Working in yeast cells, researchers at the University of Washington have identified details about the mechanisms by which dietary restriction slows the aging process.
The researchers 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.
Led by UW faculty members Brian Kennedy and Matt Kaeberlein, the researchers of this study earlier showed that lifespan-extending properties of dietary restriction are partly regulated by reduced signalling through TOR, an enzyme involved in many vital operations in a cell. Less TOR signaling in response to dietary restriction, leads to lower rate of protein formation, i.e. translation.
In the current study on lower protein producing strains of yeast cells, the researchers found that ribosomal mutations, sometimes led to increased life span. Ribosomes have a large and small subunit and the study focused on life-span-related mutation to one of those parts.
"What we noticed right away was that the long-lived strains always had mutations in the large ribosomal subunit and never in the small subunit," said Kristan Steffen, the lead author of the study.
Test via a drug called diazaborine, which specifically interferes with synthesis of the ribosomes' large subunits, but not small subunits, indicated a 50 percent increase in longevity of cells treated with the drug than untreated cells. With genetic tests, it was also shown 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.
"We knew 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," said Kennedy.
"The big question then became what's happening in these translation-deficient cells to slow aging. That's when Vivian MacKay, a co-author on the study, had the idea to look at Gcn4," added Kaeberlein.
Gcn6 gets activated when a cell is starving for amino acids and it has a unique mode of regulation.
"When ribosomes aren't working at 100 percent capacity, most proteins are made less efficiently, but Gcn4 is different. Sometimes, you actually get more Gcn4 produced even when everything else is going down. That's precisely what we found in the longer-lived yeast strains with mutations in the large subunit of the ribosome," explained Dr. MacKay, a research professor of biochemistry.
The researchers observed that cells lacking Gcn4 did not respond as strongly as Gcn4-positive cells.
"The increased production of Gcn4 in long-lived yeast strains, combined with the requirement of Gcn4 for full life-span extension, makes a compelling case for Gcn4 as an important downstream factor in this longevity pathway," said Kaeberlein.
"The role of TOR and translation in aging is known to be conserved across many different species, so it's plausible that this function of Gcn4 is conserved as well," Kennedy said.
"Clearly TOR signaling is one component, and perhaps the major component, of the beneficial health effects associated with dietary restriction. The difficulty with TOR as a therapeutic target, however, is the potential for negative side effects. As we learn more of the mechanistic details behind how TOR regulates aging, we will hopefully be able to identify even better targets for treating age-associated diseases in people," said Kaeberlein.
The study appears in the latest issue of the journal Cell.