondrial protein quality and energetics. The focus of my work is now to demonstrate the benefits of therapies that will improve the physiologic function of aging mice and to establish the mechanisms of these effects, which we hypothesize is by acute enhancement of mitochondrial function, followed by persistent structural, proteomic and metabolic remodeling. My long experience in studies of the biology of aging, mitochondrial interventions and cardiac function are well suited for proficiencies in these studies. B. POSITIONS AND HONORS Positions and Employment 1981 - 1983 Instructor, Dept. of Pathology, University of Washington, Seattle, WA 1983 - 1987 Assistant Professor, Department of Pathology, University of Washington, Seattle, WA 1987 - 1992 Professor, Department of Pathology, University of Washington, Seattle, WA 1992 - Professor, Department of Pathology, University of Washington, Seattle, WA 1997 – Full Member (Joint), Fred Hutchinson Cancer Research Center, Seattle , WA 2016 - Vice Chair of Research, Department of Pathology, University of Washington, Seattle, WA Other Experience and Professional Memberships 1984 - Director, Flow Cytometry Laboratory, Anatomic Pathology, University of Washington Medical Center 1995 - Director, Nathan Shock Center for Excellence in the Basic Biology of Aging , University of Washington 1997 - Director, Genetic Approaches to Aging Training Program (T32 AG00057), University of Washington 2000 - 2004 Secretary, International Society of Analytical Cytology 2008 - 2011 Member, NIA Biological Aging Review Committee (NIA-B Scientific Review Group) 2011 - 2013 Chair, NIA Biological Aging Review Committee (NIA-B Scientific Review Group) 2013 - 2014 Research Committee, American Federation for Aging Research Honors and Awards 2010 Senior Scholar in Aging Award, Ellison Medical Foundation 2010 Breakthroughs in Gerontology Research Award, American Federation for Aging Research 2014 Denham Harman Lifetime Achievement in Research Award, American Aging Association 2015 Aging Cell Best Paper Prize 2014: “Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart” 2015 Fellow of the American Association for the Advancement of Science 2016 Distinguished Service Award, International Society of Analytical Cytometry 2017 Aging Cell Best Paper Prize 2016: “Mitochondrial-Targeted Catalase is Good for the Old Mouse Proteome but not for the Young: Reverse Antagonistic Pleiotropy?”

C. Contribution to Science 1. My early work had a focus on analytical cytometry and its applications to the biology of aging. I developed new methods in analysis of the cell cycle and cell proliferation and in flow cytometric analysis of intracellular calcium signaling. Although early work, some of these publications remain among my most cited. a. Rabinovitch PS. Regulation of human fibroblast growth rate by both noncycling cell fraction transition probability is shown by growth in 5-bromodeoxyuridine followed by Hoechst 33258 flow cytometry. Proc Natl Acad Sci U S A. 1983 May;80(10):2951-5. PMID: 6190165; PMCID: PMC393951. b. Rabinovitch PS, June CH, Grossmann A, Ledbetter JA. Heterogeneity among T cells in intracellular free calcium responses after mitogen stimulation with PHA or anti-CD3. Simultaneous use of indo-1 and immunofluorescence with flow cytometry. J Immunol. 1986 Aug 1;137(3):952-61. PMID: 2424993. c. O'Sullivan JN, Bronner MP, Brentnall TA, Finley JC, Shen WT, Emerson S, Emond MJ, Gollahon KA, Moskovitz AH, Crispin DA, Potter JD, Rabinovitch PS. Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat Genet. 2002 Oct;32(2):280-4. PMID: 12355086. d. Risques RA, Lai LA, Brentnall TA, Li L, Feng Z, Gallaher J, Mandelson MT, Potter JD, Bronner MP, Rabinovitch PS. Ulcerative colitis is a disease of accelerated colon aging: evidence from telomere attrition and DNA damage. Gastroenterology. 2008 Aug;135(2):410-8. PMID: 18519043; PMCID: PMC2574910 2. Nutrient signaling through the mTOR pathway is among the best proven and most central determinants of longevity and health span across vertebrate and invertebrate models. It provides targets for pharmacological interventions that may act as "caloric restriction mimetics", for which rapamycin is now the leading example. Our studies of the mTOR pathway and rapamycin initially began with a focus on protein quality control; however this work has surprisingly converged on enhanced mitochondrial function and energetics in preserving health, particularly in the heart. In fact, we have found that short term rapamycin treatment of 24 mo old mice rejuvenates cardiac function, and remodels cardiac mitochondrial energetics, metabolism and the proteome towards a more youthful state. a. Johnson SC, Yanos ME, Kayser EB, Quintana A, Sangesland M, Castanza A, Uhde L, Hui J, Wall VZ, Gagnidze A, Oh K, Wasko BM, Ramos FJ, Palmiter RD, Rabinovitch PS, Morgan PG, Sedensky MM, Kaeberlein M. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science. 2013 Dec 20;342(6165):1524-8. PMID: 24231806; PMCID: PMC4055856. b. Karunadharma PP, Basisty N, Dai DF, Chiao YA, Quarles EK, Hsieh EJ, Crispin D, Bielas JH, Ericson NG, Beyer RP, MacKay VL, MacCoss MJ, Rabinovitch PS. Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects. Aging Cell. 2015 Mar 23. doi: 10.1111/acel.12317PMID: 25807975; PMCID: PMC4531069 c. Dai DF, Karunadharma PP, Chiao YA, Basisty N, Crispin D, Hsieh EJ, Chen T, Gu H, Djukovic D, Raftery D, Beyer RP, MacCoss MJ, Rabinovitch PS. Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell. 2014 Jun;13(3):529- 39. PMID: 24612461; PMCID: PMC4040127. (This work was selected for the Aging Cell Best Paper Prize of 2014) d. Chiao YA, Kolwicz SC, Basisty N, Gagnidze A, Zhang J, Gu H, Djukovic D, Beyer RP, Raftery D, MacCoss M, Tian R, Rabinovitch P. Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging (Albany NY), 2016 Feb 11. PubMed PMID: 26872208; PMCID: PMC4789585 3. The recent focus of research has been healthspan and longevity extension by interventions that enhance mitochondrial function. The extended lifespan of transgenic mice that expressed catalase targeted to mitochondria (mCAT), established by our P01 AG001751 began this line of study. The decline in cardiac function with age has been an informative healthspan indicator that has high transitional relevance. Cardiac aging is attenuated in mCAT mice and these mice are also protected from experimental models or cardiac hypertrophy and failure. The healthspan benefits of mCAT have recently been translated to an effective pharmacotherapy by showing that the peptide drug SS-31 confers similar cardiac and skeletal muscle benefits, although the mechanism appears to be primarily via protection of cardiolipin, improving cytochrome c electron carrying capacity, and only secondarily by preventing reactive oxygen release. This line of study now focuses on the enhancement of mitochondrial function in aging and its potential to improve the function of vital organs (including heart and skeletal muscle) that are highly dependent on mitochondrial energetics. a. Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 2005 Jun 24;308(5730):1909-11. PMID: 15879174. b. Dai DF, Santana LF, Vermulst M, Tomazela DM, Emond MJ, MacCoss MJ, Gollahon K, Martin GM, Loeb LA, Ladiges WC, Rabinovitch PS. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation. 2009 Jun 2;119(21):2789-97. PMID: 19451351; PMCID: PMC2858759. c. Dai DF, Chen T, Szeto H, Nieves-Cintrón M, Kutyavin V, Santana LF, Rabinovitch PS. Mitochondrial targeted antioxidant Peptide ameliorates hypertensive cardiomyopathy. J Am Coll Cardiol. 2011 Jun 28;58(1):73-82. PMID: 21620606; PMCID: PMC3742010. d. Dai DF, Hsieh EJ, Chen T, Menendez LG, Basisty NB, Tsai L, Beyer RP, Crispin DA, Shulman NJ, Szeto HH, Tian R, MacCoss MJ, Rabinovitch PS. Global proteomics and pathway analysis of pressure- overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail. 2013 Sep 1;6(5):1067-76. PMID: 23935006; PubMed Central PMCID: PMC3856238. 4. My interests in mitochondrial biology and cardiac aging have converged, such that, oxidative stress and redox state, protein quality control, and technologies to study them (including mass spectroscopy) have become a central aspect of the laboratory’s study of aging and healthspan. a. Quarles EK, Dai DF, Tocchi A, Basisty N, Gitari L, Rabinovitch PS. Quality control systems in cardiac aging. Ageing Res Rev. 2015 Feb 19. pii: S1568-1637(15)00022-7. doi: 10.1016/j.arr.2015.02.003. [Epub ahead of print] PMID: 25702865 ; PMCID: PMC4686341 b. Karunadharma PP, Basisty N, Chiao YA, Dai DF, Drake R, Levy N, Koh WJ, Emond MJ, Kruse S, Marcinek D, MacCoss MJ, Rabinovitch PS. Respiratory chain protein turnover rates in mice are highly heterogeneous but strikingly conserved across tissues, ages, and treatments. FASEB J. 2015 May 14. pii: fj.15-272666. PMID: 25977255 ; PMCID: PMC4511201 c. Kruse SE, Karunadharma PP, Basisty N, Johnson R, Beyer RP, MacCoss MJ, Rabinovitch PS, Marcinek DJ. Age modifies respiratory complex I and protein homeostasis in a muscle type-specific manner. Aging Cell. 2016 Feb;15(1):89-99. PMID: 26498839; PMCID: PMC4717270 d. Basisty N, Dai D-F, Gagnidze A, Gitari L, Fredrickson J, Beyer RP, Hsieh EJ, Maina Y, Emond MJ, MacCoss MJ, Martin GM, Rabinovitch PS. Mitochondrial-Targeted Catalase is Good for the Old Mouse Proteome but not for the Young: Reverse Antagonistic Pleiotropy? Aging Cell, 2016 Aug;15(4):634-45. PMID: 27061426 ; PMCID: PMC4933659 Complete List of Published Work in My Bibliography: http://www.ncbi.nlm.nih.gov/myncbi/peter.rabinovitch.1/bibliography/41507121/public/?sort=date&direction=des cending

D. Additional Information: Research Support and/or Scholastic Performance. RABINOVITCH, P

Ongoing Research Support,

P30 AG013280 (Rabinovitch) 8/01/15 - 6/30/20 NIH/NIA Nathan Shock Center for Excellence in the Basic Biology of Aging The Nathan Shock Center provides resources in support of investigators in studies of the basic biology of aging. Research Cores provide services in Proteomics, Metabolomics and assessments of healthspan of invertebrate aging models. A Development Core provides pilot projects in the biology of aging. An Enrichment Core provide outreach and administrative services.

P01AG001751 (Rabinovitch) 3/1/17-2/28/22 NIH Mitochondrial Antioxidants, Aging and Healthspan Project 1: Mitochondrial ROS and Cardiac Aging (Rabinovitch) Core A: Administration (Rabinovitch) This project examines effects mitochondrial ROS on cardiac aging and hypertrophy. Core A provides administrative support and coordination for the projects.

P01AG001751S1 (Rabinovitch) 3/1/17-2/28/19 Research Supplement to Promote Diversity in Health-Related Research Program for Dr. Maria Sweetwyne 3P01AG001751-33A1S2 (Rabinovitch) 09/01/2017 – 03/31/2018 Administrative supplement to develop research on Alzheimer's disease and Alzheimer's-related dementias

1R56AG055114-01 (P. Rabinovitch and D. Marcinek, Co-PIs) 09/30/2017 – 08/31/2018 NIH/NIA Preventing Skeletal and Cardiac Muscle Aging by Restoring Mitochondrial Function The goal of this award is to focus on two underdeveloped areas of study in skeletal muscle and heart: how mitochondrial antioxidants alter mitochondrial dynamics and turnover and whether altered AMPK and mTOR signaling link altered mitochondrial function to improved healthspan.

R56 AG055594-01 (M. Regnier, PI) 9/30/17-9/29/18 NIH/NIA Myocardial Infarct in Aging Animals and dATP Therapy The goal of this project is two-fold: 1) to determine how age, compounded by myocardial infarct (MI) affects cardiac function and how this affects skeletal muscle function and exercise tolerance; and 2) to determine the ability of elevated cellular levels of 2 deoxy-ATP (dATP) to affect heart and skeletal muscle performance, metabolism and exercise tolerance in age and MI induced heart failure.

Other Support 5 T32 AG000057-36 (Rabinovitch) 5/1/2013 – 4/30/2018 NIH/NIA Genetic Approaches to Aging Training Grant Dr. Rabinovitch is the longstanding Director of this training program which provides support for 8 postdoctoral and 8 predoctoral trainees in studies of the biology of aging.

David A. Sinclair, Ph.D. CURRICULUM VITAE

David Sinclair, Ph.D. is a Professor of Genetics at Harvard Medical School and Founding Director of the Paul F. Glenn Center for the Biological Mechanisms of Aging at Harvard. He is also a Conjoint Professor at the University of New South Wales, Honorary Professor, University of Sydney, and Co-Chief Editor of the journal Aging.

