Turning off the 'aging genes'

Jan 02, 2014
Turning off the 'aging genes'

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 Keren Yizhak, a doctoral student in Prof. Eytan Ruppin's laboratory at Tel Aviv University's Blavatnik School of Computer Science, and her colleagues have developed a computer algorithm that predicts which genes can be "turned off" to create the same anti-aging effect as calorie restriction. The findings, reported in Nature Communications, could lead to the development of new drugs to treat aging. Researchers from Bar-Ilan University collaborated on the research.

"Most algorithms try to find 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."

A digital laboratory

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 humans.

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 .

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 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.

Explore further: Coffee or beer? The choice could affect your genome

More information: Nature Communications 4, Article number: 2632 DOI: 10.1038/ncomms3632

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User comments : 11

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Maggnus
3 / 5 (4) Jan 02, 2014
Hmm wonder where one would go to volunteer?
Torbjorn_Larsson_OM
5 / 5 (2) Jan 02, 2014
That is exciting of course, but the excitement should be tempered by the knowledge that already the results in monkeys has been argued as faulty on statistical grounds.

"a separate study done with macaques has found no benefit of caloric restriction, and suggests that the initial positive results are the product of some specific experimental design choices."
[
http://arstechnic...ng-life/ ]

"That suggests the longevity diet didn't really extend lifespan in the Wisconsin monkeys: It only seemed to because the control monkeys ate themselves into an early grave."

""what I take away from these studies is that extreme emaciation may not be the correct paradigm," said University of Texas biologist Austad. "If I were them (companies or scientists banking on this), I'd be worried.""

[ [ http://www.huffin...197.html ]
dedereu
not rated yet Jan 02, 2014
The difficulty is that we already have a large life extension compared to others animals like dogs, and thus many of our fast aging genes are already turned off !!
So it could work on dogs but quite less on humans.
Looking to centenaries, clealy calorie consumption works for human, even in my family !!!
Eating too much junk food also shortens life, very clearly !!
Dug
not rated yet Jan 02, 2014
According to the makers of Longevinex - a trans-reservatrol compound nutriceutical complex the product effectively switches most of the same aging genes that calorie restriction does. (http://www.longev...ore-42).
Whydening Gyre
4.7 / 5 (3) Jan 02, 2014
Great. This should go hand in hand with that recent article about how we have problems with retirement ages and our pension systems NOW....
Dug
5 / 5 (2) Jan 02, 2014
The economics of solving problems related to aging - that are solved by eliminating aging on an individual basis - are far less costly than raising and educating a new generation individual to replace the aged ones. Once you have genetic maintenance in hand through genetic engineering technology, you have the potential to maintain, adapt and or upgrade the human gene pool without the need for so many expensive offspring, making finite resources stretch further and managing current unsustainable overpopulation more probable.
thingumbobesquire
5 / 5 (2) Jan 03, 2014
The problem is that proteins have a multiplicity of interconnected functions. There is the problem of unintended consequences to shutting off their production by silencing their genetic expression.
Osiris1
not rated yet Jan 03, 2014
Suspect the first human subjects will be dictators, crooked politicians, international monopolists, drug cartel dons, and eventually some of the rest of us.
_he_arketing_log
3 / 5 (2) Jan 03, 2014
Very interesting concept, this does seem impossible though. You can also check out this video too: https://www.youtu...NGd4c58o
Mike_Massen
5 / 5 (1) Jan 04, 2014
Maggnus must be getting old waay too soon with
Hmm wonder where one would go to volunteer?
Surely, it depends on the (female) nurses, if you are only concerned with longevity and not er um practicing or imagining procreation, then maybe you are beyond concerns about aging ;-)

I am still academically & physically considering some useful aspects of procreation long before any sort of decline in respect of the entropy of aging... mutter mutter
5ilence_DoGood
5 / 5 (1) Jan 05, 2014
Turning off a few genes wont stop that.

http://www.youtub...;index=2