Sirtuins, Longevity and Adaptations to Nutrient Availability

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Sirtuins, Longevity and Adaptations to Nutrient Availability

Tuesday, February 22, 2011

The New York Academy of Sciences

This meeting brings together a collection of scientists working at the frontiers of a new field that has coalesced with the discovery of a unique class of enzymes, called the sirtuins. Sirtuins are a family of NAD+ dependent enzymes that deacetylate cellular proteins and are implicated in the control of longevity and adaptations to mammalian food intake. These enzymes are thought to be important to the health benefits of low calorie diets, and regulate aging processes in mammals. The meeting is designed to bring forward the latest discoveries of how sirtuins regulate normal and pathologic biology as well as new developments in understanding and modulating the biochemical properties of these intriguing enzymes.

Presented by

Agenda

*Presentation times are subject to change.


12:30 PM

Registration

1:00 PM

Introduction
Anthony Sauve, PhD, Weill Cornell Medical College

1:10 PM

Transcriptional Cofactors and NAD+ in the Control of Metabolism
Johan Auwerx, MD, PhD, Ecole Polytechnique Fédérale Lausanne

1:50 PM

Sirtuins, Aging and Disease
Leonard Guarente, PhD, MIT

2:30 PM

Mitochondrial Protein Acetylation and Sirtuins
Eric Verdin, MD, University of California, San Francisco

3:10 PM

Coffee Break

3:40 PM

Activation of SIRT1 by Small Molecules
David Sinclair, PhD, Harvard University

4:20 PM

Chemical Approaches to Understanding Sirtuin Biochemical and Biological Functions
Anthony Sauve, PhD, Weill Cornell Medical College

5:00 PM

Program Ends

Speakers

Organizers

Anthony Sauve, PhD

Weill Cornell Medical College

Anthony Sauve, PhD, was born in Los Angeles and grew up in Thousand Oaks California. He achieved a Bachelor of Arts in Biochemistry from the University of California at Berkeley and was elected Phi Beta Kappa as a Junior. He attended graduate school at Princeton University and earned a PhD in Chemistry, working in the laboratory of John T. Groves, a world expert on the catalytic mechanism of heteroatom transfer reactions. He was an NIH postdoctoral fellow in the laboratory of Vern L. Schramm, an expert on the uses of isotopes to elucidate catalytic mechanism, and while there began work on the sirtuin enzymes. Dr Sauve described the intricate mechanism of sirtuin deacetylation in 2001, and the mechanism of nicotinamide regulation in 2003. He joined the faculty of Weill Cornell Pharmacology in 2004, and is now Associate Professor of Pharmacology. Dr Sauve's research interests include the enzymology of sirtuins, the development of chemical tools to study sirtuins in cells and the elucidation of enzyme mechanisms and pathways for NAD biosynthesis in microbial and mammalian cells.

Jennifer Henry, PhD

The New York Academy of Sciences


Speakers

Johan Auwerx, MD, PhD

Ecole Polytechnique Fédérale Lausanne

Johan Auwerx received his MD in 1982 and his PhD in Molecular Endocrinology in 1989 at the Katholieke Universiteit in Leuven, Belgium. He is a certified clinical specialist in Endocrinology, Metabolism and Nutrition and is currently professor at the Ecole Polytechnique Fédérale in Lausanne, Switzerland, where he heads a research group together with Dr. Schoonjans. Johan Auwerx is internationally known as an expert in metabolic diseases, molecular biology, and mouse molecular genetics. His work was instrumental for the development of agonists of the peroxisome proliferation activated receptors into drugs, which now are commonly used in the treatment of type 2 diabetes. He discovered the signaling activity of bile acids and was amongst the first scientists to recognize that transcriptional cofactors, such as the sirtuin and the SRC/p160 gene families, act as energy sensors that influence metabolic homeostasis. This research validated these cofactors as valid targets to treat metabolic diseases, and spurred the clinical use of natural compounds, such as resveratrol, as metabolic modulators. Dr. Auwerx spearheaded a unique large mouse phenogenomics program and was the director of the Strasbourg Mouse Clinical Institute from 2006 to 2008. Prof. Auwerx was elected as a member of EMBO in 2003 and received a dozen of scientific prizes, including the prestigious Minkowski award (1998), the Morgagni Gold Medal (2004), the International Danone Nutrition Award (2009), and the Wiendaus prize (2010). He serves on the editorial board of prestigious scientific journals and as scientific advisor to several biopharmaceutical companies.

Leonard Guarente, PhD

MIT

Leonard Guarente is the Novartis Professor and Director of the Paul F. Glenn Lab for the Science of Aging at MIT.  He discovered that a group of related proteins termed sirtuins slow aging in model organisms and mitigate aging and diseases in mammals.  Critically, he showed that sirtuins are NAD-dependent protein deacetylases.  This finding links protein acetylation, metabolism, and aging.  It also indicates that sirtuins mediate the benefit of calorie restriction on health and longevity.  More recently, the Guarente lab has shown that genetic activation of the mammalian sirtuin SIRT1 mitigates major diseases, such as Alzheimer's Disease, in appropriate murine models. 

