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April 24, 2008

UW researchers link dietary restrictions, aging

UW scientists have uncovered details about the mechanisms through which dietary restriction slows the aging process.

Working in yeast cells, the researchers have linked ribosomes, the protein-making factories in living cells, and Gcn4, a specialized protein that aids in the expression of genetic information, to the pathways related to dietary response and aging. The study, which was led by UW faculty members Brian Kennedy and Matt Kaeberlein, appears in the April 18 issue of the journal Cell.

Previous research has shown that the lifespan-extending properties of dietary restriction are mediated in part by reduced signaling through TOR, an enzyme involved in many vital operations in a cell. When an organism has less TOR signaling in response to dietary restriction, one side effect is that the organism also decreases the rate at which it makes new proteins, a process called translation.

In this project, the UW researchers studied many different strains of yeast cells that had lower protein production. They found that mutations to the ribosome, the cell’s protein factory, sometimes led to increased life span. Ribosomes are made up of two parts — the large and small subunits — and the researchers tried to isolate the life-span-related mutation to one of those parts. They found that the long-lived strains had mutations that disrupted the large ribosomal subunit, but never had mutations in the small subunit.

The researchers also tested a drug called diazaborine, which specifically interferes with synthesis of the ribosomes’ large subunits, but not small subunits, and found that treating cells with the drug made them live about 50 percent longer than untreated cells.

Using a series of genetic tests, the scientists then showed that depletion of the ribosomes’ large subunits was likely to be increasing life span by a mechanism related to dietary restriction — the TOR signaling pathway.

Scientists have known that dietary restriction decreased TOR signaling, and that decreased TOR signaling reduced translation or protein production, but this was the first direct evidence that all three were acting in the same genetic pathway, explained Kennedy, an associate professor of biochemistry.

Further research on what was happening in those cells with reduced protein production showed that Gcn4 was playing a role in the process. Gcn4 is a specialized protein called a transcription factor, which helps transfer genetic information during cell growth.

When ribosomes aren’t working at 100 percent, most proteins are made less efficiently — but Gcn4 production can sometimes go up in those situations.

The researchers found that in the long-lived strains, the cells were indeed producing more Gcn4. When they blocked that increase in Gcn4, the yeast cells did not have a longer life span. The results suggest that Gcn4 is an important player in this longevity pathway, said Kaeberlein, an assistant professor of pathology. Although they don’t know if Gcn4 plays a similar role in other organisms, there are Gcn4-like proteins in worms, flies, mice, and humans that appear to be regulated in a similar way.

The researchers hope that this work will help them learn the details of how TOR regulates aging, allowing them to identify better argets for treating age-related diseases in people.

The study’s lead author is Kristan Steffen, a graduate student in the UW Department of Biochemistry. Vivian MacKay, a research professor of biochemistry, was also a co-author on the study.