Too much of antioxidant glutathione appears to cause a form of heart disease in genetically engineered mice.

Despite the popular notion that antioxidants, such as vitamins C and E, offer health-promoting benefits by protecting against damaging free radicals, a new study in the August 10 issue of the journal Cell reveals that, in fact, balance is the key. The researchers show in mice that an overload of natural antioxidants can actually lead the heart to failure.

There is plenty of evidence about the damaging effects of oxidative stress, but “there is another side to the coin,” said Ivor Benjamin of the University of Utah, Salt Lake City. “There has been so much emphasis on free radicals to the exclusion of the potential consequences of reductants. Our study provides the first bona fide example of the role that reductive stress can play in disease.”

Reductants, sometimes referred to as antioxidants, are elements or compounds that easily give up an electron to become “oxidized,” while oxidizing agents readily accept electrons. In the body, such oxidation-reduction (redox) reactions are integral to the release and storage of energy. Many cellular pathways are also sensitive to the prevailing redox condition.

In a nutshell: A human mutation that causes muscle damage was added to mice. The scientists discovered that in mice this mutation causes an excess amount of glutathione in reduced form. They think that reductive stress (the opposite of oxidative stress) causes the protein clumping and muscle damage which accompany this mutation.

In the current study, the researchers examined mice carrying a human mutation earlier linked to so-called protein aggregation skeletal myopathies and cardiomyopathies, in which weakening skeletal and heart muscle contain clumps of proteins. Although the genetic basis for the disease had been linked to mutations in one of two genes, the mechanism responsible remained mysterious.

The researchers now show that mice with one of the mutant genes, áB-crystallin, specifically in the heart develop the same symptoms seen in human patients, including heart enlargement, progressive heart failure, and an early death. They further show that the animals’ hearts are under reductive stress.

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 pathway—in which oxidized glutathione is recycled to its reduced, antioxidant form—soon got out of hand, producing excess levels of the reduced glutathione and a condition of reductive stress.

Too much of a good thing becomes a bad thing.

Less of an enzyme involved in generation of reductive compounds allowed the mice to avoid heart disease.

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.

G6PD appears to help restore glutathione back to its reduced state. So a reduction in G6PD likely shifts glutathione back toward its reduced form. Cutting back G6PD lowered the amount of reduced glutathione in cells and doing that avoided heart disease.

Biogerontologist Aubrey de Grey has long argued that antioxidant vitamins would provide little life extension benefit. Why? Because antioxidant compounds are easy for cells to synthesize and if more of the antioxidant (aka reductant) compounds provided a net benefit then very likely selective pressures would have caused us to make more of these antioxidants.

There's no easy magic bullet to slow down the rate of aging. We need treatments that will repair the damage caused by aging. Those rejuvenating repair treatments will come in the form of cell therapies, gene therapies, and replacement organs.