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ShareNov. 11, 2004 — CHAPEL HILL -- Researchers at the University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center may have made a crucial discovery in the understanding of cellular aging.
In a study published in the Nov. 1 issue of the Journal of Clinical Investigation, the researchers report that as cells and tissues age, the expression of two proteins called p16INK4a and ARF dramatically increases. This increase in expression, more than a hundredfold in some tissues, suggests a strong link between cellular aging and the upregulation, or increased production, of p16INK4a and ARF.
"At the very least, our work suggests that looking at the expression of one or both proteins will make a great biomarker of aging - a tool to clinically determine the actual molecular age of people, as opposed to just their chronological age," said Lineberger member Dr. Norman Sharpless, the senior author of the study and assistant professor of medicine and genetics at UNC's School of Medicine.
"We all know people that we consider to be a young 65, and we believe they won't demonstrate as much p16INK4a or ARF expression as others of the same age."
In addition to identifying molecular targets that may slow aging in the future, the study may also suggest immediate clinical applications. Knowing the molecular age of a tissue may also enable physicians to select the "youngest" most viable tissues and organs for transplantation, to predict how well a patient will heal after surgery and, by being able to characterize the regenerative ability of a patient's bone marrow, predict future toxicity of chemotherapy in a cancer patient.
Both p16INK4a and ARF are known potent tumor suppressors, or proteins that halt tumor cell growth. The study suggests that the important anti-cancer function of these proteins to limit cellular growth might in turn cause aging.
"Proliferation of cells is important in the repair and regrowth of tissues. In fact, we grow old in part because our bodies' ability to regenerate tissues decreases as we age," Sharpless said. "We believe an untoward effect of increased p16INK4a and ARF expression outside of cancer is a decrease in cellular proliferation needed to sustain this regeneration."
The researchers also found that the increase in p16INK4a and ARF can be substantially inhibited by decreasing caloric intake, a known retardant of aging. This result suggests that decreased expression of p16INK4a and ARF could mediate the known anti-aging effects of caloric restriction.
"Our results suggest that going on a short-term diet will not reverse the aging process; only long-term restrictions appeared to have an effect on p16INK4a and ARF expression. Therefore, our results would not be consistent with the idea that short-term caloric restriction prior to surgery would improve post-operative wound healing," Sharpless said.
The work has strong implications for stem cell renewal, he added. Stem cells are self-replenishing cells that constantly divide and differentiate into the component cells that make up the tissues in the human body and are found in particularly high number in the bone marrow, as well as organs such as the skin, kidney and liver.
"As tissue stem cells age, they appear to express more p16INK4a and ARF, which would stop those cells from replenishing," Sharpless said. "As people age, they could just run out of functioning stem cells."
Depletion of stem cells could affect the ability of the body to heal after injury or surgery and may also predict the ability of certain diseases, such as cardiomyopathy, to progress," he added.
Along with Sharpless, study co-authors from UNC Lineberger are postdoctoral researchers Drs. Janakiraman Krishnamurthy and Grigoriy Kovalev, research technician Chad Torrice, graduate student Matthew Ramsey, and UNC Lineberger member Dr. Lishan Su, also associate professor of microbiology and immunology. Co-author Dr. Khalid Al-Regaiey is from Southern Illinois University's departments of physiology and internal medicine.
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This work was supported by grants from the Sidney Kimmel Foundation for Cancer Research, the Paul B. Beeson Career Development Awards Program (formerly the Beeson Physician Faculty Scholars Program) and the National Institute on Aging.
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