Research ArticleStress resistance

Surgical Stress Resistance Induced by Single Amino Acid Deprivation Requires Gcn2 in Mice

Science Translational Medicine  25 Jan 2012:
Vol. 4, Issue 118, pp. 118ra11
DOI: 10.1126/scitranslmed.3002629

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Stress Relief from Eating Right

Following in the footsteps of Ponce de Leon, scientists have found that tweaking certain signaling pathways can prolong life. These manipulations not only increase life span but also alter metabolism so that the organism is healthier and can better withstand stress. Peng et al. have probed deeply into these signaling pathways and found that the stress-fighting system can be triggered by a diet low in protein or even by the absence of the amino acid tryptophan. Moreover, they have identified a key signaling node, Gcn2, that can be dialed up or down to render mice resistant to tissue damage caused by oxygen deprivation.

To mimic in mice the sort of general stress experienced by patients undergoing surgery, the authors temporarily deprived the kidney of oxygen and nutrients by clamping incoming blood vessels. They pretreated the animals for a week or two with a normal diet or one formulated to be protein-free or missing specific amino acids. The counterintuitive result was that depriving the mice of protein or the amino acid tryptophan before the ischemic treatment was good for them, protecting their kidneys, preserving their ability to clear waste products from the blood. About 40% of the mice that were allowed to eat as usual ultimately died from the kidney injury; the protein-free mice all survived.

Because Gcn2 is known to sense low levels of any given amino acid, the authors tested whether it was necessary for the protective effect. Indeed, deletion of the gene for Gcn2 completely eliminated the ability of tryptophan-free diets to ameliorate ischemic injury. Further, the drug halofuginone, which acts through the Gcn2 pathway, could mimic the beneficial effect of amino acid deprivation.

Although these results are in mice, primates (including humans) also show metabolic improvements upon dietary restriction. Further testing will determine whether dietary manipulations similar to those explored here can improve human resistance to the kinds of stress imposed on the body during and after surgery. Whether through diet or agents like halofuginone, improving our body’s ability to withstand hardship moves us a bit closer toward fulfilling Ponce de Leon’s dream of immortality.