Gcn4 Slows Aging in Yeast via Reduced Protein Synthesis
Many methods of modestly slowing aging in laboratory species are accompanied by reduced rates of protein synthesis and higher levels of activity by cellular maintenance processes such as autophagy. The research noted here is one of a number of examples from recent years in which an intervention lowers the rate of protein synthesis and slows aging as a result. This is much more a tool to assist in mapping the details of metabolism and aging than it is the basis for any sort of practical therapy, however. The practice of calorie restriction lowers protein synthesis rates, and no attempt to mimic that has yet produced a practical treatment that is as reliably, effective, and free from side-effects as simply eating less. The scope of the possible results should also be apparent: no-one can reliably live to 100 just by eating less, and even if they make that far, they are still greatly impacted by the aging process. This is not the road to rejuvenation. Only repair of the forms of cell and tissue damage that cause aging, such as that addressed by the SENS research portfolio, can in principle achieve reversal of aging.
For about one hundred years it has been known that nutrient restriction and moderate stress can significantly prolong life. Researchers have now discovered how the transcription factor Gcn4, a protein that regulates the expression of many genes, extends the life of baker's yeast Saccharomyces cerevisiae. In various stress situations, the cells stimulate Gcn4 production which leads to reduced biosynthesis of new proteins and increased yeast lifespan.
It has long been known that protein synthesis - also known as translation - plays an important role in aging. Inhibition of protein synthesis, caused for example by reduced nutrient intake, can have a positive effect on the life expectancy of diverse organisms such as yeast, flies, worms, or fish. Reducing the ribosomes, the protein factories of the cell, can also considerably extend the lifespan of yeast cells. What these cellular stresses have in common is that they activate the production of Gcn4. However, how this protein promotes longevity has remained unclear.
The team exposed yeast cells to different stress conditions, measured their lifespan, protein synthesis rates and Gcn4 expression. "We observed that the level of the Gcn4 protein was positively correlated with the longevity of yeast cells. However, we wanted to understand why. We have now shown for the first time that it is the transcriptional suppression of genes that are important for cellular protein synthesis by Gcn4 that seems to account for its lifespan extension effect. As the translation machinery is limiting, the energy-intensive production of new proteins is overall dampened." From the yeast cell's point of view, this is an advantage: This enables them to live about 40 percent longer than usual.
The transcription factor Gcn4 is conserved in over 50 different organisms, including mammals, and it likely play a significant role in the aging of these organisms as well. The researchers will now investigate whether the mammalian homolog similarly slows aging and extends lifespan by regulating protein synthesis genes in response to nutrients and stress.