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New $9.7 million grant to advance research on theory of aging

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PROVIDENCE, R.I. [Brown University] — Over the last few years, scientists — including a team at Brown University — have produced mounting evidence that mobility within genomes of potentially harmful DNA snippets, called retrotransposable elements, may cause health problems associated with aging.

With a new $9.67 million, five-year grant from the National Institutes of Health, researchers at Brown University, New York University and the University of Rochester will collaborate to further strengthen the evidence and to advance toward the goal of applying the findings medically.

"There are a lot of provocative data and a lot of very cool ideas, but the issue now is how to nail this down," said John Sedivy, the Hermon C. Bumpus Professor of Biology at Brown University and principal investigator of the grant. "Let's take the bull by the horns and see what's really going on. Is this a legitimate mechanism of aging and can we control it for therapeutic purposes?"

Previous studies have shown that as cells age, or become senescent, they lose their ability to prevent retrotransposable elements from spreading into new places in the genome. In three new projects supported by two core facilities, the grant will spur the study of how retrotransposable elements function in cells and how their activity might cause specific diseases, and test possible ways of suppressing that activity. The researchers will not only work with human cells but also with mice and fruit flies, or Drosophila, where they can ask more direct questions, obtain faster answers and therefore better inform eventual interventions for people.

Sedivy will lead one of the effort's three projects, "Regulation of Retrotransposable Element Activity in Cellular Senescence and Aging," and the administrative core. Dr. Stephen Helfand, a fellow Brown professor of biology, will lead the second project, "Regulation of Retrotransposable Element Activity in Drosophila."

Professor Jef Boeke of NYU will lead the Retrotransposon Engineering and Genomics Core. Rochester Associate Professor Andrei Seluanov will lead the Mouse Intervention and Aging Core, while Rochester Professor Vera Gorbunova will lead the third project, "Repression of Retrotransposable Elements by the Longevity Gene SIRT6."

The results could shed important light on the health consequences of retrotransposable element activity, Sedivy said. Experiments demonstrating the best interventions could then become translated into future human clinical trials.

In fact, Sedivy notes, some drugs already exist and are widely used against one well known retrotransposable element, HIV. Brown researchers have already shown that some of these drugs also suppress some endogenous retrotransposable elements, although they were never intended for that purpose.

"Hence, if endogenous retrotransposable elements do promote aging in some contexts, we already have pretty good drugs that could be tested right away," Sedivy said. "What you want to come out with is a therapeutic that is directed against retrotransposable elements and then use that therapeutic to target a number of diseases. But at this point, we don't really know which human diseases are linked with these retrotransposition events."

The new grant, Sedivy said, will help the field get there.

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