Neuroscience: Early Molecule Fingered as an Alzheimer's Cause Neurobiology: Study Sheds Light on Critical Relay in Visual Circuit Pathology: Enzyme Stands Guard Against Nerve Cell Death Longevity: Molecules Discovered that Extend Life in Yeast, Human Cells Leadership: Platt Named Chair of Ambulatory Care and Prevention Metabolic Pathway in Worms May Reveal Strategy for Longer Life Span Mimicking HIV Receptor Bolsters Antibody Defense Healthy Lifestyle Aids Sexual Function in Older Men Bone Protein Reverses Kidney Disease in Mice   Excellence in Mentoring Awards Presented Collier Wins Bristol-Myers Squibb Award in Infectious Disease Kirschner Wins Cell Biology's Top Honor New Dean for Resource Development Named HSDM Breaks Ground for New Research Building New Roles Mark Changes in HMS Dean's Office HMS Launches New Research Building, Milestone Symposia, Register Online New Research Institute Opens at the University of Natal Center for Biopreparedness Launched at Children's Biostatistics Distinguished Lecture Harvard Teaching Hospitals Among Best, According to U.S. News In Memoriam: Felix Brown William Beck News Briefs   FDA Has Full Plate Ensuring Food Safety   Front Page

LONGEVITY Molecules Discovered that Extend Life in Yeast, Human Cells Mice, rats, worms, flies, and yeast all live longer on a low-calorie diet, which also seems to protect mammals against cancer and other aging-related diseases. Now, in yeast cells, researchers at HMS and BIOMOL Research Laboratories have for the first time found a way to duplicate the benefits of restricted calories with a group of compounds found in red wine and vegetables. One compound extended yeast life span by up to 80 percent. The molecules are also active in cultured human cells. "There is a growing realization from the aging field that blocking cell death--as long as it doesn't lead to cancer--extends life span." --David Sinclair The findings are reported in the Aug. 24 Nature advance online edition. The research suggests a promising route to find and develop drugs to lengthen life and prevent or treat aging-related diseases. The Wine Connection The molecules belong to a familiar group of compounds known as polyphenols, such as the resveratrol found in red wine and the flavones found in olive oil. For these particular polyphenols, the beneficial effects seem to be independent of their noted antioxidant properties. Instead, the molecules activate sirtuins, a family of enzymes known to extend the life span of yeast and nematodes. In screening tests, the researchers found 17 molecules that stimulated SIRT1, one of seven human sirtuins, as well as the yeast sirtuin SIR2. "We think sirtuins buy cells time to repair damage," said molecular biologist David Sinclair, assistant professor of pathology at HMS and co-author of the study. "There is a growing realization from the aging field that blocking cell death--as long as it doesn't lead to cancer--extends life span." "The sirtuin stimulation provided by certain, but not all, polyphenols may be a far more important biological effect than their antioxidant action," said co-author Konrad Howitz of BIOMOL, a biochemical reagents company in Pennsylvania. Calorie restriction (for mammals, reducing intake to 60 or 70 percent of normal daily calories) may be one of many mild stresses that trigger beneficial effects, a phenomenon called hormesis. To explain their new findings, the researchers propose that plant polyphenols, which increase in response to stressful conditions, cue organisms to prepare for impending harsh conditions by switching to a more beneficial survival program. They call their hypothesis "xenohormesis." The most potent molecule in the study, resveratrol, helped yeast cells live as much as 60 to 80 percent longer, as measured by the number of generations. Other studies have linked resveratrol to mitigating age-related diseases, including neurodegeneration, cancer, and clogged arteries. In this study, researchers were surprised to find that yeast cells treated with small doses of resveratrol lived for an average of 38 generations, compared to 19 for the untreated yeast. The polyphenol worked through a known sirtuin molecular pathway to help yeast and human cells survive environmental stresses. Path to Long Life In experiments with human cells, resveratrol activated a similar pathway requiring SIRT1. This enabled 30 percent of the treated human cells to survive gamma radiation compared to 10 percent of untreated cells. Little is known about the human sirtuin SIRT1, except that it turns off the tumor suppressor p53. This raises the concern that any promotion of this pathway might promote cancer. But Sinclair said that calorie-restricted animals in experiments by others have lower, not higher rates of cancer. In the paper, the researchers report that preliminary experiments in flies and worms are encouraging. Mouse studies are in the works. They are exploring synthetic variations on the molecules, which they call sirtuin-activating compounds, or "STACs," to improve the sirtuin activity. They are also searching for endogenous activators that may exist in human cells. In the May 8 Nature, Sinclair's research group reported the first known genetic link between environmental stresses and longer life in yeast. Triggered by low salt, heat, or calorie restriction (to as low as 25 percent of normal), a yeast "longevity gene" stimulated Sir2 activity. Sinclair and his colleagues are testing equivalent genes in humans to see if they similarly speed up human sirtuin activity. The work was supported by the National Institute on Aging and the Armenise-Harvard Foundation. Researchers were further supported by fellowships and training grants from the Ellison Medical Research Foundation, the American Federation for Aging Research, the National Eye Institute, and the National Science Foundation. --Carol Cruzan Morton