During his undergraduate studies and his PhD at one of Australia’s leading universities (UNSW), he received the highest grades and won a national prize for his work in the fields of Biochemistry and Molecular Genetics (CSL and The Commonwealth Prizes, respectively). He was the first non-US citizen to be awarded a prestigious Helen Hay Whitney Fellowship, allowing him to leave Australia in 2005 to work with Lenny Guarente at M.I.T. where he discovered a cause of aging in yeast, a first any organism. The work led the team to discover genes called the “Sirtuins” that enhance performance and the fitness of organisms and slow their pace of aging. At the age of 29, he was recruited to Harvard Medical School and shortly thereafter became Founding Director of the Paul F. Glenn Laboratories for Aging Research, a group that includes four labs at Harvard and a consortium of 11 universities. He is now a fully tenured professor in the world’s leading genetics department.

Dr. Sinclair’s research is focused primarily on understanding genes that fight disease and aging, with a focus on treating the major causes of death and disability. He studies cellular energy production, learning and memory, neurodegeneration as well. He has won awards for his work understanding why we age, for showing that the Sirtuins can be activated by agents such as resveratrol from red wine, and for understanding how diet and exercise can be mimicked by a drug. More recently his work has branched out to understand why stem cells stay young, how to engineer the human genome, bioinformatics, how to reverse aging, and how to enhance human fitness. He regularly lectures at Harvard, serves on NIH grant review panels, and has directly mentored more than 100 young scientists over the past 20 years.

He is a board member of the American Federation for Aging Research, a Founding Editor of the journals Aging, and has received more than 35 awards including the CSL Prize, The Australian Commonwealth Prize, a Helen Hay Whitney Postdoctoral Award, a Leukemia Society Fellowship, a Ludwig Scholarship, a Harvard-Armenise Fellowship, an American Assoc. for Aging Research Fellowship, The Nathan Shock Award from NIH, Scholarships from The Ellison Medical Foundation, The Merck Prize, the Genzyme Outstanding Achievement in Biomedical Science Award, a "Bio-Innovator award", the David Murdock-Dole Lectureship, the Fisher Honorary Lectureship at UCLA, a MERIT Award from the National Institute on Aging, the Denham Harman Award for Gerontological Research, the “ASMR Medal” from the Australian Society for Medical Research, a Knowledge Nation 100 Recipient, an ambassador for business events (Sydney), the Kersten lecturer (USC), a Pioneer Award from the Director of the NIH, Advance Global Australian Award, and will receive the Irving Wright AFAR “Award of Distinction” (2018). He is considered a leading entrepreneur of his generation having founded 14 biotechnology companies that have attracted more than US$2B in investment and are working to improving the human condition. In 2014 he was listed by TIME magazine as “one of the 100 most influential people in the world”.

Primary Titles: Professor, Harvard Medical School, Genetics Department Founding Director, Paul F. Glenn Labs for Aging Research Con-joint Professor, University of New South Wales, Medicine Co-Chief Editor, journal Aging

Citizenship: USA and Australian

Office Address: Harvard Medical School New Research Building, Room 933 Paul F. Glenn Labs for the Biological Mechanisms of Aging 77 Avenue Louis Pasteur, Boston, MA, USA 02115 (617 432-3931)

Australian address: Con-joint Professor The University of New South Wales Medicine Wallace Wurth Building, 3rd Floor Sydney, NSW Australia 2052 (617 320 7033, mobile)

Home Address: 43 Newbrook Circle, Newton, MA, 02467

Email: [email protected]

Place of Birth: Sydney, Australia

Education:

1991 Bachelor of Science, University of New South Wales, Australia Honors Class 1. CSL Prize.

1992-1996 Ph.D. in Biochemistry, University of New South Wales, Australia Biochemistry and Molecular Genetics, Highest Class Grade, Summa Cum Laude Commonwealth Prize for best thesis presentation in Australia.

1996-1999 Postdoctoral Fellow, M.I.T., with L. P. Guarente, subject: Genetics of Aging

All Faculty Positions:

1999-2004 Assistant Professor, Harvard Medical School 2004-2008 Associate Professor, Harvard Medical School 2008-2010 Tenured Professor, Harvard Medical School 2005- Founding Director, Paul F. Glenn Laboratories, Harvard Medical School 2010- Tenured Professor, Department of Genetics, Harvard Medical School 2009- Honorary Professor, University of Sydney, Australia 2011- Con-joint Professor, University of New South Wales, Australia

Selected Awards and Honors: 1992 Commonwealth Serum Laboratories (CSL) Prize 1994 Thompson Prize 1992 – 1996 Graduate Research Scholarship 1996 – 1999 Helen Hay Whitney Postdoctoral Fellowship 1999 - 2000 Charles Hood Fellowship 1999 – 2002 Leukemia Society of America Special Fellowship 2000 - 2001 Ludwig Institute Young Faculty Award 2000 - 2002 American Federation for Aging Research Fellowship 2001 – 2005 Ellison Medical Foundation New Scholar Award 2001 – 2003 Arminese - Harvard Fellowship 2005 Genzyme Outstanding Achievement in Biomedical Science Award 2006 Telluride Technology Festival Honoree 2006 Bright Sparks Award, Australia's leading scientists under 45 2006 Excellence in Teaching Award, Harvard Medical School 2007 Innovator of the Year, BioAgenda Institute 2007-2011 Ellison Medical Foundation Senior Scholarship 2008 Merck Prize, University of Alberta, CA 2008 David Murdock-Dole Lectureship, Australia 2010 Fisher Honorary Lectureship, UCLA 2010 Nathan Shock Award, NIH 2010 Firkin Oration, Melbourne, Australian Society of Biochem. Mol. Biol. 2010 Les Lazarus Award, The Garvan Institute, Australia 2012 NIH MERIT Award 2014 Denham Harmon Award for Research in Gerontology 2014 The Australian Medical Research Medal (ASMR) 2014 TIME 100 – list of “World’s Most Influential People” 2015 Frontiers in Aging Research Award 2015 Knowledge Nation 100, Australia’s 100 top contributors to knowledge economy 2016 Winner, NASA’s iTech competition, innovative solutions getting to Mars 2017 Kesten Memorial Lecture (USC) 2017 Advance Global Australian Award, National Winner 2017 NIH Director’s Pioneer Award 2017 Irving Wright AFAR Award of Distinction 2018 The Order of Australia (AO, not yet public information)

Selection of Local Community Service Related to Professional Work: Aug, 2003 "Science Alive" Seminars at the Museum of Science, Boston, MA Feb, 2004 “Longwood Seminars," annual lecture series for lay public, Boston, MA Jul, 2004 Speaker, Annual meeting of Spinal Cord Injury Association, Boston Jan, 2007 Science Café, Nova, ScienceNOW seminar to lay audience Dec, 2006 Web-based teaching aids for High School students (collaboration w PBS) Apr, 2007 Speaker at The Cambridge Science Festival, MIT Museum May, 2008 Speaker and contributor to World Science Festival in New York June, 2006 -2007 Organizer of Harvard/Glenn Symposium on Aging (~350 attendees) May, 2012 Introduction of minority students to HMS from Jackson State U June, 2013 Speaker at HMS Advisory Council Meeting Jan, 2014 Speaker at Harvard Medical School Council Dinner April, 2014 Assisted President Faust with fundraising Apr, 2014 Speaker at Herschel Lectures, HMS Jun, 2008-present Co-Organizer of Harvard/Glenn Symposium on Aging (~350 attendees) Jun, 2008 - present Co-Organizer of Boston Area Aging Data Club (bimonthly meetings) Dec, 2015 “Cleverman”, Sundance TV series (2016), John Hinde Award Oct, 2016 Arc Fusion Event, San Franscisco Science Museum 2012-2015, 2017- Genetics Bootcamp, Summer experiences in lab Nov, 2016 92Y Seminar Series, NY Apr, 2017 NASA panel speaker, Space Conference, Colorado Springs, CO Jan, 2016-present Ambassador for Business, NSW, Australia Oct, 2017 National Institutes on Aging, roundtable on translating aging research Sept 1999 – present Teaching at Harvard Medical School, Pathology, Medicine, Grad school classes

Editorial Boards:

2000-2008 Editor, FEMS Yeast Research 1999-present Served as ad hoc reviewer for Science, Nature, Cell, MCB, PNAS, Genetics, Genes and Development, Nature Cell Biology, EMBO J., Genetics, Molecular Cell, Cell Metabolism, Aging Cell, and others 2004-present Editor, Mechanisms of Ageing and Development 2008-present Co-Founder and Co-Editor-in-Chief, Aging 2016-present Editorial Board, Dose Response

Major Committee Assignments:

2000-2005 Executive Committee, Harvard Division of Aging (DOA) 2003-2004 Committee to Establish Bioinformatics Core at HMS 2003-2004 Committee to Revitalize HMS Core Curriculum 2005 Reviewer of Pepper Postdoc Fellowships for Aging at HMS 2004 RFA Study Section "Longevity Genes", NIH/NIA Extramural Program 2005 Study section for NIH/NIA, Gerontology Section 2004-2005 Steering Committee, Broad Institute 2006 Study section for NIH/NIA, Extramural Program 2006 Study Section for DOD - Breast Cancer Grants 2006 Leadership Council on Aging, Harvard Medical School 2007 Study section for NCI, Division of Extramural Activities 2007 – 2008 Grant reviewer for Brookdale Foundation 2006 Faculty search (Pathology) 2007 Vice-Chair, Gordon Conference on Aging 2008 Dana-Farber Cancer Institute Junior Faculty Search 2009 Co-organizer, "Cancer and metabolism" Meeting at CNIO, Spain 2007 Vice Chair of Gordon Research Conference on Aging, Switzerland, MA 2009 Co-organizer of Gordon Research Conference on Aging, Ventura, CA 2009 Co-organizer of Conference for ASIP, aging section, New Orleans, LA 2009 Co-organizer of first Sirtuin Banbury Conference, CSHL, NY 2010 Co-organizer of Keystone Meeting on Aging, Lake Tahoe 2005 - 2009 Paul F. Glenn Aging Labs Steering Committee 2010 Ad hoc review for NIH/NIA study section (CMAD committee) 2011 Co-organizer, Cell Press Symposium, Metabolism & Aging, Hyannis, MA 2013 Advisor to NCI, Key Questions Panel, Bethesda, MA USA 2010 – 2014 Chair, Foundation Funds Committee, Harvard Medical School 2008 – 2014 Chair, Harvard Fellowship Selection Committee (Neuro. Imaging, aging) 2005 – present Organizer, Glenn Symposium on Aging, Harvard (Annual event) 2011 – 2015 Permanent member, CMAD, NIA/NIH study section grant review. 2005 – present Grant reviewer or American Federation for Aging Research (AFAR) 2008 – present Co-Chair, Cold Spring Harbor Meetings on Aging (semi-annual) 2015 Organizer of FASEB Meeting on Sirtuins and Deacetylases (Germany) 2016 – present Board member, American Federation for Aging Research 2017 – present Scientific Board Member, Sanford Lorraine Cross Innovation Award 2017 – present Scientific Board Member, Zymo Research

Other Professional Positions: 2004-2013 Sirtris Pharmaceuticals, Co-Founder, SAB, BOD (public in 2007 then sold to GlaxoSmithKline in 2008) 2006-2009 Genocea Biosciences, Co-Founder, SAB, BOD (public in 2014) 2007-2013 Lux Capital, Advisor 2009-2012 Horizon Science, BOD, a Nestle company 2008-2015 GlaxoSmithKline (GSK), Consultant 2014-2016 BigDataBio, Co-Founder, SAB, Investor (now Arc-Bio) 2009- Advisor to Longwood Partners 2011-2016 OvaScience, Co-Founder, SAB (public in 2012) 2010- CohBar, Co-Founder, SAB (public in 2015) 2011- Segterra (InsideTracker), SAB, Founding board member, investor. 2013- MetroBiotech Companies, East, Mid-Atlantic, NSW, Co-Founder, SAB, BOD 2014- Liberty Biosecurity, Co-founder, SAB, BOD 2015- Wellomics, Co-founder, SAB, BOD (until 2016) 2016- Metrobiotech International, Co-founder 2016- Arc-Bio LLC, Founder, SAB 2016- EdenRoc Sciences, Cofounder, SAB, Vice Chairman 2016-2017 Hydra Sciences, Cofounder, Chief Investment Advisor 2017- Galilei Biosciences, Co-founder, President 2017- Continuum Biosciences, Board Member 2017- Senolytic Therapeutics, Board Member 2017- Jumpstart Fertility, Board Member 2017- Founder and board member, Life Biosciences 2017- Board member, Animal Life Biosciences 2017- Founder and Board member, Spotlight Biosciences

Regional, National or International contributions:

Selection of Invited Seminars (2000 – present):