Anthony Sauve, PhD

Weill Cornell Medical College

Anthony Sauve, PhD was born in Los Angeles and grew up in Thousand Oaks California. He achieved a Bachelor of Arts in Biochemistry from the University of California at Berkeley and was elected Phi Beta Kappa as a Junior. He attended graduate school at Princeton University and earned a PhD in Chemistry, working in the laboratory of John T. Groves, a world expert on the catalytic mechanism of heteroatom transfer reactions. He was an NIH postdoctoral fellow in the laboratory of Vern L. Schramm, an expert on the uses of isotopes to elucidate catalytic mechanism, and while there began work on the sirtuin enzymes. Dr Sauve described the intricate mechanism of sirtuin deacetylation in 2001, and the mechanism of nicotinamide regulation in 2003. He joined the faculty of Weill Cornell Pharmacology in 2004, and is now Associate Professor of Pharmacology. Dr Sauve's research interests include the enzymology of sirtuins, the development of chemical tools to study sirtuins in cells and the elucidation of enzyme mechanisms and pathways for NAD biosynthesis in microbial and mammalian cells.

David Sinclair, PhD

Harvard University

Professor David Sinclair, PhD is a Professor at Harvard Medical School in the Departments of Pathology and Genetics, co-Director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, and a Senior Scholar of the Ellison Medical Foundation. At M.I.T. he worked with Lenny Guarente and codiscovered a cause of aging for yeast and the role of Sir2 in epigenetic changes driven by genome instability. In 1999, he moved to Harvard Medical School where his lab works primarily on understanding the role of sirtuins in disease and aging, with interests in chromatin, energy metabolism, mitochondria, learning and memory, neurodegeneration, and cancer. He has also contributed to the understanding of how sirtuins are modulated by endogenous molecules such as nicotinamide and NAD+, and pharmacological agents such as resveratrol. He has co-founded two companies that develop medicines for diseases of aging (Sirtris) and vaccines for infectious diseases (Genocea). Dr. Sinclair is co-chief editor of the journal Aging and has received awards including The Australian Commonwealth Prize, a Helen Hay Whitney Postdoctoral Award, a Leukemia Society Fellowship, a Ludwig Scholarship, a Harvard-Armenise Fellowship, an American Association 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.

Eric Verdin, MD

University of California, San Francisco

Dr. Verdin received his MD degree from the University of Liege, Liege, Belgium. He trained as a diabetologist/endocrinologist and held positions at the Joslin Diabetes Center and Harvard Medical School, the University of Brussels, the NIH, and the Picower Institute for Medical Research. He joined the Gladstone Institute of Virology and Immunology in 1997 and became its Associate Director in 2004. He is also Professor of Medicine, University of California, San Francisco. Dr. Verdin is a fellow of the American Association for the Advancement of Science, and member of the the American Society of Microbiology, the American Society for Biochemistry and Molecular Biology, the American Society for Clinical Investigation and the American Association of Physicians. He has served as reviewer on study sections for the National Institute of Health, as the organizer of international meetings and as the editor of several books and reviews. He has published more than 140 international papers and is associated with 10 published patents. Dr. Verdin's laboratory studies the role of reversible protein acetylation in aging and focuses on a family of protein deacetylases, called sirtuins, and their role in aging.

Sponsors

For sponsorship opportunities please contact Cristine Barreto at cbarreto@nyas.org or 212.298.8652.

Grant Support

This event is funded in part by the Life Technologies™ Foundation.

Promotional Partner

Fondation IPSEN

Abstracts

Transcriptional Cofactors and NAD+ in the Control of Metabolism

Johan Auwerx, MD, PhD, Ecole Polytechnique Fédérale Lausanne

A century after the identification of a co-enzymatic activity for NAD+, NAD+ metabolism has come in the spotlight again due to the potential therapeutic relevance of a set of enzymes whose activity is tightly regulated by the balance between the oxidized and reduced forms of this metabolite. In fact, the actions of NAD+ have been extended from being an oxidoreductase cofactor for single enzymatic activities to acting as a substrate for a wide range of proteins. These include NAD+-dependent sirtuin protein deacetylase, poly(ADP-ribose) polymerases, and transcription factors that affect a large array of cellular functions. Through these effects NAD+ provides a direct link between the cellular redox status and the control of signaling and transcriptional events. Of particular interest within the metabolic/ endocrine arena are the recent results, which indicate that the regulation of these NAD+-dependent pathways may have a major contribution to oxidative metabolism and lifespan extension. I will provide an integrated view on how the control of NAD+ production and cycling, as well as its cellular compartmentalization, alters transcriptional pathways via NAD+'s commanding role on cofactor networks that involve and SIRT1, GCN5, and PGC-1a. As such the modulation of NAD+-producing and -consuming pathways have a major physiological impact and hold promise for the prevention and treatment of metabolic disease.

