Genetic basis for possible anti-aging therapies

Shin-ichiro Imai, M.D., Ph.D.

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    Imai discovered the enzymatic acitivity of Sir2 (silent information regulator 2) and demonstrated its role in cellular metabolism and its importance to the regulation of longevity in organisms such as yeast and roundworms. Increasing Sir2 activity lengthens lifespan in those organisms. Now, he is studying the roles of Sir2 in mammals. Because mammals are more complex organisms, he is focusing on the function of Sir2 in various tissues that are important to metabolism, such as pancreatic beta cells, liver, and adipocytes (fat cells).
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    Imai has found that the mammalian version of Sir2 promotes increased insulin secretion in response to glucose. His laboratory genetically engineered mice with extra Sir2 in their pancreatic beta cells, and they discovered that those mice could secrete more insulin and clear glucose faster than regular mice.

(Imai speaks on “Genetic basis for possible antiaging therapies” on February 17 as part of a program called “Antiaging therapy: Biological prospects and potential demographic consequences.” The session runs from 1:45 p.m. to 4:45 p.m.)

Shin-ichiro Imai has been investigating the mechanism of aging and longevity at the cellular and organismal levels for 18 years. While a postdoctoral researcher at the Massachusetts Institute of Technology, Imai discovered a novel enzymatic activity of Sir2 (silent information regulator 2), a member of a family of evolutionarily conserved proteins and demonstrated its importance for the regulation of longevity.

Since then, Sir2 has been shown to regulate aging and longevity in a variety of organisms. Increasing the activity of Sir2 extends life span in yeast, worms and flies. Imai demonstrated that Sir2 silences genes by removing acetyl groups from the proteins that package DNA. He found this enzymatic activity was dependent on NAD, a molecule important in energy metabolism. As a result of this unique activity, Sir2 functions to sense the energetic status of cells and convert that information into the regulation of gene expression.

At Washington University School of Medicine in St. Louis, Imai focuses on the mammalian version of Sir2. Recent studies have demonstrated the importance of the endocrine control of aging and longevity in model organisms, particularly by the insulin/IGF-I system. Imai’s research asks if a control center regulates the pace of aging and longevity, if such a control center secretes hormones, and if any key regulatory factor regulates the production of such hormones.

Imai addresses those questions by investigating the function of Sir2. Currently, he has two main projects, one investigating whether Sir2 controls the pace of aging by regulating the production of hormones important for glucose metabolism in different tissues. His recent research has shown that the mammalian ortholog of Sir2 enhances glucose-stimulated insulin secretion in pancreatic beta cells.

His second project is devoted to NAD metabolism. He speculates that NAD biosynthesis might play an essential role in aging by regulating Sir2 activity. He is identifying the principal enzymes involved in NAD biosynthesis to assess the impact of alterations in the pathway on the aging process.

Washington University School of Medicine’s full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.