Environmental Factor, September 2009, National Institute of Environmental Health Sciences
Aging Research Yields Promising Medical Compounds
By Robin Arnette
Harvard School of Medicine Professor David Sinclair, Ph.D., concluded the 2008-2009 NIEHS Distinguished Lecture Series on August 11 with a thought-provoking seminar titled "Pathways That Control the Pace of Aging and Disease: Prospects for New Medicines." NIEHS Principal Investigator Xiaoling Li, Ph.D., (http://www.niehs.nih.gov/research/atniehs/labs/lst/mammalian/index.cfm) hosted the talk, which drew a capacity audience.
Sinclair (http://pathology.hms.harvard.edu/sinclair.htm) is best known for his work with resveratrol, a naturally occurring molecule found in red wine grape skins and other plants. Resveratrol increases the lifespan of yeast, roundworms, flies and mice, and studies also show that rodents on high-fat diets and resveratrol are actually healthier.
The history of resveratrol begins with early studies on the association between longevity and caloric restriction (CR). Early studies demonstrated that a 30 - 40 percent daily reduction of calories slowed the aging process in rats and monkeys, so Sinclair decided to study lifespan extension in yeast as a postdoctoral fellow at M.I.T. with Leonard Guarente, Ph.D. In 1995 Guarente's lab discovered that a family of stress genes called sirtuins controlled the process of aging in yeast. Sirtuin homologues have been found in a variety of organisms, and Guarente and Sinclair believed that these genes may have evolved to help organisms survive adversity such as starvation.
The yeast sirtuin gene, SIR2, has a human homologue called SIRT1, and both protein products are deacetylases, enzymes that remove acetyl groups from target proteins in conjunction with other genes. A microarray study reported that one of the genes that was upregulated when yeast were placed under stress was PNC1, so Sinclair made a GFP-fusion protein with PNC1 and determined that its activity increased under CR conditions in yeast. The experiment indicated that PNC1 regulated SIR2, and both were needed for yeast to live longer. In addition PNC1-regulation of sirtuins is conserved in other organisms such as the roundworm Caenorhabitis elegans. Sinclair noted, "The transfection of an inactive PNC1 into C. elegans abolishes sirtuin activity, but if you put in extra copies of PNC1, it extends the lifespan compared to the wild-type worm with one copy of PNC1."
In 2003 Sinclair and his collaborators at Biomol International (http://www.biomol.com/1/) found several molecules that extended the lifespan of yeast cells in a SIR2-dependent manner. Sinclair called them SIRT1-activating molecules (STACs), and one of these STACs turned out to be resveratrol. A few years later, Sinclair wanted to see if resveratrol could mimic the benefits of CR without having to diet, so along with a collaborator at NIH, he divided up his mice into three feeding groups: mice on a lean or standard diet (SD), mice on a high-fat diet, also called the Western diet, and mice on a Western diet plus resveratrol.
At 15 months the SD mice were lean, while the Western diet mice and the Western diet plus resveratrol mice were obese. However, the resveratrol mice were physiologically different. "Looking at the resveratrol mice, there's no way they could live longer or be healthier or run further, but that is exactly what we found," Sinclair explained. "Even pathologists who were studying the tissue samples couldn't tell the difference between the resveratrol and SD mice."
Harvard University and Sinclair co-founded a company called Sirtris (http://www.sirtrispharma.com/) that is developing synthetic STACs for humans. The drug is well-tolerated, seemingly safe and in early clinical trials lowered blood glucose levels and improved insulin sensitivity in diabetic patients. Sirtris, now owned by GlaxoSmithKline, has designed new chemical molecules that are up to a 1000 times more potent than resveratrol. In three different diabetes models, these drugs reduced glucose and cholesterol levels and were highly anti-inflammatory.
Li, who described Sinclair as "the inspiration for my own research," has also been investigating the role of SIRT1 in lipid metabolism and inflammation. She says that Sinclair's observations are in line with her recent findings that deletion of hepatic SIRT1 results in hepatic steatosis or fat buildup and inflammation.