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

A protein-free diet or one missing certain amino acids can protect against kidney and liver damage due to ischemia in mice. 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. Dietary restriction, or reduced food intake without malnutrition, increases life span, health span, and acute stress resistance in model organisms from yeast to nonhuman primates. Although dietary restriction is beneficial for human health, this treatment is not widely used in the clinic. Here, we show that short-term, ad libitum feeding of diets lacking essential nutrients increased resistance to surgical stress in a mouse model of ischemia reperfusion injury. Dietary preconditioning by 6 to 14 days of total protein deprivation, or removal of the single essential amino acid tryptophan, protected against renal and hepatic ischemic injury, resulting in reduced inflammation and preserved organ function. Pharmacological treatment with halofuginone, which activated the amino acid starvation response within 3 days by mimicking proline deprivation, was also beneficial. Both dietary and pharmacological interventions required the amino acid sensor and eIF2α (eukaryotic translation initiation factor 2α) kinase Gcn2 (general control nonderepressible 2), implicating the amino acid starvation response and translational control in stress protection. Thus, short-term dietary or pharmacological interventions that modulate amino acid sensing can confer stress resistance in models of surgical ischemia reperfusion injury.