Environmental Factor, June 2011, National Institute of Environmental Health Sciences
NIEHS holds symposium on the proteins of aging
By Robin Arnette
Symposium organizer Li was excited to have so many sirtuin researchers together in one place. (Photo courtesy of John Maruca)
"Understanding the mechanism behind some of the sirtuin-associated diseases might be important to us who are aging," Miller quipped. (Photo courtesy of John Maruca)
Guarente said that early on he wondered why a gene that counteracted aging existed evolutionarily. Answering this question made him want to study the biochemistry of Sir2 genes. (Photo courtesy of John Maruca)
Deng mentioned that although SIRT1 has been shown to inhibit the tumor suppressor gene p53 and is over expressed in certain kinds of cancers, deletion of SIRT1 in mice leads to genomic instability and increased incidence of cancer. (Photo courtesy of John Maruca)
Laboratory of Toxicology and Pharmacology principal investigator Jau-Shyong Hong, Ph.D., was interested in more detail about work in the areas of neurodegenerative diseases. (Photo courtesy of John Maruca)
NIEHS hosted an all-day symposium April 27 that dealt with the genetic factors and environmental influences that contribute to aging. The event, "Sirtuins in Aging and Age-associated Diseases," focused on a genetic pathway controlled by a group of proteins called sirtuins. Sirtuins regulate the body's metabolism and are believed to play a role in a number of cellular processes, including metabolism, stress response, DNA repair, genome stability, and aging.
Xiaoling Li, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/lst/mammalian/index.cfm), a tenure-track investigator in the NIEHS Laboratory of Signal Transduction and head of the Mammalian Aging Group where she studies sirtuins, invited an all-star lineup of sirtuin researchers to talk about their work (see text box). Acting Scientific Director David Miller, Ph.D., provided opening remarks for the seminar and noted the importance of sirtuins to NIEHS and the National Institutes of Health.
"Sirtuins have also been implicated in a number of diseases, for example Alzheimer's disease and diabetes," said Miller. "These proteins seem to be expressed in a wide variety of organisms, and there are a large number of them."
The keynote address
Leonard Guarente, Ph.D.(http://web.mit.edu/biology/www/facultyareas/facresearch/guarente.html) , a Novartis Professor of Biology at the Massachusetts Institute of Technology, was the first lecturer of the morning session. He said that he and his lab started working on yeast sirtuins more than 20 years ago. They wanted to identify the yeast genes that affected the lifespan of mother cells - yeast that give rise to progeny by budding off daughter cells. It took almost a decade and several people conducting a series of genetic screens to find what they were looking for.
"We determined that in normal, wild-type yeast, a mother cell divided 20-25 times before it underwent senescence, but knocking out the Sir2 gene shortened that lifespan, and adding an extra copy increased the lifespan," Guarente explained. "We carried out similar experiments in the roundworm, Caenorhabditis elegans, and found that the worm version of the gene, Sir2.1, functioned the same way."
Guarente said that the Sir2 genes later came to be known as sirtuins and generally counteract the aging process.
Raluca Dumitru, M.D., Ph.D., an Intramural Research Training Award (IRTA) fellow in the Laboratory of Molecular Carcinogenesis, thoroughly enjoyed Guarente's presentation. She said afterwards, "Dr. Guarente gave us a broad overview of sirtuins and his research has provided enough evidence to link sirtuins to diabetes and cancer, as well as neurodegenerative diseases."
Covering all aspects of sirtuins
Following Guarente's talk, Chuxia Deng, Ph.D., chief of the Mammalian Genetics Section at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), discussed the role sirtuins play in cancer. Deng said that the closest mammalian homolog of Sir2 is called SIRT1, and that mammals have seven sirtuin genes. His work with BRCA1, a gene that is involved in the development of hereditary breast and ovarian cancer in humans, demonstrated that BRCA1 forms a complex with another protein and binds to the SIRT1 promoter. Deletion of SIRT1 increases the incidence of cancer in mice.
After a short break, several other investigators talked about various aspects of sirtuins, including function, structure, and disease models. NIEHS postdoctoral fellows relished the opportunity to engage the speakers one-on-one during the lunch hour in the cafeteria.
Li presented the last seminar of the day, which debated the role of phosphorylation in the regulation of SIRT1. Although the function of SIRT1 has been extensively studied in the past decade, researchers still don't know how environmental signals regulate SIRT1 activity. Li and her lab have recently shown that SIRT1 can be activated by phosphorylation modification in response to environmental stresses. Their new data indicate that this modification probably modulates SIRT1 protein's oligomeric status.
At the end of the day, speakers and members of the audience left the symposium with a better understanding of sirtuins and their capacity to regulate key cellular mechanisms.
Presenters for "Sirtuins in Aging and Age-associated Diseases"
SIRT1 and SIRT3 in Aging and Diseases
Leonard Guarente, Ph.D. (Keynote Speaker)
Novartis Professor of Biology
Massachusetts Institute of Technology
Knockout Mouse Models for Sirtuins: Metabolism, Cancer, and Aging
Chuxia Deng, Ph.D.
Chief, Mammalian Genetics Section
National Institute of Diabetes and Digestive and Kidney Diseases
Marcia Haigis, Ph.D.
Assistant Professor of Pathology
Harvard Medical School
Nutrient Signaling for the SIRT1/PGC1 Chromatin Complex: Implication for Metabolic Diseases
Pere Puigserver, Ph.D.
Associate Professor of Cell Biology
Dana-Farber Cancer Institute
Advances in Metabolic Regulation by SIRT1
Domenico Accili, M.D.
Professor of Medicine
Chromatin Regulation and Genome Maintenance by Mammalian Sirtuins
Katrin Chua, M.D., Ph.D.
Assistant Professor of Medicine
Regulation of the Regulator
Xiaoling Li, Ph.D.
National Institute of Environmental Health Sciences