Sirtuins, Aging and Disease

Leonard Guarente, PhD, MIT

SIR2 and related genes are NAD-dependent deacetylases that slow aging in yeast, C. elegans, and Drosophila.  In yeast and flies, SIR2 genes are also involved in the longevity conferred by dietary or calorie restriction (CR).  The mammalian SIR2 homologs termed SIRT genes, or sirtuins, are involved in changes in stress resistance and metabolism and are known to be associated with CR.  Critically, the CR diet in rodents not only extends life span, but also protects against many diseases of aging.  In this talk, I will describe recent findings in the lab regarding SIRT1 function in specific mammalian tissues in relation to murine disease models.  Our findings indicate that SIRT1 can influence many of the major diseases of aging, including metabolic diseases like diabetes, neurodegenerative diseases, cancer and osteoporosis.  Therefore small molecules that alter the activity of SIRT1 (i.e. CR mimetic drugs) offer a new approach to prevent and possibly treat the major diseases of aging.

Supported by NIA, Glenn Foundation.  Guarente consults for Sirtris/GSK

Mitochondrial Protein Acetylation and Sirtuins

Eric Verdin, MD, University of California, San Francisco

Sirtuins are NAD+-dependent protein deacetylases and mediate adaptive responses to a variety of stresses, including calorie restriction and oxidative stress. SIRT3 is localized in the mitochondrial matrix where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2, long chain acylcoA dehydrogenase and superoxide dismutase. Mice lacking both SIRT3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins and metabolic abnormalities during fasting. We will present the results of our ongoing studies of mice lacking SIRT3 and discuss our current model for the role of SIRT3 in metabolism control and aging.

Activation of SIRT1 by Small Molecules

David Sinclair, PhD, Harvard University

The sirtuins are a family of NAD+-dependent deacetylases that were originally identified in budding yeast, and have since been shown to mediate some of the beneficial health effects of calorie restriction in multiple species.  Overexpression of SIRT1 in mice improves metabolic function, suppresses cancers, and delays atherogenesis, among other health benefits. Human genetics studies also support a role for SIRT1 in maintaining human health status with age.  Increasing SIRT1 activity could therefore potentially provide significant benefits to society.

Small molecule activators of SIRT1, such as resveratrol and SRT1720, improve multiple health parameters in mice, including atherosclerosis, fatty liver, hyperglycemia, and endurance.  In inbred strains of mice, germline knockout of SIRT1 is embryonic lethal.  Published studies show that outbred SIRT1 knockout mice are compromised in their response to caloric restriction and resveratrol, but they are also small, sterile, and suffer from developmental abnormalities.  Therefore a better system is needed to avoid the developmental defects of SIRT1 germline knockout. 

To this end, we have generated an adult-inducible whole body SIRT1 knockout mouse.  We have confirmed efficient deletion of SIRT1 in multiple tissues and observe no gross phenotypic differences between SIRT1 knockout and control mice after SIRT1 deletion. Initial findings from these experiments suggest that knocking out SIRT1 in adults does not grossly impair glucose metabolism, but these animals have dramatically impaired mitochondrial function in skeletal muscle, including decreases in mitochondrial DNA content, mitochondrial membrane potential, ATP levels, and mitochondrial gene expression. We also observe a decrease in state 3 and FCCP-induced respiration, which indicates a decrease of electron transport chain capacity, a phenotype exacerbated by a high fat diet. Studies are under way examining how adult-specific SIRT1 knockout mice respond to feeding of sirtuin-activating compounds (STACs) SRT1720 and resveratrol, and the role of AMPK. Biochemical and biophysical experiments investigating the direct activation of SIRT1 by STACs are also yielding insights.

Chemical Approaches to Understanding Sirtuin Biochemical and Biological Functions

Anthony Sauve, PhD, Weill Cornell Medical College

This talk discusses the chemical basis for the NAD dependence of sirtuin catalysed deacetylation and how aspects of the chemical mechanism provide a set of regulatory steps that allow NAD metabolism to interact with sirtuin activity, thereby upregulating or downregulating activity.  This includes steps that are NAD sensitive, and steps that are nicotinamide sensitive.  Examples of sirtuins that illustrate these regulatory paradigms will be featured.  Additional insight into metabolic coupling of sirtuins and catalytic mechanism can be obtained by directed chemical synthesis of isotopically labeled NAD molecules and metabolites.  How these can be employed in the study of metabolism will be illustrated, along with uses in the elucidation of enzyme catalytic mechanism.  Finally the talk discusses new chemical approaches for determining SIRT1-7 activities in one assay.  A description of how these tools could be useful for examining sirtuin activities in cells is provided.  These tools are being developed to detect sirtuin activity and cell localization changes in real-time.

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