Aging alone does not explain breakdown in liver cell processes, UF research team finds

UF department of surgery researchers have uncovered more information about why elderly patients often fare poorly after liver surgery, and why livers donated by elderly people often experience ischemia-reperfusion injury during transplantation, while younger people’s livers typically are more stable. Ischemia-reperfusion injury is a form of damage that occurs when blood to the liver is cut off during surgery, then restored.

Kevin E. Behrns, M.D., chair of the department of surgery; Jae-Sung Kim, Ph.D., an assistant professor in the department’s Laboratory of Inflammation Biology and Surgical Science; Jin-Hee Wang, Ph.D., a post-doc in the department; Jae-Il Byeon, Ph.D.,  then a post-doc in the department; In-Sook Ahn, Ph.D., a biological scientist in the department; and Trevan D. Fischer, M.D., a surgical resident; co-authored an article on the topic that appeared in the December 2011 issue of Gastroenterology, along with William A. Dunn, Jr., Ph.D., a professor and interim chair in the department of anatomy and cell biology; and Christiaan Leeuwenburgh, Ph.D., a professor in the department of aging and geriatrics.

In October 2010, Kim presented the research team’s findings on the importance of autophagy, a natural cell process which clears out damaged parts and helps the cell maintain its health and usefulness. The presentation also addressed findings on how to increase autophagy in liver cells, including the use of gene therapy to boost cells’ levels of Atg4B, a protein known to direct autophagy. This technique improved liver function in liver ischemia-reperfusion mouse models.

The research team’s newest study helps explain why liver cells sometimes experience a decrease in autophagy. One factor is the effect of two substances, calcium and calpain 2 (calcium-dependent protease), that decrease levels of Atg4B in aged livers. Another factor, Kim said, could be the basis for a new explanation of the relationship between aging and autophagy in liver cells.

“The current paradigm in liver aging is that autophagy decreases with aging,” he said. “However, our finding is that aging itself does not substantially affect liver autophagy. Our study strongly suggests that marked reduction in liver autophagy occurs only when aged livers are exposed to additional stress, such as ischemia-reperfusion injury. Thus, our work provides a new idea that could change a longstanding paradigm. In addition, it suggests that liver diseases of elderly patients can potentially be treatable.”

In addition, the team described a molecular signaling sequence caused by ischemia-reperfusion injury and used multiphoton imaging to view an entire liver, something that has not been done before.

Kim called the latter “a significant technical advance of live-animal imaging and, potentially, patient diagnosis.”

Lastly, the team discussed their finding “that Atg4B may be an important biomarker of age-related liver diseases. The level of Atg4B in the liver will predict how patients respond to stresses, including liver surgery and transplantation. For instance, surgeons can predict the outcome of these operations before the surgery.”