Yale Bulletin and Calendar

March 23, 2007|Volume 35, Number 22

Of genetic switches and misfolded RNAs: Scientists exploring the process of aging

Two Yale scientists have been named Senior Scholars in Aging research by the Ellison Medical Foundation, a four-year award made to established investigators for research into understanding development processes that affect lifespan, and age-related diseases and disabilities.

The Yale award winners are Frank J. Slack, associate professor of molecular, cellular and developmental biology, and Dr. Sandra L. Wolin, professor of cell biology and of molecular biophysics and biochemistry.

Frank Slack

Slack studies the genetic switches that control development, and aging as a developmental process. According to Slack, "Changes in gene expression in aged adults -- across many species -- do not solely seem to be a response to mounting cellular damage. Rather, a conserved, developmentally timed regulation of gene activity during young adulthood seems to control features of aging."

Past research on C. elegans and Drosophila, laboratory round worms and fruit flies, demonstrated that in early adulthood these animals turn off a conserved group of genes that mobilize energy from food, and turn on stress-response genes. There is a similar trend in human brain tissue, where the switch occurs at around age 40 -- suggesting that aging, or specifically the time of death, is under a timed control at the genetic level, explains Slack.

"We found that genes that regulate the timing of events during C. elegans development also regulate timing of aging and death during adulthood," he notes.

Consistent with the lifespan analysis, mutants that Slack studied were stress-sensitive and aged prematurely. His work provided some of the best evidence of a novel role for non-coding RNAs called microRNAs in aging, and opened the potential of using microRNAs to regulate human health during aging.

Slack joined the Yale faculty in 2000. He is also a member of the Yale Cancer Center.

Sandra Wolin

Wolin is determining how RNA damage that occurs because of normal cellular activity contributes to aging. She is studying how RNA molecules fold into intricate structures inside cells and how cells recognize misfolded RNAs.

"In both mammalian cells and yeast, we focus on proteins and RNA-protein complexes that play critical roles in these processes," says Wolin. "Our work has revealed unexpected connections between RNA misfolding, radiation damage repair and autoimmune disease."

Damaged RNAs have often been detected in the brains of aging animals and patients with neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. However, because the cellular pathways for recognizing and degrading these RNAs are unknown, it has not been possible to determine whether RNA damage contributes to aging or to age-related diseases. Wolin is attempting to identify genes involved in detecting and degrading damaged RNAs and determine whether they contribute to senescence.

"Once we have identified these important genes in yeast, we will determine whether the same components are involved in this process in mouse and human cells," says Wolin. "We will also determine whether the failure to degrade damaged RNAs contributes to senescence in mouse and human cells. Knowing how RNA damage contributes to aging or to neurodegeneration could be of broad importance for designing therapeutics that slow the aging process."

Wolin, who holds both an M.D. degree and a Ph.D. in molecular biophysics and biochemistry from Yale, joined the Yale faculty in 1991. She is also a member of the Yale Cancer Center.

The Ellison Medical Foundation Senior Scholar Program in Aging brings an award of $150,000 per year over the four years to support established investigators in the development of new and creative research programs.

According to executive director Richard L. Sprott, "The Ellison Medical Foundation's goal is to provide scientists with the resources, freedom and flexibility to pursue high-risk research that could have a scientific impact worldwide. The foundation expects that its programs will stimulate exciting innovative research that will improve lives and influence future discoveries."

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