New & Noteworthy
January 23, 2014
Ponce de Leon searched the New World for the fountain of youth. Turns out that if he had some of the tools at our disposal, he wouldn’t have even had to leave Europe. He just needed to go to the local bakery or brewery and look inside the yeast he found there. Of course, then he wouldn’t have found Florida…
Using in silico genome-scale metabolic models (GSMMs) in yeast, Yizhak and coworkers identified GRE3 and ADH2 as two genes that significantly increased the lifespan of yeast when knocked out. Even more importantly, their method also allowed them to identify the mechanism behind this increased lifespan—the mild stress of increased reactive oxygen species (ROS). This last finding may help scientists identify drug targets that they can target to increase the lifespan of people too. If only Ponce de Leon had lots of -omics data and a powerful computer or two!
After constructing an in silico starting state, Yizhak and coworkers entered two sets of data from previous work that had been done on aging in yeast. They next used gene expression profiling to identify which metabolic reactions were different and which were the same in young and old yeast. They then systematically tested the effect of knocking out these reactions one at a time in their computer model to identify those that could potentially transform yeast from old to young with minimal side effects.
Their first finding was that many of their best hits, like HXK2, TGL3, and FCY2, had already been identified as important in prolonging a yeast cell’s life. They decided to look at seven genes that had not been previously identified as being involved in aging.
When two of these seven, GRE3 and ADH2, were knocked out, these yeast strains lived significantly longer with minimal side effects. For example, the strain lacking GRE3 lived ~100% longer than the wild type strain.
Figuring out why these yeast probably lived longer was made simpler because they used metabolic models to identify the genes. The hormesis model of aging suggests that mild stress, like that found in caloric restriction, can lead to increased life span. With this model in mind, the authors focused in on the possibility that knocking out GRE3 and/or ADH2 would lead to increased stress through the production of increased levels of ROS. When they looked, they found that the two knockout strains did indeed have higher levels of two common forms of ROS, hydrogen peroxide and superoxide.
Of course none of us is particularly interested in extending the life of a yeast! But these results could suggest new drug targets to go after that might mimic the effects of caloric restriction without us having to starve ourselves. And these same methods can be used on human cells to find key pathways to target in people. In fact, the authors have started to use their computer models to investigate aging in human muscle cells and found that like in yeast, many of the genes they have identified are consistent with previous work on human aging.
Now we probably shouldn’t get too far ahead of ourselves here. This is a promising first step but it really isn’t much more than Ponce de Leon boarding his ship to begin his trip to the New World. We still have a long voyage ahead of us before we find the fabled fountain of youth.
by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics