According to Keren Yizhak and her colleagues, the algorithm predicts which genes can be ‘turned off’ to create the same anti-ageing effect as calorie restriction and could lead to a number of new drug developments to treat ageing.
"Most algorithms try to find drug targets that kill cells to treat cancer or bacterial infections," says the doctoral student in Prof. Eytan Ruppin's laboratory at Tel Aviv University's Blavatnik School of Computer Science.
"Our algorithm is the first in our field to look for drug targets not to kill cells, but to transform them from a diseased state into a healthy one."
Professor Ruppin's lab is a leader in the growing field of genome-scale metabolic modeling or GSMMs. Using mathematical equations and computers, GSMMs describe the metabolism, or life-sustaining, processes of living cells.
Yizhak's algorithm, which she calls a ‘metabolic transformation algorithm,’ or MTA, can take information about any two metabolic states and predict the environmental or genetic changes required to go from one state to the other.
In the study, Yizhak applied MTA to the genetics of aging. After using her custom-designed MTA to confirm previous laboratory findings, she used it to predict genes that can be turned off to make the gene expression of old yeast look like that of young yeast.
Some of the genes that the MTA identified were already known to extend the lifespan of yeast when turned off. Of the other genes she found, Yizhak sent seven to be tested at a Bar-Ilan University laboratory. Researchers there found that turning off two of the genes, GRE3 and ADH2, in actual, non-digital yeast significantly extends the yeast's lifespan.
"You would expect about 3% of yeast's genes to be lifespan-extending," said Yizhak. "So achieving a 10-fold increase over this expected frequency, as we did, is very encouraging."
Shed light on gene expression
Since MTA provides a systemic view of cell metabolism, it can also shed light on how the genes it identifies contribute to changes in genetic expression.
In the case of GRE3 and ADH2, MTA showed that turning off the genes increased oxidative stress levels in yeast, thus possibly inducing a mild stress similar to that produced by calorie restriction.
Next, Yizhak says she will study whether turning off the genes predicted by MTA prolongs the lifespan of genetically engineered mice, and this could one day see drugs developed to target genes in humans, and have an anti-ageing effect.
The findings were published in Nature Communications.