2000, Jun Genome Stability and Cancer Symposium, Cold Spring Harbor, NY 2000, Oct University of Florida, Gainesville, FL 2000, Nov Harvard Medical School, Advisory Council Meeting 2001, Aug M.I.T. Biology, Cambridge, MA 2001, Sept Brown University, Providence, RI 2001, Oct UT Southwestern Medical School, Dallas, TX 2002, Jan Washington University, St. Louis, MO 2002, Apr Genomics of Aging Conference, Seville, Spain 2002, Jun FASEB Summer Research Conference, Genes and Gene Expression, VT 2002, Oct Metabolism and Aging Conference, Bethesda, MD 2002, Nov Genetics of Aging Conference, Cold Spring Harbor, NY 2003, Apr Museum of Science, Boston, Science Live!, layperson seminar 2003, Apr Indiana University, Indianapolis, IN 2003, Apr Biomol Research Laboratories, Philadelphia, PA 2003, July Museum of Science, Boston, Science Live! Stage 2003, Sept Oncogenes EMBL Conference, Salk Institute, San Diego, CA 2003, Sept Development and Growth Control Meeting, Arolla, Switzerland 2003, Sept Student invitation, Brandeis University, MA 2003, Sept NIA-RFA meeting, Mechanisms of Calorie Restriction, Bethesda, MD 2003, Oct Gerontology Fellows Seminars, Beth Israel Deaconess Hospital, MA 2003, Oct New York University, Frontiers in Biotechnology Seminar Series 2003, Nov Advisory Council Meeting, Harvard Medical School 2003, Dec Student invitation, Carnegie-Mellon University, Pittsburgh, PA 2004, Jan Evening Seminars for Fellows and Faculty, Children's Hospital, MA 2004, Jan Cleveland University, Cleveland, OH 2004, Jan Yale University, New Haven, CT 2004, Feb Beth Israel East Deaconess, Endocrine Grand Rounds 2004, Mar Department of Neurobiology, HMS, Boston MA. 2004, Mar Dean's Longwood Seminars, Harvard Medical School, MA 2004, Mar Keynote Speaker, National Council on Spinal Cord Injury, MA 2004, Apr Harvard National Pepper Centers Conference, MA 2004, May Student Invitation, University of Calgary, Canada 2004, Aug Invited Speaker, Wood's Hole Course on Aging, MA 2004, Sept Redox Symposium, University of Nebraska, Lincoln, NE 2004, Sept Biology of Aging, Gordon Research Conference, Aussois, France 2004, Sept University of Nebraska, Redox Biology Conference 2004, Oct Time and Aging Conference, EMBL, Heidelberg, Germany 2004, Oct Exeter Hospital, NH, Medical Education Lecture 2004, Oct Cold Spring Harbor, NY, Biology of Aging Conference 2004, Nov University of Texas SW, seminar series 2005, Jan Young Presidents Association, keynote speaker 2005, Feb The Wistar Institute, PA 2005, Mar Cold Spring Harbor seminar series 2005, Mar Caltech, CA, seminar series 2005, Apr Cornell University, Ithaca, seminar series 2005, Apr HMS Entrepreneur Symposium, 2005 2005, May U. Colorado, Boulder, seminar series 2005, Jun RAND, Summer Workshop on Aging, Santa Monica 2005, Aug FASEB Summer Glucose Transporter Meeting 2005, Aug Cold Spring Harbor Aging Course, guest lecture series 2005, Aug NIH, National Institutes for Diabetes (NIDDK), seminar series. 2005, Aug Procter and Gamble, Academic Seminar Series, invited speaker 2005, Sept UT San Antonio, Invited Speaker 2005, Sept Neurological Society, Hynes Convention Cntr., Boston 2005, Sept Abingworth Advisory Ltd. London Marriot Hotel, County Hall 2005, Nov CNIO Cancer Conference, Madrid, Spain 2005, Dec National Institutes on Aging Seminar series 2006, Jan Gordon Aging Conference, Ventura Beach, CA 2006, Feb Lorne Cancer Conference, Melbourne, Australia 2006, Feb University of Sydney, Australia 2006, Mar Genomic of Ageing Meeting, Palermo, Italy 2006, Mar BioInnovator of 2006, BioAgenda conference, FL 2006, Apr Harvard Medical School Dean's Advisory Council presentation 2006, May Distinguished Speaker at Baylor College of Medicine Annual Symposium 2006, May Massachusetts General Hospital Seminar series on Neurodegeneration 2006, June Varmus Presidential Lecture at Memorial Sloan Kettering, NY 2006, June Werner-Gren/Royal Swedish Academy "Aging" Conference, Sweden 2006, Aug The Burnham Institute 2006, Aug Telluride Tech Festival, CO, keynote speaker 2006, Aug Woods Hole Ellison Aging Course, lecturer 2006, Sept Albert Einstein, NY, Diabetes Section, invited speaker 2006, Sept Mayo Clinic Graduate Student Symposium, Keynote Speaker 2006, Oct Woods Hole RUNN Neurological Surgeon Course 2006, Oct Columbia University, College of Physicians and Surgeons, NY 2006, Oct Cold Spring Harbor Symposium on Aging, invited Speaker 2006, Oct Lux Capital Entrepreneur Symposium, Charles Hotel, MA 2006, Oct Massachusetts General Hospital, CBRC, Charlestown, MA 2006, Nov USCD, Department of Pharmacology, invited speaker 2006, Nov Gerontological Society of America Annual Meeting, TX 2007, Jan NovaNOW, Science Café, lay-person seminar, Cambridge, MA 2007, Jan Proctor and Gamble, OH, USA, Invited Speaker 2007, Jan Heredity Disease Foundation, Sirtuins as Targets for HD, Boston, MA. 2007, Jan NIH Directors Meeting 2007, Feb Scripps, Frontiers in Research Symposium 2007, Feb UTSW, Texas, Biochem Dept. 2007, April Molecular Basis of Aging Conference, Titisee, Germany 2007, April Cambridge Science Festival, MIT Museum 2007, May Harvard/Paul F. Glenn Symposium, 2007 2007, June BioAgenda Conference, Innovator of the Year Award Recipient 2007, July Albert Einstein College of Medicine, NY 2007, Aug Woods Hole Ellison Aging Course, lecturer 2007, Oct Woods Hole RUNN Neurological Surgeon Course, keynote 2007, Oct The Harvard Club, NY, for lay people 2007, Nov Symposium on Nutrition and Aging, The Buck Institute 2007, Dec NIH workshop on the therapeutic potential of resveratrol, Bethesda 2008, Jan Boston University, Dept of Biochemistry, seminar series 2008, Jan Harvard "Pasteur Frontiers in Medicine" series 2008, Feb Glaxo Smith Kline, CEO Presentation 2008, Jan New York Academy of Science, Nutrients and Aging, NY 2008, Feb Boston University, Cardiac Division 2008, Feb Gladstone Institute, UCSF 2008, Mar Invited speaker, Australian Academy of Sciences, Canberra 2008, Mar Edmonton Canada, Student Symposium, Keynote 2008, Mar Nutrient Signaling and Aging, Keystone Conf., Colorado, invited speaker 2008, Mar University of Alberta, Keynote speaker, Merck Prize 2008, April HMS Beth Israel Combined Grand Rounds 2008, May Case Western Reserve, Genetics Symposium, Keynote speaker 2008, June American Diabetes Association (ADA) Annual Meeting, San Francisco 2008, June World Science Festival, NY, Panel Participant 2008, July RAND, Summer Workshop on Aging, Santa Monica 2008, July GSK SciNovations Symposium, Pennsylvania 2008, July NIH Workshop on Epigenetics and Aging, Bethesda 2008, July FASEB meeting on "Molecular Mechanisms of Nutrient Control", Arizona 2008, Aug Woods Hole Ellison Aging Course, lecturer 2008, Oct Harvard Biotechnology Conference, Harvard 2008, Oct CNIO, Spain, Madrid, invited speaker 2008, Oct Arias Symposium on Liver Disease, Colonnade Hotel, Boston 2009, Jan Keystone Meeting on Diabetes, Banff, Canada 2009, Jan Salk Institute Symposium on Aging 2009, Feb Joslin Diabetes Weekly Seminar Series 2009, Feb Anzac Institute, Sydney, Australia 2009, Feb Centenary Institute, Australia 2009, Mar Diabetes Dialog Conference, Istanbul 2009, Apr Pre-Diabetes and Metabolic Syndrome, 3rd International, Nice, France 2009, Apr Banbury Conference on Sirtuins, Organizer/speaker 2009, Apr Iona College, NY (student invited speaker) 2009, Apr ASIP conference, Aging Session, New Orleans 2009, May 98th International Pathology Conference, Kyoto Japan 2010, Feb Keystone Meeting on Molecular Mechanism of Aging, Tahoe 2010, Feb Rockefeller University, Invited speaker 2010, Mar Colloquium on Aging, Seville, Spain 2010, May Salk Institute, invited lecture series 2010, Apr Pennington Center, Baton Rouge, Louisiana, invited speaker 2010, Apr Cancer Consortium Colloquium, Cincinnati 2010, May Student invited speaker, Harvard School of Public Health, Boston 2010, May Fisher Lectureship (3 seminars around the UCLA campus) 2010, May UTSCA Barshop Institute lecture, Texas (student invited speaker) 2010, April Nature colloquium on Frailty, Boston 2010, June Glenn Workshop on Aging, Santa Barbara, CA 2010, June Kogod Symposium on Aging, Mayo Clinic, MN 2010, Aug Woods Hole Ellison Aging Course, lecturer 2010, Sept UNSW Alumni dinner speaker, Australia Consulate, NY 2010, Sept NIH Nathan Shock Symposium on Stress and Longevity, Bethesda, MD 2010, Oct Cold Spring Harbor Meeting, Conference Organizer (lab members – 4 talks) 2010, Oct Keynote Speaker, 5Th international Congress on GRS and insulin signaling, NY 2010, Nov Firkin Oration, Melbourne 2010, Nov ASMB, Professional Development Lecture 2010, Nov Plenary Lecture, ASBMB Conference, Melbourne 2010, Nov Les Lazarus Award Lecture, Garvan Institute, Sydney 2010, Dec Am. Soc. Hematology, Orlando, FL 2011, Jan Keystone Diabetes and Obesity Meeting, Keystone, CO - Keynote 2011, Jan BU Endocrinology Grand Rounds, MA 2011, Jan Keystone DNA Damage and Repair, Keystone, CO 2011, Feb Coimbra University, Portugal, Grad course on mitochondria 2011, Feb NY Academy of Sciences, Sirtuin Symposium, NY 2011, Feb Invited Speaker, National Cancer Institute, MA 2011, Mar Organizer, Speaker, Cell Press Symposium on Aging and Metabolism, Hyannis 2011, Apr University of Texas, Medical School, Houston, Annual Cheves Smythe Lecture 2011, June Cold Spring Harbor, 78th Symposium on Metabolism and Disease 2011, June FASEB Meeting on Acetylation, Steamboat Springs, Colorado 2011, Aug Ellison Medical Foundation Annual Meeting, Woods Hole, MA 2011, Sept SwissEx Conference on Aging 2011, Oct Dean’s Lecture, University of New South Wales, Sydney 2011, Oct RUNN lecture, Neurobiology, Woods Hole, MA 2012, Jan Brown University, Aging Seminar Series 2012, Feb Keystone Sirtuin Meeting, Tahoe City, CA 2012, Mar Keynote Speaker, Annual Glenn Symposium M.I.T. 2012, May Inventages Meeting, Barcelona, Spain 2012, Jun UNSW, Sydney. Invited speaker 2012, Jul Freie Universitaat Berlin. Invited speaker 2012, Aug Woods Hole Seminar on Aging 2012, Aug Symposium in Honor of Lenny Guarente. MIT 2012, Nov Keynote Speaker, Keystone Meeting on Sirtuins, Tokyo 2012, Dec Symposium on Sirtuins, Sirtris, a GSK Company, Cambridge, MA 2013, Feb Memorial Sloan Kettering, NY 2013, Feb Stanford University, CA 2013, May Glenn Symposium, Albert Einstein College of Medicine, NY 2013, June AGE Meeting, Baltimore, USA 2013, Jun RUNN Course for Neuroscientists, Woods Hole 2013, Aug FASEB Conference on HDAC/Sirtuins, Barga, Italy 2013, Sept Boston University, Symposium on Obesity and Metabolic Control 2013, Sept Symposium on Resveratrol and Aging, Caudalie Headquarters, Paris 2013, Oct Interventions to slow aging, Erice, Italy 2013, Nov Geroscience Summit, NIH 2013, Nov GSK, Sirtuin DPU, PA 2013, Nov Sanford-Burnham Institute, Florida, Invited speaker 2014, Jan Stanford University, Glenn Symposium on Aging 2014, Feb Harvard Medical School Council Members Lecture 2014, Mar Dartmouth University, Student Selected Speaker 2014, Mar Conference on Metabolism and Inflammation, Sydney 2014, Mar US Patent Office presentations 2014, Apr Denham Harmon Award in Gerontology, University of Nebraska 2014, Apr GSK SAB meeting, Philadelphia 2014, Jun RUNN Course for Neuroscientists 2014, Sep U. Arizona, Grad Student Invitation 2014, Sept Therapeutics of Aging Meeting, Harvard 2014, Oct John Little Symposium, Harvard 2014, Oct Ideas Week Chicago, IL 2014, Oct Keio University Symposium on Aging 2014, Nov Dean’s Lecture, UNSW 2014, Dec Unilever, CT, Invited Speaker 2015, Jan Beth Israel Deaconess Diabetes Lecture, Harvard Medical School 2015, Jan Keystone Mitochondria and Diabetes Meeting, Santa Fe, NM 2015, Feb Fusion Aging Meeting Cancun 2015, Mar Keystone Sirtuin Meeting, Santa Fe, NM 2015, Apr Northeastern University, Boston, Science and Engineering Club 2015, Apr Washington University, invited speaker 2015, May U. Penn, invited speaker 2015, May GlaxoSmithKline, invited speaker 2015, June Glenn/AFAR Symposium on Aging 2105, Aug NAD biology, FASEB Conference, Timmendorfer Strand, invited speaker 2015, Aug Sirtuins and HDACs FASEB Conference, Timmendorfer Strand, invited speaker 2015, Sept Harvard “The World is Waiting” seminars 2015, Sept ASIP Conference, Baltimore 2015, Oct RUNN lecture, Neurobiology, Woods Hole, MA 2015, Dec Aging Symposium, Albert Einstein College of Medicine, Invited speaker 2016, Jan NIH Hallmarks of Aging Conference 2016, Jan HMS, Genetics Retreat 2016, Mar Royal College of Physicians and Surgeons, Annual Meeting, Sydney Australia 2016, Apr Keystone Epigenetics Conference, Santa Fe 2016, May Glenn/AFAR Meeting Santa Barbara 2016, July Cell Symposium on Aging and Metabolism, Sitges, Spain 2016, Sept Cold Spring Harbor Meeting on Aging, NY 2016, Sept Yale University, CT, Dept. of Biochemistry 2016, Sept Glenn Aging New England Meeting, CT 2016, Oct Arc Fusion Event, San Francisco 2016, Nov Contestant and team winner, NASA iTech 2016, Nov 92Y NY evening event 2017, Jan Conference on Aging and Aging-based Therapeutics, Scripps Florida 2017, Feb The Kastan Lecture, USC, named lecture 2017, Mar Fusion Conference on Aging, 2017, Cancun, Mexico 2017, Mar Aging and Senescence meeting, Harvard Medical School 2017, Apr NASA panel speaker, Space Conference, Colorado Springs, CO. 2017, Apr Australian Biology of Aging Meeting, Sydney 2017, May University of Virginia, Aging and Healthspan Conference 2017, May University of Rochester, Invited Speaker 2017, May University of Washington, Grad Student invited speaker 2017, May Harvard Med. School, Brigham and Women’s Hospital Grand Rounds 2017, June AMPlify Conference, Sydney Australia 2017, June Carlyle Investor Conference, JFK Center, Boston 2017, June Charles Perkins Center, Sydney, Australia 2017, June Charoen Pokphand, Thailand, invited speaker 2017, June Harvard/Paul F. Glenn Symposium 2017, July New Orleans FASEB meeting on NAD 2017, Aug AFAR Board Meeting, Advances in Aging Research 2017, Aug FASEB meeting on acetylation and sirtuins, Big Sky Montana. 2017, Sept CLSA Investor Conference, Hong Kong 2017, Oct IUBMB Symposium on Aging, Athens Greece, Plenary Lecturer 2017, Nov Pepper Center, Symposium on NAD precursors. Harvard Medical School

