A Different Approach to Designing Calorie Restriction Mimetics

A calorie restriction mimetic - usually a drug - is a treatment that can recapture some of the same alterations to metabolism caused by the practice of calorie restriction. Since calorie restriction extends life and improves health, so should a calorie restriction mimetic. Most such work at the moment focuses on finding existing drugs that have some calorie restriction mimetic effects and side-effects that are manageable. Regulation makes it so expensive to produce new medical technologies that research and development is guided into marginal repurposing of existing drugs rather than working on better new directions.

Here is an example of the other end of the drug design spectrum, in which researchers work on identifying which epigenetic alterations should be made, and then think about how to design drugs to make those alterations. Despite the headlines none of this can turn off or reverse aging - it can only slow it down modestly, the same way that calorie restriction does. If you want rejuvenation, you have to look at the SENS approach of damage repair biotechnologies, not epigenetic manipulation.

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. "Most algorithms try to find drug targets that kill cells to treat cancer or bacterial infections. 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."

[This] 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. [The algorithm, 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.

Some of the genes that the MTA identified were already known to extend the lifespan of yeast when turned off. Of the other genes found, [researchers] sent seven to be tested [and] 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. So achieving a 10-fold increase over this expected frequency, as we did, is very encouraging."

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.

Link: http://www.aftau.org/site/News2?page=NewsArticle&id=19593


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