The findings are reported in the August 24 Nature advanced online edition. The research suggests a promising route to find and develop drugs to lengthen life and prevent or treat aging-related diseases.
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 famed antioxidant properties. Instead, the molecules activate sirtuins, a family of enzymes known to extend the life span of yeast and tiny lab round worms. In screening tests, the researchers found 17 molecules that stimulated SIRT1, one of seven human sirtuins, and the yeast sirtuin SIR2.
"We think sirtuins buy cells time to repair damage," said molecular biologist David Sinclair, assistant professor of pathology at Harvard Medical School and co-author of the new 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, director of molecular biology at BIOMOL, a biochemical reagents company in Pennsylvania.
Calorie restriction (in mammals, reducing intake to 60 or 70 percent of the 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 health benefits in 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.
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 gene p53. This raises the concern that any promotion of this pathway might promote cancer even as it switches on a longevity program. 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 naturally 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 Harvard-Armenise 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. A provisional patent has been filed for refined versions of the natural molecules.
David Sinclair, PhD is an assistant professor of pathology at Harvard Medical School. His research is focused on finding small molecules and genes that can delay or prevent diseases caused by aging. His lab is one of the few in the world that studies a variety of different organisms--baker's yeast, nematode worms, fruit flies and mice--to understand aging. In 1997, Sinclair's research at M.I.T. identified the discovery of the cause of aging in yeast, a first for any species. This work was published in the journal Cell. In May 2003, Sinclair's laboratory reported the discovery of a conserved "master regulatory gene" for aging in yeast that was published in the journal Nature. Sinclair's work was featured in two books, Merchants of Immortality (S. Hall, 2003) and Timeless Quest (L. Guarente, 2003).
Dr. Sinclair received a bachelor of science with highest honors in 1991 and a PhD in Biochemistry and Molecular Genetics in 1995 from the University of New South Wales, Australia. He worked as a postdoctoral researcher with Dr. Leonard Guarente at M.I.T. for four years before joining Harvard Medical School.
Dr. Sinclair has received several awards and honors for his research, including The Thomson Prize for first place in undergraduate studies, a Helen Hay Whitney Postdoctoral Award (1996-1999), and a Special Fellowship from the Leukemia and Lymphoma Society (1999 - 2002). Sinclair was a Ludwig Scholar (2000-2002), a Harvard-Armenise Fellow (2000-2003), an American Association for Aging Research (AFAR) Fellow (2002), and is currently a New Scholar of the Ellison Medical Foundation (2001-present).
Dr. Sinclair lives in West Roxbury, Massachusetts with his wife and daughter.
PREVIOUS SINCLAIR RESEARCH RELEASES AND ARTICLES
(May 8, 2003)
Genetic Regulator Of Lifespan Identified
Gene That Extends Lifespan In Yeast Points To Paradigm Shift In Longevity Research May Explain Life Extension Via Calorie Restriction
(May 24, 2002)
New Molecular Model Increases Longevity and Could Allow You to Eat Cake, Too
Discovery Shows Life Extension Seen With Calorie Restriction Can Be Gained in Other Ways & Opens Search for Molecules to Do It
(March 23, 2001)
Cancer Cells' Immortality May Depend on Longevity Protein: http://focus.hms.harvard.edu/2001/Mar23_2001/pathology.html
Konrad T. Howitz, PhD is Director of Molecular Biology at BIOMOL Research Laboratories, Inc. a biochemical research reagents company in Plymouth Meeting, PA. Dr. Howitz was educated at Temple University (B.A., Biochemistry, 1980) and Cornell University (Ph.D., Biochemistry, Molecular and Cell Biology, 1985). His thesis work in the laboratory of Richard McCarty elucidated the mechanism of chloroplast transport of the photorespiratory metabolites, glycolate and glycerate. Continuing his work in plant membrane biochemistry, Dr. Howitz went on to postdoctoral positions at the Plant Sciences Institute, University of Pennsylvania, first with Anthony Cashmore (chloroplast protein import), then with Phil Rea (Arabidopsis MDR (P-glycoprotein) homologs). Joining BIOMOL in 1996, Dr. Howitz has helped oversee a continual expansion of the company's biochemical research and production facilities. The laboratory develops and produces recombinant enzymes important for mammalian signal transduction research and assay systems for high-throughput screening. Dr. Howitz's recent work has focused on the histone deacetylases (HDACs), including the sirtuins, enzymes for which he has invented several fluorescent substrates and assay systems.
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