BIBLIOGRAPHY

154 papers as of February, 2017, h-index 68; 40,113 citations, 35+ patents) Original Research Articles 1. Sinclair, DA, Dawes, IW, Dickinson, JR. Purification and characterization of the branched- chain -ketoacid dehydrogenase complex of Saccharomyces cerevisiae. Biochem Mol Biol Int 1993; 31:911-921

2. Sinclair, DA, Kornfeld, G, Dawes, IW. Yeast intragenic transcriptional control: activation and repression sites within the coding region of the LPD1 gene of Saccharomyces cerevisiae. Mol Cell Biol 1994; 14:214-225

3. Sinclair, DA, Dawes IW. The genetics of the synthesis of serine from glycine and the use of glycine as sole nitrogen source in Saccharomyces cerevisiae. Genetics 1995; 140: 1213- 1222

4. Sinclair, DA, Hong, SP, Dawes IW. Specific induction by glycine of the P-subunit of the glycine decarboxylase of S. cerevisiae. Mol Microbiol 1996; 19: 611-23

5. McNeil, JB, Zhang F., Taylor, BV, Sinclair, DA, Pearlman, RE, Bognar, AL. Cloning, and molecular characterization of the GCV1 gene encoding the glycine cleavage T-protein from S. cerevisiae. Gene 1997; 186:13-20

6. Kennedy, BK, Gotta M., Sinclair DA, Mills K, McNabb DS, Murthy M, Pak SM, Laroche T, Gasser SM, Guarente L. Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in S. cerevisiae. Cell 1997; 89:381-391

7. Sinclair, DA, Mills, K, Guarente, L. Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Science 1997; 277:1313-1316

8. Sinclair, DA, Guarente L. Extrachromosomal rDNA circles - a cause of aging in yeast. Cell 1997; 911033-1042

9. Hong, SP, Piper M, Sinclair, DA, Dawes, IW. The glycine response of S. cerevisiae genes involved in one carbon metabolism is mediated by a tetrahydrofolate-responsive protein binding to a core 5'-CTTCTT-3' motif. J Biol Chem 1999; 274:10523-10532

10. Mills K*, Sinclair DA*, Guarente, L. MEC1-dependent relocalization of the Sir3 silencing protein from telomeres to DNA double strand breaks. Cell 1999; 97:609-620, * - equal contribution.

11. Ashrafi, K, Sinclair DA, Gordon, G., Guarente, L. Stationary phase accelerates the aging program of Saccharomyces cerevisiae. Proc Natl Acad Sci USA 1999; 96(16):9100-9105

12. Cohen HC, Sinclair, DA. Recombination-mediated telomere lengthening requires the Sgs1 helicase. Proc Natl Acad Sci USA 2001; 98:3174-3179

13. Anderson, R.M., Kevin J. Bitterman, Wood, JG Medvedik, O, Cohen, H, Lin, SS, Manchester, JK, Gordon JI, Sinclair, DA. Manipulation of a nuclear NAD+ salvage pathway delays aging without increasing steady state NAD+ levels in S. cerevisiae. J Biol Chem 2002; 277:18881-90.

14. Bitterman, K.J, Anderson, R., Latorre, M. and Sinclair, D.A. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem 2002; 277(47):45099-107

15. Anderson, R., Bitterman, K., Wood, J., Medvedik, O. and Sinclair, DA. Nicotinamide and Pnc1 govern lifespan extension by calorie restriction in S. cerevisiae. Nature, 2003; 423:181-185

16. Howitz, KT., Bitterman, KJ., Cohen, HY., Lamming, DW., Lavu, S., Wood, JG., Zipkin, RE., Chung P., Kisielewski, A., Zhang, L., Scherer, B., Sinclair DA. Small molecule sirtuin activators that extend S. cerevisiae lifespan. Nature 2003; 425:191-196.

17. Anderson, RA., Latorre-Esteves, M., Neves, A., Lavu, S., Taylor, C., Howitz, KT., Santos, H., Sinclair, DA. Lifespan extension by calorie restriction is independent of NAD fluctuation. Science 2003; 302:2124-2126.

18. Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME. Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase. Science 2004; 303:2011-5.

19. Cohen, HY, Lavu, S., Bitterman, KJ, Hekking, B., Imahiyerobo, TA, Miller, C., Frye, R., Ploegh, H, Kessler, BM, Sinclair DA. Acetylation of the C-terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Molecular Cell; 2004; 13: 627-38

20. Cohen, H.Y., Miller, C., Bitterman, K.J., Wall, N.R., Hekking, B., Kessler, B., Howitz, KT., Gorospe, M., de Cabo, R, Sinclair, DA. Calorie restriction promotes cell survival by inducing SIRT1. Science 2004; 305(5682):390-2

21. Wood, J., Rogina, B., Lavu, S., Howitz, K.T., Helfand, S.L., Tatar, M., Sinclair, DA. Sirtuin activators mimic calorie restriction and delay aging in metazoans. Nature, 2004; 430:686-9

22. Lamming, D, Latorre-Esteves, M, Medvedik, O, Wong, S.N., Tsang, F.A, Wang, C, Lin, S- J, Sinclair, DA. HST2 mediates SIR2-independent lifespan extension by calorie restriction. Science 2005; 309(5742):1861-4.

23. Mai, A, Massa, S, Lavu, S, Pezzi, R, Simeoni, S, Ragno, R, Mariotti, FR, Chiani, F, Camilloni, G, Sinclair, DA. Design, synthesis, and biological evaluation of sirtinol analogues as Class III histone deacetylase inhibitors. J Med Chem 2006; 48(24):7789-95.

24. Baur*, J, Pearson*, K, et al. (25 authors), deCabo, R*, Sinclair, DA*. Resveratrol increases health and survival of mice on a high calorie diet. Nature 2006; 444(16): 337-342 (* co-first authors, co-corresponding)

25. Yu, M., Lamming, D.W., Eskin, JA, Sinclair, DA, and Silver, PA. The role of protein arginine methylation in the formation of silent chromatin. Genes Dev 2006; 20(23):3249-54.

26. Yang, HY, Baur, J and Sinclair DA. Design and synthesis of SIRT1 activators that extend yeast lifespan. Aging Cell 2007; 6:35-43

27. Barbosa MT, Soares SM, Novak CM, Sinclair D, Levine JA, Aksoy P, Chini EN. The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity. FASEB J 2007; 21(13):3629-39

28. Kim, D, Nguyen, MD, Fischer, A, Sananbenesi, F, Dellale I, Sui, G, Baur, J, Armour, SM, Puigserver, P., Sinclair, DA, Tsai, L-H. SIRT1 deacetylase protects against age-dependent neurodegeneration. EMBO J 2007; J6:3169-79

29. Li Y., Yokota, T., Gama, V., Yoshida, T., Gomez, J.A., Ishikawa, K., Sasaguri, H., Cohen, H.Y., Sinclair D.A., Mizusawa, H., Matsuyama, S. Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation. 2007. Cell Death Differ.14(12):2058-67.

30. Yang, HY, Yang, T, Baur, JA, Perez, E, Matsui, T, Carmona, JJ, Lamming, DW, Souza- Pinto, NC, Bohr, VA, Rosenzweig, A, de Cabo, R, Sauve, AA, Sinclair, DA. Nutrient- regulated NAD+ levels in mitochondria dictate cell survival. Cell, 2007; 130(6):1095-107

31. Medvedik, O, Lamming, D, Sinclair, DA. Msn2/4 link calorie restriction and TOR to sirtuin- mediated lifespan extension in Saccharomyces cerevisiae. PLoS Biol 2007; 5:e261

32. Milne, JC, Lambert, PD, Schenk, S, Carney, DP, Smith, JJ, Gagne, DJ, Jin, L, Boss, O, Perni, RB, Vu, Chi B, Bemis, JE, Xie, R, Disch, JS, Ng, PY, Nunes, JJ, Lynch, AV, Yang, H, Galonek, H, Israelian, K, Choy, W, Iffland, A, Lavu, S, Sinclair, DA, Olefsky, JDA, Jirousek, M, Westphal, C. Novel Small Molecule Activators of SIRT1 as Therapeutics for Treatment of Type 2 Diabetes 2007; Nature, 450(7170):712-6

33. Firestein, RA, Blander, G. and Michan, S., Bhimavarapu, A, Luikenhuis, S., de Cabo, R., Hahn, WC, Guarente, LP, and Sinclair, DA. SIRT1 mimics the ability of caloric restriction to suppress colon cancer. 2008; PLoS One, 3(4):2020

34. Howitz, KT and Sinclair, DA. Xenohormesis - sensing the chemical cues of other species. Cell 2008; 133(3):387-391 (Essay).

35. Pearson, K*, Baur, J*, Lewis, KN, Peshkin, L, Price, NL et al. Navas, P., Ingram, D., Wolf, N., Ungvari, Z, Sinclair, DA*, de Cabo, RA* Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending lifespan. Cell Metabolism, 2008. 8(2):157-68. (* co-first authors, co-corresponding).

36. Oberdoerffer, P. Michan, S. Mostoslavsky, R., Stegmuller, J, Vann, J, Park, S-K, Loerch, P, Wright, S.M., Mills, KD. Bonni, A, Yankner, BA, Prolla, T., Alt, FW, and Sinclair, DA. DNA damage-induced alterations in chromatin as a cause of age-related changes in genomic integrity and gene expression. Cell, 2008; 135(5):907-18.

37. Jin, L, Galonek H,., Israelian K., Choy, W, Morrison, M., Xia, Y., Wang, X., Xu, Y., Yang, Y., Smith, J.J., Hoffmann, E., Carney, D.P., Perni, R.B., Jirousek, M.R., Bemis, J.E., Milne, J.C., Sinclair, D.A., Westphal, C.H. Biochemical characterization, localization, and tissue distribution of the longer form of mouse SIRT3. Protein Sci. 2009; 18(3):514-525.

38. Jiménez-Hidalgo, M., Santos-Ocaña, C., Padilla, S., Villalba, JM., Lopez- Lluch, G., Martín- Montalvo, A., Minor, RK., Sinclair, DA, de Cabo, R, Navas, P. NQR1 controls lifespan by regulating the promotion of respiratory metabolism in yeast. Aging Cell 2009; 8(2):140-51.

39. Armour, S.M., Baur, J.A., Hsieh, S.N., Land-Bracha, A., Thomas, S.M. and Sinclair, D.A. Inhibition of mammalian S6 kinase by resveratrol delays autophagy. Aging, 2009 Jun 3;1(6):515-28.

40. Rutanen J, Yaluri N, Modi S, Pihlajamäki J, Vänttinen M, Itkonen P, Kainulainen S, Yamamoto H, Lagouge M, Sinclair DA, Elliott P, Westphal C, Auwerx J, Laakso M. SIRT1 mRNA expression may be associated with energy expenditure and insulin sensitivity. Diabetes, 2010 Apr;59(4):829-35.

