Researchers Find Aging Genes That Can Be Turned Off
for Anti-Aging Effect
Discovery to move forward in search of drugs to treat
the aging process
Jan. 3, 2014 - Restricting calorie consumption is
one of the few proven ways to combat aging. Though the underlying
mechanism is unknown, calorie restriction has been shown to prolong
lifespan in yeast, worms, flies, monkeys, and, in some studies, humans.
Now researchers have developed a computer algorithm that predicts which
genes can be "turned off" to create the same anti-aging effect as
calorie restriction, which could lead to new drugs to treat aging.
The work by Keren Yizhak, a doctoral student in
Prof. Eytan Ruppin's laboratory at Tel Aviv University's Blavatnik
School of Computer Science, and her colleagues is reported in Nature
Communications. Researchers from Bar-Ilan University collaborated on
"Most algorithms try to find drug targets that kill
cells to treat cancer or bacterial infections," says Yizhak. "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."
Prof. 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. Once built, the individual
models serve as digital laboratories, allowing formerly labor-intensive
tests to be conducted with the click of a mouse.
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.
"Gene expression" is the measurement of the
expression level of individual genes in a cell, and genes can be "turned
off" in various ways to prevent them from being expressed in the cell.
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. Yeast is the most
widely used genetic model because much of its DNA is preserved in
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 three percent 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."
Hope for humans
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.
As a final test, Yizhak applied MTA to human
metabolic information. MTA was able to identify a set of genes that can
transform 40-to-70 percent of the differences between the old and young
information from four different studies. While currently there is no way
to verify the results in humans, many of these genes are known to extend
lifespan in yeast, worms, and mice.
Next, Yizhak will study whether turning off the
genes predicted by MTA prolongs the lifespan of genetically engineered
mice. One day, drugs could be developed to target genes in humans,
potentially allowing us to live longer. MTA could also be applied to
finding drug targets for disorders where metabolism plays a role,
including obesity, diabetes, neurodegenerative disorders, and cancer.
For more genetics research news from Tel Aviv