The find initially took Benjamin by surprise, he said. They had conducted a test traditionally used to measure the level of oxidative stress in the animals, expecting they might see higher than normal levels. Instead, they found the mice had markedly reduced oxidative stress levels due to an abundance of a natural antioxidant known as glutathione.

The mutant mouse hearts exhibited a heightened stress response, including higher activity of heat shock proteins that have been documented in human heart failure, Benjamin explained. Such stress responses yield reactive oxygen species, triggering antioxidative pathways to kick in. In the diseased animals, however, that pathwayin which oxidized glutathione is recycled to its reduced, antioxidant formsoon got out of hand, producing excess levels of the reduced glutathione and a condition of reductive stress.

Moreover, they showed that the offspring of the heart-diseased animals and mice with lower levels of one of the antioxidant enzymes, glucose-6-phosphate dehydrogenase (G6PD), were relieved of their symptoms. That finding suggests that drugs or other treatments targeting the antioxidant pathway through G6PD might modify the phenotype and the natural history of this inherited disorder in humans, according to the researchers.

The results found in the heart suggest that reductive stress might underlie other diseases, as well. Our findings open up a whole new line of investigation in protein aggregation diseases, including neurodegenerative diseases such as Alzheimers and Huntingtons disease, Benjamin said.