41. Michan, S., Chou, M-H, Allard, J., Lewis, K., Miller, M, Xu, W., McBurney, M, Sinclair, D.A, Baudry, M., de Cabo, R., Longo, V. SIRT1 is essential for normal cognitive function and synaptic plasticity. J. Neuroscience, 2010, 30(29):9695-707.

42. Yang, Y., Hubbard, B.P., Sinclair, D.A. and Tong, Q. Characterization of murine SIRT3 transcript variants and corresponding protein products. J. Cell. Biol. 2010, 111(4):1051-8

43. Hafner AV, Dai J, Gomes AP, Xiao CY, Palmeira CM, Rosenzweig A, Sinclair DA. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging. 2010 Dec 29

44. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R. Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice. J Gerontol A Biol Sci Med Sci. 2011 Feb;66A(2):191-201.

45 Hua, J., Guerin, K., Chen, J., Michan, S., Stahl, A., Krah, N.M., Seaward, M.R., Dennison, R.J., Juan, A., Hatton, C.J., Sapieha, P., Sinclair, D.A., Smith. L.E. Resveratrol Inhibits Pathological Retinal Neovascularization in Vldlr-/- Mice. 2011. Opthal. Vis. 25;52(5):2809- 16

46. Bernier M, Paul RK, Martin-Montalvo A, Scheibye-Knudsen M, Song S, He HJ, Armour SM, Bohr VA, Wang L, Zong Y, Sinclair DA, de Cabo R. Negative regulation of STAT3- mediated cellular respiration by SirT1. J Biol Chem. 2011, 286,19270-9

47. Minor, R., Baur, J, Gomes, A., Price, N., Hubbard, B., Westphal, C., Ellis, J., Vlasuk, G. et al., Sinclair, D.A. and deCabo, R. SRT1720 improves survival and healthspan of obese mice. Nature Scientific Reports, 2011, 1, 70.

48. Ramadori, G., Fujikawa, T., Anderson, J., Berglund, E.D., Frazao, E., Michan, M., Vianna, C., Sinclair, D.A., Elias, C., Coppari, R. SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance. Cell Metabolism 2011 15(5):675-90

49. Vendrell, A., Martínez-Pastor, M., González-Novo, A., Pascual-Ahuir, A., Sinclair, D.A., Proft, M. and Posas, F. Sir2 histone deacetylase prevents programmed cell death caused by sustained activation of the Hog1 SAPK. EMBO Rep. 2011 Sep 30;12(10):1062-8

50. Beirowski, Gustin, J., Armour, S.M., Yamamoto, S, Viader, A., North, B.J., Baloh, R.H., Golden, J., Schmidt, R., Sinclair, D.A., Auwerx, J., and Milbrandt, J. Sirt 2 modulates peripheral myelination through Par-3/aPKC polarity signaling. Proc. Natl. Acad. Sci., 2011.108(43):E952-61

51. Price, N.L., Gomes, A.P., Ling, A.J., Martin-Montalvo, A, North, B.J., Hubbard, B.P., Agarwal,B. Davis,J., Varamini, B. Hafner, A., Rolo,A., Palmeira,C.M., de Cabo,R., Baur,J., and Sinclair, D.A. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metabolism, 2012, 15(5):675-90

52. Rascón B, Hubbard BP, Sinclair DA, Amdam GV. The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction. Aging, 2012, 4(7):499-508. PMC3433935

53. Nakamura et al., Sinclair DA, Ryo A, Lu K.P. Prolyl isomerase Pin1 regulates neuronal differentiation via β-catenin. 2012. Mol. Cell. Biol. 32(15):2966-78. PMC3434519

54. Escande, C., Nin, V., Price, N., Capellini, V., Gomes, A., Barbosa, M.T., O’Neil, L., White, T.A, Sinclair, D.A., Chini, E.N. The flavonoid apigenin is an inhibitor of the NAD+ase CD38. 2012. Diabetes, 62(4):1084-93 PMID: 23172919

55. Han, J., Hubbard, BP., Lee, J., Montagna, C., Lee, H.W., Sinclair, DA., and Suh, Y. 2013 Analysis of 41 cancer cell lines reveals excessive allelic loss and novel mutations in the SIRT1 gene. Cell Cycle, 12:263-70 PMID: 23255128

56. Armour, SM., Bennett, EJ., Braun, CR., Zhang, XY., McMahon, SB., Gygi, SP., Harper, JW., and Sinclair, DA. A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex. 2013. Molecular Cell Biology, 33(8):1487-502 PMID: 23382074.

57. Hubbard, BP., Gomes, AP., Dai, H., Li, J., Case, AW., Considine, T., Riera, TV., Lee, JE., E, Sy., Lamming, DW., Pentelute, BL., Schuman, ER., Stevens, LA., Ling, AJ., …. Ellis, JL., Vlasuk, GP., and Sinclair, DA. Evidence for a common mechanism of SIRT1 regulation by allosteric activators. 2013. Science, Vol. 339: 1216-1219. PMID: 23471411

58. Biason-Lauber, A., Boni-Schnetzler, M., Hubbard, BP., Bouzakri, K., Brunner, A., Cavelti- Weder, C., Keller, C., Meyer-Boni, M., Meier, DT., Brorsson, C., et al., Sinclair, DA., and Donath, MY. Identification of a SIRT1 mutation in a family with type 1 diabetes. 2013. Cell Metabolism, PMID: 23473037

59. Lai, L., Yan, L., Gao, S., Hu, CL., Ge, H., Davidow, A., Park, M., Bravo, C., Iwatsubo, K., Ishikawa, Y., Auwerx, J., Sinclair, DA., Vatner, SF., and Vatner, DE. Type 5 adenylyl cyclase increases oxidative stress by transcriptional regulation of manganese superoxide dismutase via the SIRT1/FoxO3a pathway. 2013. Circulation, PMID: 23526361

60. Hubbard BP, Loh C, Gomes AP, Li J, Lu Q, Doyle TL, Disch JS, Armour SM, Ellis JL, Vlasuk GP, Sinclair DA. Carboxamide SIRT1 inhibitors block DBC1 binding via an acetylation-independent mechanism. 2013. Cell Cycle. 20;12(14). 61. Stottmann RW, Donlin M, Hafner A, Bernard A, Sinclair DA, Beier DR. (2013) A mutation in Tubb2b, a human polymicrogyria gene, leads to lethality and abnormal cortical development in the mouse. 2013. Hum Mol Genet. 22(20):4053-63. 62. Martin-Montalvo, A., Mercken EM, Mitchell SJ, 21 authors, Sinclair, D.A., Wolf, N.A., Spindler, S., Bernier, M. and de Cabo, R. Metformin improves healthspan and lifespan in mice. 2013. Nature Communications, 4:2192 63. Santos Franco S, De Falco L, Ghaffari S, Brugnara C, Sinclair DA, Mattè A, Iolascon A, Mohandas N, Bertoldi M, An X, Siciliano A, Rimmelé P, Cappellini MD, Michan S, Zoratti E, Janin A, De Franceschi L. Resveratrol accelerates erythroid maturation by activation of FOXO3 and ameliorates anemia in beta-thalassemic mice. 2013. Haematologica. Aug 23. 64. Schmeisser K, Mansfeld J, Kuhlow D, Weimer S, Priebe S, Heiland I, Birringer M, Groth M, Segref A, Kanfi Y, Price NL, Schmeisser S, Schuster S, Pfeiffer AF, Guthke R, Platzer M, Hoppe T, Cohen HY, Zarse K, Sinclair DA, Ristow M. Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide. Nat Chem Biol. 2013 Sep 29. 65. Hubbard BP and Sinclair DA. Measurement of sirtuin enzyme activity using a substrate- agnostic fluorometric nicotinamide assay. Methods Mol Biol. 2013;1077:167-77 66. Sinclair DA. Studying the replicative life span of yeast cells. Methods Mol Biol. 2013;1048:49-63.

67. Chen J, Michan S, Juan AM, Hurst CG, Hatton CJ, Pei DT, Joyal JS, Evans LP, Cui Z, Stahl A, Sapieha P, Sinclair DA, Smith LE. Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy. Angiogenesis. 2013 Oct;16(4):985-92

68. Michan, S., Juan, A.M., Hurst, C.G., Cui, Z., Evans, L.P., Hatton, C.J., Pei, D.T., Ju, M., Sinclair, D.A., Smith, L.E.H., Chen, J. Sirtuin1 over-expression does not impact retinal vascular and neuronal degeneration in a mouse model of oxygen-induced retinopathy. PLoS One 2013, 9(1):e85031.

69. Strong R, Miller RA, Astle CM, Baur JA, de Cabo R, Fernandez E, Guo W, Javors M, Kirkland JL, Nelson JF, Sinclair DA, Teter B, Williams D, Zaveri N, Nadon NL, Harrison DE. Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium- chain triglyceride oil on life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2013 68(1):6-16. PMID: 22451473

70. Gomes, A.P., Price N.L., Lin A.Y, Moslehi, J., Montgomery, M., Rajman, L., White, J.P., Teodoro, J.S., Wran, C.D., Hubbard, B.P., Mercken, E.M., Palmeira, C., de Cabo, R., Rolo, A.P., Turner, N., Bell, E. and Sinclair, D.A. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 2013 155(7):1624-38.

71. Yoon, C., Ling, A.Y., Isik, M., Lee, D.D., Steinbaugh, M.J., Sack, L., Boduch. A.N., Blackwell, T.B., Sinclair, D.A*, Elledge, S.J.* GLTSCR2/PICT1 links mitochondrial stress and Myc signaling. Proc. Natl. Acad. Sci., 2014, 111(10):3781-6. 72. Miranda MX, van Tits LJ, Lohmann C, Arsiwala T, Winnik S, Tailleux A, Stein S, Gomes AP, Suri V, Ellis JL, Lutz TA, Hottiger MO, Sinclair DA, Auwerx J, Schoonjans K, Staels B, Lüscher TF, Matter CM. The Sirt1 activator SRT3025 provides atheroprotection in Apoe- /- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression. Eur Heart J. 2015 Jan 1;36(1):51-9. 73. Mitchell SJ, Martin-Montalvo A, Mercken EM, Palacios HH2, Ward TM2, Abulwerdi G2, Minor RK, Vlasuk GP, Ellis JL, Sinclair DA, Dawson J, Allison DB, Zhang Y, Becker KG Bernier M, de Cabo R. The SIRT1 Activator SRT1720 Extends Lifespan and Improves Health of Mice Fed a Standard Diet. Cell Rep. 2014 Feb 25.

