Study gives hope that reversing age might be possible
Protein that protects genes focus of research
Aging may be a case of neglect at the cellular level, an absentee landlord that allows gene activity to go awry, according to a study published yesterday.
In experiments on mouse embryonic stem cells, Harvard Medical School researchers found that a multitasking protein called SIRT1 that normally acts as guardian of the genome gets called away to fix damaged DNA, a chore that increases with age. When the protein abandons its normal post to work as a genetic handyman, order unravels. Inactive genes that are normally under its careful watch begin to flip on.
Knowing how that happens may open the way to stopping or slowing it, said David Sinclair, a Harvard Medical School biologist and senior author of the paper.
"What this paper actually implies is that aspects of aging may be reversible," Sinclair said. "It sounds crazy, but in principle it should be possible to restore the youthful set of genes."
What's not yet clear is how much having the gene expression of one's youth really matters.
Scientists not involved in the study pointed out that it is not clear that keeping gene expression young is the key to a person actually staying young.
"The paper says you might be able to maintain or go back to a younger gene expression profile, but does that mean you will be younger?," said Dr. Stephen Helfand, a professor in the department of molecular biology, cell biology, and biochemistry at Brown University. "You may have passed through that gate already, and you can't go back."
The study, published in the journal Cell, is just the latest to draw attention to sirtuins, proteins involved in the aging process that have been a drug target for the biotech company Sinclair cofounded, Sirtris Pharmaceuticals.
Over the last decade, sirtuins have been catapulted into the spotlight for the role they played in aging yeast. Since then, various studies have documented the role sirtuins play in health and lifespan in many organisms.
A chemical found in red wine called resveratrol and compounds that target sirtuins, are being studied as a potential drug for diseases as diverse as type 2 diabetes and cancer.
SIRT1 is "involved in a sort of musical chairs in the mammalian genome over a lifetime . . . that's remarkably similar to what happens in yeast," said Leonard Guarente, the MIT biologist who did the pioneering early work in yeast and is cochairman of Sirtris's scientific advisory board. "My suspicion is in mammals there are going to be a number of things conspiring against us simultaneously as we get old, and the sirtuins are high enough in the hierarchy they can affect all of them."
To understand SIRT1's double duty in the cell, researchers inflicted DNA damage on mouse embryonic stem cells to emulate the effects of aging. They found that when SIRT1 was busy with repairs, genes that it had kept silent switched on.
To test whether that connects to genetic changes seen in aging, the researchers looked at elderly mouse brains.
Each tissue has a certain pattern of genes that should be on, but in old age, extra genes may intrude. For example, a gene that is normally on in the liver suddenly goes on in the brain. Researchers found that many of the genes that suddenly flipped on in their experiment in the absence of SIRT1 were the same ones that flipped on in the aging mouse brain.
What remains to be tested is whether shutting off those genes actually slows aging or has an effect on lifespan.
"That's the rate-limiting question that is in the field right now, whether the changes in expression patterns are causally responsible for different aging outcomes," said Thomas E. Johnson, a professor of integrative physiology at the University of Colorado at Boulder, who was not involved in the study.
Carolyn Y. Johnson can be reached at cjohnson@globe.com. 