Researchers at the Harvard School of Public Health (HSPH; Boston, MA, USA) analyzed two groups of mice. One group was allowed to eat normally for 6 to 14 days; the other group was given a diet free of protein or lacking the single essential amino acid tryptophan. Both groups were then subjected to surgical stress induced by ischemia reperfusion injury, which could potentially harm the kidneys or liver.

The results showed that in the mice that were allowed to eat as usual, about 40% died; the protein- and amino acid-free mice all survived. Pharmacological treatment with halofuginone, which activates the amino acid starvation response by mimicking proline deprivation, was also found to be beneficial. The researchers also found that removing the gene that modulates the eukaryotic translation initiation factor 2α (eIF2α) kinase general control nonderepressible 2 (Gcn2), which senses levels of any type of amino acid, eliminated the protective effect. The study was published in the January 25, 2012, issue of Science Translational Medicine.

“Food restriction as a way to increase stress resistance may seem counterintuitive, but in fact our data indicate that the well-fed state is the one more susceptible to this kind of injury,” said James Mitchell, PhD, an assistant professor of genetics and complex diseases at HSPH. “The pathway activated by amino acid deficiency - rather than the absence of any particular amino acid - is responsible for the observed benefits, and opens up the potential for targeting drugs toward that pathway.”

Numerous studies have shown that long-term dietary restriction can improve health and longevity, and acute stress resistance in model organisms from yeast to nonhuman primates. Benefits include increased stress resistance, reduced inflammation, improved blood sugar regulation, and better cardiovascular health. The debate stills exists, however, whether the benefits stem from the source of the calories (fat, sugar, or protein) or simply the total calories.

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