74. Mercken, EM*, Mitchell, SJ*, Martin-Montalvo, A,1 Minor, RK, Almeida, M., Gomes, A., Scheibye-Knudsen, M., Palacios, H., Licata, JJ, Zhang, Y, Becker, K.G. Khraiwesh, H., Gonzalez-Reyes, J., Villalba, JM, Baur, JA, Vlasuk, G, Ellis, JL, Sinclair, DA, Bernier, M, and de Cabo, R. SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass. Aging Cell 2014, in press 75. Solon-Biet SM, McMahon AC, Ballard JW, Ruohonen K, Wu LE, Cogger VC, Warren A, Huang X, Pichaud N, Melvin RG, Gokarn R, Khalil M, Turner N, Cooney GJ, Sinclair DA, Raubenheimer D, Le Couteur DG, Simpson SJ. The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metab. 2014 19(3):418-30. 76. North BJ, Rosenberg MA, Jeganathan KB, Hafner AV, Michan S, Dai J, Baker DJ, Cen Y, Wu LE, Sauve AA, van Deursen JM, Rosenzweig A, Sinclair DA. SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. EMBO J. 2014 33:1438-51. 77. Rimmelé P, Bigarella CL, Liang R, Izac B, Dieguez-Gonzalez R, Barbet G, Donovan M, Brugnara C, Blander JM, Sinclair DA, Ghaffari S. Aging-like phenotype and defective lineage specification in SIRT1-deleted hematopoietic stem and progenitor cells. Stem Cell Reports. 2014 3(1):44-59 78. Moroz N, Carmona JJ, Anderson E, Hart AC, Sinclair, DA, Blackwell TK. Dietary restriction involves NAD⁺ -dependent mechanisms and a shift toward oxidative metabolism. Aging Cell. 2014 13(6):1075-85. 79. Gomes AP, Sinclair DA. Measuring PGC-1α and its acetylation status in mouse primary myotubes. Methods Mol Biol. 2015;1241:49-57 80. Rumpf T, Schiedel M, Karaman B, Roessler C, North BJ, Lehotzky A, Oláh J, Ladwein KI, Schmidtkunz K, Gajer M, Pannek M, Steegborn C, Sinclair DA, Gerhardt S, Ovádi J, Schutkowski M, Sippl W, Einsle O, Jung M. Selective Sirt2 inhibition by ligand-induced rearrangement of the active site. Nat Commun. 2015 6:6263 81. Zhang QS, Deater M, Schubert K, Marquez-Loza L, Pelz C, Sinclair DA, Grompe M. The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice. Stem Cell Res. 2015 May 22;15(1):130-140. 82. Riepsamen A, Wu L, Lau L, Listijono D, Ledger W, Sinclair DA, Homer H. P. Nicotinamide Impairs Entry into and Exit from Meiosis I in Mouse Oocytes. PLoS One. 2015 Jun 3;10(6):e0130058 83. Zhang QS, Deater M, Schubert K, Marquez-Loza L, Pelz C, Sinclair DA, Grompe M. The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice. Stem Cell Res. 2015 15:130-40. 84. Abdesselem H, Madani A, Hani A, Al-Noubi M, Goswami N, Ben Hamidane H, Billing AM, Pasquier J, Bonkowski MS, Halabi N, Dalloul R, Sheriff MZ, Mesaeli N, ElRayess M, Sinclair DA, Graumann J, Mazloum NA. SIRT1 Limits Adipocyte Hyperplasia Through c- Myc Inhibition. J Biol Chem. 2015 Dec 11 85. Kim J, Sturgill D, Tran AD, Sinclair DA, Oberdoerffer P. Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability. Nucleic Acids Res. 2015 Dec 19. 86. Anderson EN, Corkins ME, Li JC, Singh K, Parsons S, Tucey TM, Sorkaç A, Huang H, Dimitriadi M, Sinclair DA, Hart AC. C. elegans lifespan extension by osmotic stress requires FUdR, base excision repair, FOXO, and sirtuins. Mech Ageing Dev. 2016 Mar;154:30-42 87. Cagnone GL, Tsai TS, Makanji Y, Matthews P, Gould J, Bonkowski MS, Elgass KD, Wong AS, Wu LE, McKenzie M, Sinclair DA, John JC. Restoration of normal embryogenesis by mitochondrial supplementation in pig oocytes exhibiting mitochondrial DNA deficiency. Sci Rep. 2016 Mar 18;6:23229 88. Mohamad M, Mitchell SA, Lindsay Wu, Alessandra Warren, White, MY, Cordwell SJ, Boyer D, Nines D, Mach J, Solon-Biet SM, Hilmer SN, Sinclair DA, Simpson SJ, de Cabo R, Le Couteur D, Cogger V. Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age-related insulin resistance. Aging Cell, 2016, 15(4):706-15 89. Ferrer CM, Lu TY, Bacigalupa ZA, Katsetos CD, Sinclair DA, Reginato MJ. O- GlcNAcylation regulates breast cancer metastasis via SIRT1 modulation of FOXM1 pathway. Oncogene. 2016 15(4):706-15. 90. Mitchell SJ,…..Sinclair DA, Cohen P, Egan JM, Mitchell JR, Baur JA, Allison DB, Anson RM, Villalba JM, Madeo F, Cuervo AM, Pearson KJ, Ingram DK, Bernier M, de Cabo R. Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice. Cell Metab. 2016 Jun 14;23(6):1093-112 91. Van Meter M, Simon M, Tombline G, May A, Morello TD, Hubbard BP, Bredbenner K, Park R, Sinclair DA, Bohr VA, Gorbunova V, Seluanov A. JNK Phosphorylates SIRT6 to Stimulate DNA Double-Strand Break Repair in Response to Oxidative Stress by Recruiting PARP1 to DNA Breaks. Cell Rep. 2016 Sep 6;16(10):2641-50

92. Fang EF, Kassahun H, Croteau DL, Scheibye-Knudsen M, Marosi K, Lu H, Shamanna RA, Kalyanasundaram S, Bollineni RC, Wilson MA, Iser WB, Wollman BN, Morevati M, Li J, Kerr JS, Lu Q, Waltz TB, Tian J, Sinclair DA, Mattson MP, Nilsen H, Bohr VA. NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair. Cell Metab. 2016 Oct 11;24(4):566-581.

93. Uddin GM, Youngson NA, Sinclair DA, Morris MJ. Head to Head Comparison of Short- Term Treatment with the NAD(+) Precursor Nicotinamide Mononucleotide (NMN) and 6 Weeks of Exercise in Obese Female Mice. Front Pharmacol. 2016 Aug 19;7:258. 94. Prola A, Silva JP, Guilbert A, Lecru L, Piquereau J, Ribeiro M, Mateo P, Gressette M, Fortin D, Boursier C, Gallerne C, Caillard A, Samuel JL, François H, Sinclair DA, Eid P, Ventura- Clapier R, Garnier A, Lemaire C. SIRT1 protects the heart from ER stress-induced cell death through eIF2α deacetylation. Cell Death Differ. 2017 24(2):343-356 95. Li, J., Bonkowski MS, Moniot S, Zhang D, Hubbard BP, Ling, AJY, Rajman LA, Qin B., Lou Z., Gorbunova V, L Aravind, Steegborn C. and Sinclair, DA. A conserved NAD+ binding pocket that regulates protein-protein interactions during aging. 2017 Science, 355(6331):1312-1317. 96. Pollack RM, Barzilai N, Anghel V, Kulkarni AS, Golden A, O'Broin P, Sinclair DA, Bonkowski MS, Coleville AJ, Powell D, Kim S, Moaddel R, Stein D, Zhang K, Hawkins M, Crandall JP. 2017. J Gerontol A Biol Sci Med Sci. 72(12):1703-1709 97. Golam, M.U., Youngson, N.A., Doyle, B.M., Sinclair, D.A., Morris, M.J.. Nicotinamide mononucleotide (NMN) supplementation ameliorates the impact of maternal obesity in mice: comparison with exercise. Scientific Reports, 7(1):15063 98. Costford SR, Brouwers B, Hopf ME, Sparks LM, Dispagna M, Gomes AP, Cornnell HH, Petucci C, Phelan P, Xie H, Yi F, Walter GA, Osborne TF, Sinclair DA, Mynatt RL, Ayala JE, Gardell SJ, Smith SR. Skeletal muscle overexpression of nicotinamide phosphoribosyl transferase in mice coupled with voluntary exercise augments exercise endurance. Mol Metabolism 2017 S2212-8778(17)30681-6 99. Sarah J. Mitchell, Michel Bernier - 11 authors - James L. Ellis J.L., Elliott, P., Frederick, D.W., Bohr, V., Brenner, C., Sinclair, D.A., Sauve, A.A., Baur, J.A., and de Cabo, R. Impact of chronic nicotinamide supplementation on health and survival in mice. Cell Metabolism, in press.

Published Reviews, Chapters and Editorials

1. Sinclair DA, Mills K, Guarente L. Molecular mechanisms of yeast aging. Trends Biochem Sci 1998; 23:131-134 2. Sinclair DA, Mills K, Guarente L. Aging in Saccharomyces cerevisiae. Annu Rev Microbiol 1998; 51:533-560 3. Johnson B, Sinclair DA, Guarente L. Molecular biology of aging. Cell 1999; 96:291-302 4. Sinclair, DA. Yeast aging research: recent advances and medical relevance. Cell. Mol. Life Sci 2000; 56:807-816. 5. Wood, J. and Sinclair, D. A. TPE or not TPE? It's no longer a question. Trends Pharmacol Sci 2001; 23:1-3 6. Sinclair DA, Ekerdt, DJ, Applebaum, RA, Holden, KC, Post, SG, Rockwood, K, Schulz, R, Sprott, R.L. and Uhlenberg, P. (Eds.). In Encyclopedia of Aging. 2002 New York: Macmillan Reference USA. 7. Sinclair, D.A. Paradigms and Pitfalls of Yeast Longevity Research. Mech Ageing Dev 2002; 253: 857-867. 8. Cohen HC, Bitterman K and Sinclair DA. Metabolic regulation of heterochromatin and aging. In Aging at the Molecular Level. Kluwer Academic Press, 2003. 9. Anderson, R. and Sinclair, D.A. Yeast RecQ helicases: clues to DNA repair, genome stability and aging. In Werner Syndrome, Lebel, M. (Ed), Eurekah press, 2003. 10. Sinclair, DA. Is DNA cut out for a long life? Science (Knowledge Environment), 2003, Vol. 16 11. Bitterman, K., Medvedik, O. and Sinclair, DA. Longevity Regulation in Saccharomyces cerevisiae: Linking Metabolism, Genome Stability, and Heterochromatin. Molec. Mol Biol. Rev. 2003; 67: 276-399. 12. Sinclair, DA. An Age of Instability. Science, 2003; 301:1859-1860. 13. Lamming, D. and Sinclair DA Mechanisms and mimetics of caloric restriction, Experimental Medicine, 2004; 22:806-815. 14. Lamming, D. Wood, J., Sinclair, DA. Small Molecule Mimetics of Calorie Restriction: evidence for xenohormesis. Molecular Microbiology Reviews, 2004; 53(4):1003-9 15. Howitz, K.T. and Sinclair, DA. Dietary restriction and small molecule mimetics In Handbook of Aging, Austad, S. and Masoro, E. eds. 2005, Academic Press. 16. Sinclair, DA. Sirtuins for healthy neurons. Nature Genetics, 2005, 37(4):339-40. 17. Sinclair, DA. Towards a unified theory of caloric restriction. Mech Ageing Dev., 2005, 26(9):987-1002. 18. Baur, J, Sinclair, DA. Therapeutic Potential of Resveratrol. Nature Reviews Drug Discovery, 2006, 5:493. 19. Sinclair, DA and Guarente, L. Unlocking the Secrets of Longevity Genes. Scientific American, March 2006. 20. Yang, HY, Lavu, S., Sinclair, DA. Nampt/PBEF/visfatin: a regulator of mammalian lifespan? Experimental Gerontology, 2006 41(8):718-26. 21. North, B. and Sinclair, DA. Sirtuins: a conserved key unlocking AceCS activity. Trends in Biochemical Sciences, 2006; 32(1):1-4 22. Sinclair, DA and Komaroff, A. Can we slow aging? Newsweek, 2006, Dec issue. 23. Michan, S. and Sinclair, DA. Sirtuins in Mammals: insights into their function. 2007, Biochem J. 404:1-13 24. Calabrese, E.J., Bachmann, K.A., Bailer, A.J. Sinclair, DA., et al. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework. Tox Appl Pharmacol 2007, 222:122-8. 25. Medvedik, O, Sinclair, DA. Biological Aging: Methods and Protocols. Methods in Molecular Biology 2007, 371:97-110. 26. Oberdoerffer, P. and Sinclair, DA. Nuclear architecture in genomic instability and ageing. Nature Reviews Mol Biol 2007 8:692-702 27. Lin, SJ and Sinclair, DA. Molecular Mechanisms of Aging: insights from Budding Yeast in The Molecular Biology of Aging. 2007. Guarente, Partridge and Wallace eds. Cold Spring Harbor Press, NY. pp. 483-516. 28. Baur, J. and Sinclair, DA. (2008) What is Xenohormesis? Am. J. Pharmacology and Toxicology, 3 (1): 152-159 29. Oberdoerffer, P. and Sinclair, DA. The aging epigenome: damaged beyond repair. Aging Res. Rev.2009; 8(3): 189-191 30. Blagosklonny MV, Campisi J, Sinclair DA. Aging: past, present and future. Aging (Albany NY). 2009 Jan 7;1(1):1-5. 31. Blagosklonny MV, Campisi J, Sinclair DA. Impact papers on aging in 2009. Aging, 2010. Mar;2(3):111-21 32. Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010 5:253-95. 33. Le Couteur DG and Sinclair DA. Blueprint for Developing Therapeutic Approaches That Increase Healthspan and Delay Death. 2010. J Gerontol A Biol Sci Med Sci. April 9 34. Haigis MC, Sinclair DA. Sirtuins in diseases and healthspan. Chapter in the Handbook of the Biology of Aging, 2010 35. Baur JA, Chen D, Chini EN, Chua K. et al. Dietary restriction: standing up for sirtuins. 2010. Science (letter), 329(5995):1012-3 36. North, B. and Sinclair, DA. At the intersection between aging and cardiovascular disease. Circ. Research 2012 110(8):1097-108 37. Sinclair, DA. Studying the replicative lifespan of yeast cells in Biological Aging: Methods and Protocols. Methods in Molecular Biology, Tollefsbol, ed. Springer, 2013, 371:97-110. 38. Rajman, L., Cassiday, L., and Sinclair, D.A. Genome Instability in Molecular and Cellular Biology of Aging. Chapter 28. Vijg, J., Campisi, J., Lithgow, G., and Austad, S. eds., Jones and Barlett, NY. in press.

39. Nogueiras R, Habegger KM, Chaudhary N, Finan B, Banks AS, Dietrich MO, Horvath TL, Sinclair DA, Pfluger PT, Tschöp MH. Sirtuin 1 and sirtuin 3: physiological modulators of metabolism. Physiol Rev. 2012 Jul;92(3):1479-514.

40. Sinclair, D.A., Verdin, E. The longevity of Sirtuins. Cell Reports 2012 Dec 27;2

41. Sinclair, D.A. and Tilly, J. Germline energetics, aging and female infertility. 2013. Cell Metabolism, 17(6):838-50. NIHMS 482422

42. Sinclair, DA. Studying the Replicative Life Span of Yeast Cells in Biological Aging. Ed. Trygve Tollesbol. Springer, NY, USA. 2013.

43. Klionsky DJ, Sinclair, D.A. et al., Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012 Apr;8(4):445-544.

44. Sinclair D.A. and Guarente, L. Small molecule activators of sirtuins for the treatment of age- related diseases. Annual Revews Pharmacol. Sci. 2013. 54:363-80.

