This Is How a Low Calorie Diet Prolongs Life

Various researches have showed that a restrictive diet slows down the aging process. A new study carried out at the University of Washington and published in the Cell journal has taken a few further steps in explaining why that happens. The research made on yeast cells connected ribosomes, the protein-making organelles in living cells, and Gcn4, a protein involved in genome activity, to the pathways of diet and aging.

It’s a known fact that the life prolonging effects of a restrictive diet are partially caused by decreased activity of TOR, an enzyme controlling many cell activities, resulting in a lower rhythm of protein synthesis (scientifically called translation).

This research focused on yeast strains with lower protein synthesis. It appeared that ribosomal mutations may boost overall lifespan. Ribosomes are constituted of two pieces, the large and small subunits.

"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 lead author Kristan Steffen, a graduate student in the UW Department of Biochemistry.

When the team exposed the yeast cells to diazaborine, a chemical impacting the synthesis of the ribosomal large subunits, but not the small ones, these cells lived 50% longer than unexposed cells. The impaired ribosomal large subunit appeared to increase life span similarly to the TOR signaling pathway.

"We knew that dietary restriction decreased TOR signaling, and that decreased TOR signaling reduced protein production, but this was the first direct evidence that all three were acting in the same genetic pathway," said Brian Kennedy, an associate professor of biochemistry.

To see how low protein synthesis prolongs cell life, the team focused on the activity of the protein Gcn4, a transcription factor that controls the transfer of DNA information during cell growth. The protein appeared to boost its activity when a cell experienced shortage of amino acids.

"When ribosomes aren’t working at 100% 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," said co-author Dr. Vivian MacKay, a research professor of biochemistry.

To see how Gcn4 impacts the lifespan, the team hampered its activity. Cells with a deactivated Gcn4 had a weaker response in increasing lifespan when facing starvation compared to 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 co-author Matt Kaeberlein, an assistant professor of pathology.

So far, this effect of Gcn4 in increasing lifespan is proven in yeast, but it could be similar in the same case of animals, too, invertebrates and vertebrates (like worms, flies, mice and humans), as all possess a similar protein working in the same way.

"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," said Kennedy.

"The difficulty with TOR as a therapeutic target 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.

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