Female Brain Cells Better Able to Survive Starvation Than Male Ones, Pitt Researchers Say

Neurons from female rats and mice are better able to survive starvation than neurons from the males because they consume fat rather than protein, said researchers from the University of Pittsburgh School of Medicine. The finding could have implications for the nourishment of critically ill patients.

The research team cultured sets of neurons from male and female rats and mice and deprived them of nutrients for 72 hours to gauge the potential impact of starvation on the brain. The team was led by Robert Clark, a professor of critical care medicine at Pitt, associate director of molecular biology in Pitt’s Safar Center for Resuscitation Research, and a pediatric intensivist at Children’s Hospital of Pittsburgh of UPMC; and Lina Du, research associate in Pitt’s Department of Critical Care Medicine.

“Within 24 hours, neurons from the males were dying off because they initiated a self-eating process called autophagy,” Clark said. “But neurons from the females mobilized fatty acids and made lipid droplets to use as a fuel source, prolonging their survival.”

The findings, published in the Jan. 23 issue of the Journal of Biological Chemistry, are the first indication that critical nutritional stress can kill neurons. Known to happen in other tissues during periods of starvation, possibly as a last-ditch survival effort, the process of autophagy leads to cell destruction and the breakdown of complex proteins, generating amino acids and other biological building blocks that could nourish remaining cells.

Sex differences in response to famine have been apparent for nearly a century, with females the heartier of the sexes. Part of the explanation for this observation could be that during nutritional deprivation, male cells tend to lean on energy primarily from protein sources, while female ones lean on fat. The current research suggests that during times of critical nutritional stress, males might be better off if they used fat-derived fuel, as females do.

Autophagy-induced cell death in the brain could result in permanent damage, Clark said. Other research has revealed brain atrophy, or shrinkage, on scans of brain-injured and other critically ill patients, who likely were stressed and possibly insufficiently nourished during long hospitalizations.

“We really need to take critical care nutrition to the next level,” he said. “We can show that undernourishment of the brain during times of illness could lead to worse neurological outcomes, so it may be important to feed men and women, and boys and girls, differently to prevent brain-cell death.”

Intensive care specialists are able to save more lives than ever before, noted study coauthor and Safar Center director Patrick Kochanek, a vice chair and professor of critical care medicine in Pitt’s School of Medicine.

“Prevention of subtle neurological problems, such as mild cognitive disturbances, is becoming a key final frontier in the intensive care unit,” he said. “Many times when these problems arise, the cause is somewhat of a mystery.”

In future work, Clark and his team hope to develop a bedside test to determine whether the autophagy process is occurring in the brains of critically ill patients.

The research was supported by grants from the National Institutes of Health.