45. Hubbard and Sinclair, D.A. Small molecule sirtuin activators. J. Experimental Medicine (2013) Book Chapter: https://www.yodosha.co.jp/jikkenigaku/book/9784758103350/

46. Hubbard BP, Sinclair DA. Measurement of sirtuin enzyme activity using a substrate- agnostic fluorometric nicotinamide assay. Methods Mol Biol. 2013, 1077:167-77.

47. Sinclair D.A. and Guarente, L. Small molecule activators of sirtuins for the treatment of age- related diseases. Annual Revews Pharmacol. Sci. (2013) 54:363-80.

48. Wu, E.W., Gomes, A.P. and Sinclair, D.A. Geroncogenesis: Metabolic changes during aging as a driver of tumorigenesis. 2014. Cancer Cell, 25:12-19 49. Cronise RJ, Sinclair D.A., Bremer AA. The "metabolic winter" hypothesis: a cause of the current epidemics of obesity and cardiometabolic disease. Metab Syndr Relat Disord. 2014 Sep;12(7):355-61

50. Wu LE, Sinclair D.A. SIRT2 controls the pentose phosphate switch. EMBO J. 2014 Jun 17;33(12):1287-8. 51. Cronise RJ, Sinclair D.A., Bremer AA. The "metabolic winter" hypothesis: a cause of the current epidemics of obesity and cardiometabolic disease. Metab Syndr Relat Disord. 2014 12(7):355-61. 52. Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, Curiel TJ, de Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, Kenyon C, Klein S, Kopchick JJ, Lepperdinger G, Madeo F, Mirisola MG, Mitchell JR, Passarino G, Rudolph KL, Sedivy JM, Shadel GS, Sinclair DA, Spindler SR, Suh Y, Vijg J, Vinciguerra M, Fontana L. Interventions to Slow Aging in Humans: Are We Ready? Aging Cell. 2015 Apr 22.

53. Garg N, Sinclair DA. Oogonial stem cells as a model to study age-associated infertility in women. Reprod Fertil Dev. 2015

54. Winnik S, Auwerx J, Sinclair DA, Matter CM. Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. Eur Heart J. 2015 Jun 2

55. Schultz MB, Sinclair DA. When stem cells grow old: phenotypes and mechanisms of stem cell aging. Development. 2016143:3-14

56. Rajman, L., Cassiday, L., Sinclair, DA. ‘Genome instability’ in Molecular and Cellular Biology of Aging, ed J Vijg, J Campisi, G Lithgow, GSA, Washington DC, pp 713-743. 2015 Available from: GSA Press eBook. Web.

57. Schultz MB, Sinclair DA. Why NAD(+) Declines during Aging: It's Destroyed. Cell Metab. 2016 Jun 14;23(6):965-6.

58. Wu LE, Sinclair DA. Restoring stem cells - all you need is NAD+. Cell Res. 2016 Jun 24

59. Dai H, Ellis JL, Sinclair DA, Hubbard BP. Synthesis and Assay of SIRT1-Activating Compounds. Methods Enzymol. 2016;574:213-44

60. Bonkowski MS, Sinclair DA. Slowing ageing by design: the rise of NAD+ and sirtuin- activating compounds. Nat Rev Mol Cell Biol. 2016 Aug 24.

61. Cronise, R., Sinclair, DA, Bremer, A. Oxidative priority, meal frequency, and the energy economy of food and activity: implications for longevity, obesity, and cardiometabolic disease. Metabolic Syndrome and Related Disorders. In press. 62. Cronise RJ, Sinclair DA, Bremer AA. Response to: "If the Metabolic Winter Is Coming, When Will It Be Summer?" Metab Syndr Relat Disord 2017;15:3.

Theses

Sinclair D.A. Intragenic transcriptional control of the yeast LPD1 gene. Honors thesis, 1991 Sinclair D.A. Multienzyme complexes of the yeast S. cerevisiae. Ph.D. thesis, 1995

Selected Patents (from 35+)

1. Sinclair, D.A., Dawes I.W. Systems for the rapid detection of gaseous emissions released from multiple biological reactions. Australian patent, 1995 2. Guarente, L., Sinclair, D.A., Lombard, D. Assays for compounds that extend life span. US Patent granted, 2001. Licensed 2003 3. Sinclair, D.A. Howitz, K., Zipkin, R., Bitterman, K. Lamming, D. Assays and methods for extending the lifespan of cells and organisms. Final patent application filed, 2004. Licensed 2004. 4. Sinclair, DA, Alexander-Bridges, M. Novel compositions for preventing and treating insulin resistance, diabetes and obesity. Provisional patent filed, 2003. Licensed 2005 5. Sinclair, DA, Tsai, LH. Compositions for treating neurological disorders. PCT, 2004. Unlicensed 6. Sinclair, DA, Baur, J. and Armor. Stress-induced molecules for treating disease and improving health. Provisional patent filed March, 2006. Licensed 2006 7. Firestein, R, Hubbard, B, and Sinclair, DA. SIRT6 in treating cancer. Provisional patent filed July, 2006. Licensed 2009 8. Firestein, R and Sinclair, DA. Methods for detecting and assaying ADP-ribosylation. 9. Firestein, R., Guarente, L., Sinclair, D. SIRT1 activation as treatment for cancer. Filed April 2007. Licensed 2009 10. Carmona, J and Sinclair, DA. Use of SIRT3 to impart the benefits of exercise and diet. Filed Oct, 2007. Licensed 2009. 11. Hafner, A. and Sinclair, DA. Modulation of SIRT3 for cellular resistance. Licensed 2008. 12. Hubbard, B. and Sinclair D.A. Assay for sirtuins and PARPs. Licensed to Millipore, 2011 13. Hafner, A. and Sinclair, DA. SIRT3 as a target neuroprotection and memory. Licensed 2008. 14. Hubbard, B and Sinclair, DA. Compositions and methods for activating SIRT1. 15. Tilly, J. and Sinclair, D.A. Compositions and methods for enhancing bioenergetic status in female germ cells. Licensed 2011. 16. Sinclair, D.A., Chini, E., Clardy, J. Small molecule inhibitors of CD38. 2011 17-20. Sinclair D.A. and Gomes, A.P. NAD-boosting compounds as treatments for aging and age-related diseases. Licensed 2014. 21. Sinclair D.A. and Gomes, A.P. 14/434,573. Granted. Nad biosynthesis and precursors for the treatment and prevention of cancer and proliferation. Licensed 2014.

22. Nguyen et al., Algorithms and methods to determine biological age. (2014) 62/044,546 23. Schultz, M., Bonkowski, M, and Sinclair, DA. Biomarkers to identify and utilize germline stem cells. Provisional 2014. 24. Normington, K, Sinclair, D, Livingston, D, McKearin, JM, Szczepankiewicz, B, Kremsky, JN. Nicotinamide mononucleotide derivatives and their uses. Provisional, 2014 25. Ear, P. and Sinclair DA. Methods for increasing the production of hyaluronic acid. Provisional, 2015. 26. Das A., Wu L. and Sinclair, DA. Compositions to increase angiogenesis, endurance and blood flow. Provisional, 2016

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OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: Suh, Yousin eRA COMMONS USER NAME (credential, e.g., agency login): YOUSINSUH POSITION TITLE: Professor EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) Completion DEGREE Date FIELD OF STUDY INSTITUTION AND LOCATION (if applicable) MM/YYYY

Ewha Woman University, Seoul, Korea B.S. 03/1983-02/87 Biology Texas A&M University, College Station, TX Ph.D. 09/1988-12/89 Biology (candidate) University of Houston, Houston, TX Ph.D. 01/1990-03/94 Biochemistry Harvard University School of Public Health, Postdoc 04/1994-07/96 Cancer CellBiology Boston, MA

A. Personal statement My research utilizes a diverse array of state-of-the-art functional genomics tools to identify (epi)genetic factors that contribute to aging and diseases. Aging is the single largest risk-factor for most complex human disease and is emerging as a major component in basic, translational and clinical research. To gain further insight into the (epi)genetic link between aging and disease, I started to focus on the identification of functional sequence and epigenetic variation in human populations and the assessment of their potential functional impact on aging- related phenotypes. Our comprehensive approach should ultimately result in an integrated approach to study human aging/disease at different levels, i.e., from genetic and epigenetic determinants, through cell type- and tissue-specific regulated gene expression, to molecular and cellular endpoints in the tissues. Ultimately, this should lead to new (epi)genetic markers for aging and its associated diseases as well as targets for interventions. Therefore my expertise precisely coincides with the objectives of this project specifically focused on rapamycin effects on the enhancer and architectural codes of cellular senescence. Some reviews include: 1. Vijg, J. and Suh, Y. Genetics of longevity and aging. Annual Review of Medicine. Vol. 56: 193-212. 2005. 2. Tazearslan, C., Cho, M., and Suh,Y. Discovery of functional gene variants associated with human longevity: opportunities and challenges. J Gerontol A Biol Sci Med Sci. PMID: 22156437. 67(4):376-83. 2012 3. Cho, M., Suh, Y. Genome maintenance and human longevity. Current Opinion in Genetics & Development. 26C:105-115. 2014. PMC4254320 4. Lau, CH, Suh, Y. CRISPR-based strategies for studying regulatory elements and chromatin structure in mammalian gene control. Mammalian Genome. 2017 Dec 1. doi: 10.1007/s00335-017-9727-2. [Epub ahead of print] PMC in progress.

B. Positions and Honors Positions 1996-1999 Senior Research Scientist, Seoul National University College of Medicine, Seoul, Korea 1999-2001 Senior Investigator, Seoul National University College of Medicine, Seoul, Korea 2001-2003 BK Assistant Professor, Seoul National University College of Medicine, Seoul, Korea 2002-2003 Adjunct Assistant Professor, Dept. of Cellular and Structural Biology, University of Texas Health Science Center (UTHSCSA), San Antonio, TX 2003-2005 Assistant Professor, Dept. of Physiology, UTHSCSA, San Antonio, TX 2005-2007 Assistant Professor, Dept. of Molecular Medicine, UTHSCSA, San Antonio, TX 2007 -2012 Associate Professor, Dept. of Medicine and Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 2012 - Professor, Dept. of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY Honors 2001 - 2005 Associate Editor, Mechanisms of Aging and Development 2003 Guest Editor for Special Issue on “Functional Genomics of Ageing I”, Mechanisms of Aging and Development 2003 South Texas Health Research Center, Junior Faculty Development Awards 2004 Guest Editor for Special Issue on “Functional Genomics of Ageing II”, Mechanisms of Aging and Development 2005 Guest Editor for Special Issue on “Methods for Single Nucleotide Polymorphisms (SNPs): Detection, Interpretation, and Application”, Mutation Research 2006 Guest Editor for Special Issue on “Functional Genomics of Ageing III”, Mechanisms of Aging and Development 2006-present Editorial Board, Mechanisms of Aging and Development 2011-present Supervising Editor, Aging Cell 2011-present Academic Editor, PLoS ONE 2016-present Associate Editor, PLoS Genetics 2017-present Associate Editor, Nature Partner Journal Aging and Mechanisms of Disease 2007 Glenn Award for Research in Biological Mechanisms of Aging 2009 Member, National Institute on Aging Special Emphasis Panel 2009-present Member, National Scientific Advisory Council, American Federation for Aging Research 2009-present Distinguished Prof. in Aging Research, Guangdong Medical College, Dongguan, China 2014-present F1000 Faculty 2015 Elected Co-chair of Gordon Research Conference on the Biology of Aging

C. Contributions to Science I investigate the (epi)genetic component that underlies the interface of intrinsic aging and disease. The approach I follow is based on the identification of genome sequence variants associated with age-related disease risk or its opposite, i.e., an unusual resistance to such disease. For this purpose my target populations are either cohorts of middle-aged individuals followed longitudinally for signs of all major age-related diseases, or cohorts of extremely long-lived individuals who managed to ward off such diseases. To tackle the key problem of identifying the functional impact of any observed association, I apply specific functional tests, including in silico modeling, cell culture assays and mouse models, unraveling molecular mechanisms underlying genetic association. Ongoing research involves novel, large-scale strategies to identify functional (epi)genetic variations in the gene coding and regulatory regions that are part of conserved aging networks and test their relevance to human aging and disease.

