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Scientist’s research seeks to identify critical genetic triggers behind aging

Steve Fisch Photography

Anne Brunet studies the role that FOXO transcription factors play in the molecular regulation of longevity.

BY PAM LOWNEY

Whether a stray gray hair or a crick in the knee, the first signs of aging are often viewed as a force beyond our control. What is aging, it seems, but entropy played out on a more personal level.

But is it?

The notion of aging as a haphazard process is fast losing ground at the frontiers of genetic research where today scientists such as Anne Brunet, PhD, assistant professor of genetics, are uncovering the fundamental mechanisms that help govern the body's resistance to the wear-and-tear of daily life—and ultimately each individual's life span.

The emerging picture shows aging as the result of an orchestrated response by cells to a variety of stimuli. Whether repairing cellular damage or triggering cell death, this response allows the body to evaluate how best to allocate its limited resources as it adapts to changing conditions.

Brunet's research aims to understand this dynamic in its entirety, including which environmental stimuli damage the body, which genes help the body resist or repair this damage and which molecular mechanisms turn these genes on or off.

Understanding this dynamic could potentially shed light on a range of seemingly unrelated human diseases, such as cancer, diabetes and neurodegenerative disorders, which all have a clear age dependency, said Brunet.

Brunet's lab is focused on investigating transcription factors, the proteins that bind to parts of DNA and then act as master switches to trigger the specific genetic programs. She is particularly interested in the forkhead box O, or FOXO, group of factors, which regulates genes responsible for programmed cell death, DNA repair and the detoxification of free radicals, the reactive oxygen molecules produced by the body during metabolism.

Brunet's goal is to use FOXO as a molecular handle to pry open the black box of how longevity is regulated.

"These factors are more of a tool at the beginning," said Brunet. "Once we begin to understand their role in aging, it will allow us to expand our research into why and how we age in a more global manner. But we need to start somewhere."

Brunet first became interested in FOXO factors as a key to longevity in 1997 when researchers at UCSF and Harvard Medical School found that worms with hyperactive factors lived two to three times as long as their normal counterparts. Realizing that these factors exist across species, Brunet decided to study their importance in mammals.

Since then, Brunet has helped to elucidate FOXO's role in what she calls one of the most compelling examples of the molecular regulation of longevity: the insulin-Akt pathway.

After eating, the body releases insulin into the bloodstream. When insulin binds to a cell's surface, it jumpstarts a number of reactions, including the signaling pathway responsible for activating the serine/threonine kinase Akt.

Working with human and mouse cell cultures, Brunet found that Akt inhibits FOXO function by adding a phosphate group to factors in the cell's cytoplasm. The modified factors are in turn prevented from entering the nucleus and turning on their target genes.

Brunet's findings, which were published in Cell in 1999, show that lowering insulin levels helps promote the processes of cell maintenance under FOXO control. Because the body produces less insulin when it consumes less food, these findings may also explain why calorie restriction has been shown to extend life span in species ranging from yeast to primates.

Building on this link between FOXO and longevity, Brunet has gone on to explore other aspects of these factors, including new target genes and other stimuli that regulate their function. In 2004, she published results in Science showing that oxidative stress, caused by free radicals in the cellular environment, prompts these factors to express genes for stress resistance.

Brunet's lab has also shed light on a signaling network within the nucleus that regulates FOXO's response to different conditions. "When activated, these factors do not express all of the genes under their control at the same time," said Brunet. "We are working to understand how specific protein partners in the nucleus combine with them to tell them whether to repair damage, resist damage or induce cell death if a cell is beyond repair."

Having studied their behavior within cell cultures, Brunet is now developing mouse models to uncover their action on the level of the organism. Among other questions, these models will help Brunet explore why an individual's organs tend to age at the same rate and whether the brain plays a central role in controlling this process.

Brunet's current hypothesis points to the hypothalamus-pituitary axis, a region in the brain known to send chemical messengers throughout the body. Early studies by her lab have already confirmed the presence of FOXO factors in high concentrations in this region of the brain.

While aging has long been a subject of study, scientists have only recently made significant headway. "Before, scientists didn't have genes to understand the pathways," said Brunet. "They basically saw a million things happening and didn't know which one was causative."

Today, with the discovery of specific genetic mutations that play a role in aging, Brunet and other scientists have the leverage they need to understand its interrelated processes. And in Brunet's case, this means making full use of FOXO as a molecular tool.

"We want to understand this one piece," said Brunet, "and then from there, hopefully we can shed light on the entire black box."