Although most health professionals believe chronic stress can lead to a variety of medical conditions, definitive proof of the mechanism by which this occurs has been absent.

New research from scientists at Duke University Medical Center explains the stress response in terms of DNA damage.

“We believe this paper is the first to propose a specific mechanism through which a hallmark of chronic stress, elevated adrenaline, could eventually cause DNA damage that is detectable,” said senior author Robert J. Lefkowitz, M.D., a Howard Hughes Medical Institute (HHMI) investigator at Duke University Medical Center.

In the study, mice were given an adrenaline-like compound that works through a receptor called the beta adrenergic receptor. The scientists found that this model of chronic stress triggered certain biological pathways that ultimately resulted in accumulation of DNA damage.

“This could give us a plausible explanation of how chronic stress may lead to a variety of human conditions and disorders, which range from merely cosmetic, like graying hair, to life-threatening disorders like malignancies,” Lefkowitz said.

“The study showed that chronic stress leads to prolonged lowering of p53 levels,” said Makoto Hara, Ph.D. P53 is a tumor suppressor protein and is considered a “guardian of the genome” – one that prevents genomic abnormalities.

“We hypothesize that this is the reason for the chromosomal irregularities we found in these chronically stressed mice.”

G-protein-coupled receptors (GPCRs) such as the beta adrenergic receptor are located on the surface of the membranes that surround cells, and are the targets of almost half of the drugs on the market today, including beta blockers for heart disease, antihistamines and ulcer medications.

Scientists discovered a molecular mechanism through which adrenaline-like compounds acted through the G-protein pathway to trigger DNA damage.

In the study, infusing the adrenaline-like compound for four weeks in the mice caused weakening of the protective action of p53, which was also present in lower levels over time.

Future studies will evaluate mice that are placed under stress (restrained), thus creating their own adrenaline or stress reaction.

This methodology will allow the scientists to learn whether the physical reactions of stress, rather than an influx of adrenaline in the lab as was done in the current study, also leads to accumulation of DNA damage.

The paper was published in the online issue of Nature.

Source: Duke University