1. Genetic variation in human aging and longevity. We provided the first line of evidence that “reduced- function” mutations in IGF1 signaling may contribute to human longevity by demonstrating the enrichment of rare IGF1R mutations in centenarians as compared to controls of Ashkenazi Jewish populations and these mutations cause impaired IGF1 signaling, down-regulation of IGF1-induced gene expression and cell cycle progression in engineered MEFs in an Igf1r null background. We also established genotype-molecular phenotype-physiological outcome correlations by demonstrating that centenarian carriers of these longevity-associated IGF1R mutations are smaller in stature and higher in serum IG1F levels, revealing a mechanistic parallel between models organisms and humans in this highly conserved pathway of aging. We are currently testing the in vivo effects of the longevity-associated IGF1R mutations in newly generated humanized knock-in mouse models including conferring resistance to stress and diseases and ultimately life span. 1. Suh, Y., Atzmon, G., Cho, M.-O., Hwang, D., Liu, B., Barzilai, N., Cohen, P. Functional insulin-like growth factor-I receptor mutations in centenarians. Proc. Natl. Acad. Sci. USA. 105: 3438–3442. 2008. PMC2265137 2. Tazearslan, C., Huang, J., Barzilai, N., and Suh,Y. Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles. Aging Cell. 10(3)551-4. 2011. PMC3094477 3. Han, J., Ryu, S., Moskowitz, D.M., Rothenberg, D., Atzmon, G., Barzilai, N., and Suh, Y. Discovery of novel non-synonymous SNP variants in 988 candidate genes from 6 centenarians by target capture and next-generation sequencing. Mechanisms of Ageing and Development. doi: 10.1016/j.mad. [Epub ahead of print] 2013. PMCID in progress 4. Johnson, S.C., Dong, X., Vijg, J., Suh, Y. Genetic evidence for common pathways in human age-related diseases. Aging Cell. 2015 Jun 15. doi: 10.1111/acel.12362. PMC4568968

2. MicroRNA in human aging and longevity. Aging is accompanied by the continual breakdown of the robustness of gene regulatory networks leading to organismal dysfunction. Recently, microRNAs (miRNAs) have emerged as a critical component of gene regulatory networks, and are proposed to function in ensuring biological robustness. We investigate a novel role for miRNAs as a major genetic component of aging and longevity in humans. We discovered a panel of longevity-associated miRNAs, some of which we now demonstrated to target the conserved pathway of aging, including IGF1 signaling. Generation of transgenic mouse models that overexpress the longevity-associated, IGF1 signaling targeting miRNAs is under way for their in vivo role in longevity. We have established cutting-edge technologies such as miRNA-seq and miRNA target capture-seq necessary to unravel miRNA regulatory networks in human aging. 1. Gombar, S., Jung, H.-J., Dong, F., Calder, R.B., Atzmon, G., Barzilai, N., Tan, X.-L., Pothof, J., Hoeijmakers, J.H.J., Campisi, J., Vijg, J., and Suh, Y. Comprehensive microRNA profiling in B-cells of human centenarians by massively parallel sequencing. BMC Genomics. 2012 Jul 31;13(1):353. [Epub ahead of print] 2. Xiong, X.D., Cho, M., Cai, X.P., Cheng, J., Jing, X., Cen, J.M., Liu, X., Yang, X.L., Suh, Y. A common variant in pre-miR-146 is associated with coronary artery disease risk and its mature miRNA expression. Mutation Research. 761:15-20. 2014. PMID:24447667. 3. Xiong, X.-D., Jung, H.J., Gombar, S, Park, J.Y., Zhang, C.L., Zheng, H.-L., Ruan, J., Li, J.-B., Kaeberlein, M., Kennedy, B.K., Zhou, Z., Liu, X., and Suh, Y. MicroRNA transcriptome analysis identifies miR-365 as a novel negative regulator of cell proliferation in Zmpste24-deficient mouse embryonic fibroblasts. Mutation Research 777:69-78. doi: 10.1016/j.mrfmmm.2015.04.010. Epub 2015 Apr 24. PMID: 25983189 4. Jung HJ, Lee KP, Milholland B, Shin YJ, Kang JS, Kwon KS, Suh Y. Comprehensive miRNA Profiling of Skeletal Muscle and Serum in Induced and Normal Mouse Muscle Atrophy During Aging. J Gerontol A Biol Sci Med Sci. 2017 Mar 10. doi: 10.1093/gerona/glx025. [Epub ahead of print] PubMed PMID: 28329037. PMC in Progress

3. Cellular response to stress, genome maintenance, and aging. My research has focused on the antagonistic role of the cellular responses to DNA damage in aging and disease. I demonstrated an aging-related decrease in the rate of DNA damage-induced apoptosis in rat liver, which may contribute to the age-related increase in the incidence of cancer. I have been participating in an international collaborative study on aging in DNA repair defective mouse models. We showed that genetic defects in a cell’s repertoire of genome maintenance systems can either result in increased cancer or the premature appearance of non-cancer-related degenerative aging phenotypes. These latter phenotypes are likely due to increased cellular responses, i.e. apoptosis, as a consequence of increased DNA damage loads. Our results suggest a complex interplay between cellular responses to endogenous DNA damage and metabolic adjustments to compensate for the increased DNA damage as the cause of the premature aging phenotype. 1. Suh, Y., Lee, K.-A., Kim, W.-H., Vijg, J., and Park, S.C. Aging alters the apoptotic response to genotoxic stress. Nature Medicine. 8: 3-4. 2002. PMID: 11786880 2. Park, J.Y., Cho, M.O., Leonard, S., Calder, B., Kim, W.H., Wijnhoven, S., van Steeg, H., Mitchell, J.R , van der Horst, G.T.J., Hoeijmakers, J., Vijg, J, and Suh, Y. Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging XpdTTD mice. PLoS ONE. 3: e2346. 2008 3. Park, C., Suh, Y*., and Cuervo*, A.C. Regulated degradation of Chk1 by chaperone-mediated autophagy in response to DNA damage. Nature Communications. 2015. Apr 16;6:6823. doi: 10.1038/ncomms7823. PMCID: PMC4400843 *Co-corresponding authors 4. Milholland B, Dong X, Zhang L, Hao X, Suh Y, Vijg J. Differences between germline and somatic mutation rates in humans and mice. Nature Communications. 2017 May 9;8:15183. doi: 10.1038/ncomms15183. PubMed PMID: 28485371. PMC in Progress

4. Non-coding variants in aging and aging-related disease. The greatest challenge in the ‘post-GWAS’ era is to understand the functional consequences of risk variants in non-coding regions and the mechanisms underlying the genetic risk conferred by these variants. My research has aimed to provide principles for the initial functional characterization of disease risk loci, with a focus on non-coding variants, and to define ‘post-GWAS’ functional characterization. We have identified and characterized SIRT1 promoter variants associated with risk of myocardial infarction (MI) in Mexican American individuals, revealing an unexpected role of CTCF in licensing stress-induced promoter pause:release that causes increased transcription of SIRT1, exerting protective effects against MI in older individuals. We have shown that the oxidative stress-induced recruitment of CTCF to SIRT1 promoter leads to the association of CTCF with the FACT component, SPT16, as well as recruitment of JMJD3 and P-TEFb to the SIRT1 promoter, overcoming promoter stalling. In contrast, a MI risk variant in the SIRT1 promoter permits preferential binding of a repressive zinc finger protein, ZFP161, instead of CTCF, precluding SIRT1 activation. In addition, we have been focusing on uncovering the molecular mechanisms underlying the clustering of GWAS variants associated with multiple age-related diseases in the 9p21 gene desert locus. Our studies collectively suggest a critical role of non-coding variants in gene regulation networks, involving complex interactions of enhancer, promoter, nuclear architectural structure. 1. Wang, J., Telese, F., Tan, Y., Li, W., Jin, C., He, X., Basnet, H., Ma, Q., Merkurjev, D., Zhu, X., Liu, Z., Zhang, J., Ohgi, K., Taylor, H., White, R.R., Tazearsalan, C., Suh, Y., Macfarlan, T.S., Pfaff, S.L., Rosenfeld, M.G. LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control. Nature Neuroscience 2015 Jul 27. doi: 10.1038/nn.4069. [Epub ahead of print]. PMID: 26214369 2. Milholland, B., Auton, A., Suh, Y*., Vijg, J*. Age-related somatic mutations in the cancer genome. Oncotarget. 2015 Sep 17. [Epub ahead of print] PMID: 26384365. *Co-corresponding authors 3. Ryu, S., Atzmon, G., Barzilai, N., and Suh, Y. Genetic landscape of APOE in human longevity revealed by high-throughput sequencing. Mechanisms of Ageing and Development. 2016 27;155:7-9 4. Lau CH, Suh Y. Genome and Epigenome Editing in Mechanistic Studies of Human Aging and Aging- Related Disease. Gerontology. 2017;63(2):103-117. doi: 10.1159/000452972. Epub 2016 Dec 15. PMC5310972.

5. Enhancer and epigenomic codes of replicative senescence. I have been investigating global alterations in senescence epigenome by integrating changes in gene transcription program, histone modification, and chromatin architecture. By Gro-Seq analysis, we have identified 1516 genes down regulated and 1882 genes upregulated during senescence. Intriguingly, up-regulated genes were associated with the release of stalled polymerases and increased elongation, while down-regulated genes were likely due to loss of transcription initiation. Analysis of a total of 18 histone marks identified a signature of senescence-associated histone modifications: levels of H3K79me3, which is known to be enriched along gene bodies and positively correlated with pausing release, increased with senescence and levels of H4R3me2sym, which is associated with increased pausing, decreased during senescence. The histone signature correlates with the pause-release of the upregulated genes in senescence detected by Gro-seq. We are currently investigating the functional impact of specific enzymes that might regulate the candidate “epigenomic” alterations in senescent cells, which contribute to the senescent epigenome, on onset, progression, maintenance, or reversal of cellular senescence by modulating their expression.

Complete List of Published Work in MyBibliography: http://www.ncbi.nlm.nih.gov/sites/myncbi/1zAJWPPXL_uQB/bibliography/47915578/public/?sort=date&direction=ascending.

D. Research Support Active 1. 1RF1AG057341-01 PI: Suh, Murphy 9/15/17-6/30/22 NIH/NIA “Systems Modeling of Alzheimer’s Disease in C. elegans” The objective of this project is to identify gene regulatory networks that may contribute to the susceptibility to AD by leveraging the strengths of C. elegans model system combined with data from genomic and genetic studies of AD and experimental results from human neuronal cells.

2. 1R01AG057433-01 PI: Suh, Rando 9/15/17-6/30/21 NIH/NIA “From in vivo to in vitro heterochronic parabiosis to identify geronic factors” The objective of this project is to identify and validate circulating anti-geronic factors by utilizing both in vivo and in vitro heterochronic parabiosis experimental systems and to assess whether anti-geronic factors, alone or in combination, delay or reverse the age-associated functional decline of cells and tissues, thereby revealing potential targets for therapeutic intervention.

3. 1R01AG057706-01, PI: Rosenfeld, Glass, Gage, Suh 9/30/17-5/31/22 NIH/NIA “Combinatorial Actions of Genetic Variants and Gender Bias of Alzheimer’s Disease” The objective of this project is to use powerful contemporary global genomic approaches to determine the coding transcriptional targets of several of the most significant SNPs in enhancers, and the link to roles of estrogen receptor in the gender disparity for AD.

4. U19AG056278-01, PI: Jan Vijg, Paul Robbins, Suh Role: PL of Project 1 9/30/17-5/31/22 NIH/NIA “Identification of rare variants and miRNAs associated with human longevity” The objective of this project is to identify and functionally characterize genetic and epigenetic variants, the latter in the form of inter-individual variation in miRNA expression levels, associated with human healthy aging and extreme longevity for therapeutic modulation to improve human health span and lifespan.

5. 1R01AG057909-01, PI: Barzilai, Zhang, Suh Role: Co-I 9/15/17-5/31/22 NIH/NIA “Resilience to Alzheimer’s disease in humans with exceptional longevity” The objective of this project is to integrate high-level data from longevity cohorts that includes genotypes, whole exome sequencing, biochemical, clinical and neurocognitive profiles and to interrogate it in an effort to identify cognitive resilience genes with the ultimate goal of identifying and validating genotypes and molecular networks that mediate cognitive resilience.

6. 1 R01 AG055501-01A1, PI: Tu, Suh Role: Co-I 09/01/17-08/31/22 NIH/NIA “Human tissue specific age-related gene expression changes, their genetic regulations and the link to human diseases”

7. R01GM104459-01 PI: Suh 4/1/13-1/31/018 NIH/NIGMS “New Methods to Uncover Global Transcriptional Programs for Disease Risk Variants” The objective of this project is to investigate the link between the disease locus to alterations in global transcriptional programs by establishing the three-dimensional network of short- and long-distance genomic region interactions, the local and global alterations in gene transcription, and the key role of enhancer-RNA harboring risk alleles.

8. 1R01CA180126-01 PI: Suh, Spivack, Vijg, Auton NIH/NCI 9/1/13-6/30/018 “Age-cancer interplay of genome and epi-genome in human lung” The objective of this project is to delineate the mechanistic interplay between somatic mutagenesis, epigenomic alterations, aging and genome maintenance in causing tobacco smoke-induced lung cancer in mice and humans.

9. PO2 AG17242-11 PI: Vijg Suh Role: PL of Project 4 4/1/09-8/31/019 NIH/NIA “DNA Repair, Mutations and Cellular Aging” The objective of this project is to test the hypothesis that genetic variations at loci involved in genome maintenance relates to the onset and severity of aging phenotypes in humans and to aging rate in general.

10. R01 HG008153 PI: Zhang Suh Role: Co-I 10/01/16 – 09/30/19 NIH/NHGRI “Interpreting human enhancer variants with a network-regularized composite model” To develop computational methods that analyze genomic data to identify a set of functional non-coding variants that may contribute to differences in human disease risk and other traits.

11. No Number. PI: Barzilai Suh Role: Co-I 8/1/13-7/30/19 Glenn Center for the Biology of Human Aging “The role of systemic factors in human longevity” The objective of this project is to identify and characterize genetic variants involved in systemic factors of aging that are associated with human longevity.

12. No Number. PI: Suh 06/01/13-12/31/19 Korea Research Institute for Bioscience and Biotechnology “The Role of MicroRNA in Muscle Aging” The objective of this project is to identify and characterize miRNAs contributing to muscle aging.