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	Bruce Demple

One of the most powerful prescriptions for a long life seems to be eating less, according to researchers who are trying to dissect the mechanisms of calorie restriction in yeast, worms and mice. There is some evidence that cells and animals respond to a reduced diet with far-reaching changes in gene expression, even when the cells and animals have entered later stages of life.

The subject of longevity was part of a larger two-day John B. Little Symposium in Radiation Sciences and Environmental Health held recently at HSPH. The annual symposium seeks to bridge the interests of radiation biologists and scientists studying basic mechanisms in cancer biology. The event drew more than 400 scientists.


	John Little

This year’s theme, "Cellular Mechanisms in Genetic Stability and Aging," reflects the growing overlap between what scientists are learning about the aging process and what they know about the effects of ionizing radiation and other environmental challenges, said co-organizer Bruce Demple, professor of toxicology in the Department of Genetics and Complex Diseases.


Leonard Guarente

Leonard Guarente, Novartis Professor of Biology at the Massachusetts Institute of Technology, opened one of the sessions on the mechanisms of aging. Several years ago, Guarente’s group found that a "longevity gene" called SIR2 in yeast and worms promoted survival in the face of scarcity by diverting the organisms into a kind of hibernation. In particular, the starving yeast and worms with extra copies of the gene lived longer than yeast and worms with fewer or no copies of the gene.

"Aging has many and variable causes that differ from organism to organism, but SIR2 seems to be able to override them," Guarente said.

In yeast, SIR2 seems to sense reduced caloric intake and change mitochondrial metabolism to a more efficient process that produces cellular food known as ATP.

In experiments in mice, the equivalent longevity gene SIRT1 downregulated the tumor suppressor gene p53. That result suggested the gene may work to preserve organ integrity by minimizing cell loss and expanding lifespan, Guarente said. The result also, however, raised concern about a potential cancer-promoting effect.


Tomas Prolla

The number one carcinogen in the human diet is calories, according to Tomas Prolla from the University of Wisconsin-Madison. In experiments conducted by Prolla’s group, mice live longer on a restricted diet, with more youthful sleek and shiny fur, compared to mice allowed to gorge themselves.

The gluttonous mice are not just fat; they develop patchy fur and spontaneous tumors. Calorie-restricted mice also get tumors, but later in life, indicating slower aging, Prolla said.

Researchers in Prolla’s lab have been comparing how genes are expressed in mice to identify early markers of aging.

In one study of middle-aged mice, Prolla and his colleagues found that restricting calories increased lifespan, reduced heart disease and reduced cancer incidence. In side experiments, the popular supplements alpha-lipoic acid and co-enzyme q10 had no effect, and two forms of vitamin E may have delayed some changes in the heart, but not as effectively as eating less food.


	Gary Ruvkun

Gary Ruvkun, HMS professor of genetics at Massachusetts General Hospital, has been studying another gene that helps worms live longer through hibernation. Calorie restriction in worms downregulates a gene associated with insulin. The reduced signaling in starved worms has widespread effects, such as inducing hibernation, lowering metabolism, reducing free radical production, increasing fat storage and extending lifespan, said Weiqing Li, a postdoctoral fellow in the Ruvkun lab.

Living longer can pose risks for organisms that make new cells every day. Cells have the potential for runaway division, which is a hallmark of cancer. To avoid this, long-lived complex organisms use tumor suppressor genes to help prevent cancer.


Judith Campisi

However, explained Judith Campisi, senior scientist at Lawrence Berkeley National Laboratory and professor at the Buck Institute for Age Research, some tumor suppressor genes that are beneficial in early life stages may actually drive late-life cancer. Campisi and her colleagues are studying this phenomenon, called antagonistic pleitropy, by comparing genes involved in two human diseases, Werner syndrome and Bloom syndrome.

For more information, about the John B. Little Center for Radiation Sciences and Environmental Health, visit http://www.hsph.harvard.edu/ccb/JBL/JBLHome.htm.

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