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Buildup of damaged DNA in cells drives aging

the investigators obtained cells from the boy and tested them for NER activity, they found almost none. Further analysis of the boy’s DNA revealed a mutation in a gene known as XPF, which codes for part of a key enzyme required for the removal of DNA damage. The XPF portion of the enzyme harbors the DNA-cutting activity; whereas a second portion, known as ERCC1, is essential for the enzyme to bind to the damaged DNA. Mutations in either XPF or ERCC1 lead to reduced activity of this key DNA repair enzyme.

"We were completely surprised by the finding that the patient had a mutation in XPF, because mutations in this gene typically cause xeroderma pigmentosum, which is a disease characterized primarily by skin and other cancers rather than accelerated aging," said Dr. Hoeijmakers. "This patient, therefore, has a unique disease, which we named XPF-ERCC1, or XFE-progeroid syndrome."

To understand why this XPF mutation caused accelerated aging, the investigators compared the expression pattern of all of the genes (approximately 30,000) in the liver of 15-day-old mice that had been generated in the laboratory to harbor a defect in their XPF-ERCC1 enzyme and that had symptoms of rapidly accelerated aging to the genes expressed by normal mice of the same age. This comparison revealed a profound suppression of genes in several important metabolic pathways in the progeroid mice. Most notably, the progeroid mice had a profoundly suppressed somatotroph (growth hormone) axis—a key pathway involved in the promotion of growth and development—compared to normal mice.

The investigators also found low levels of growth hormones in the progeroid mice and ruled out the possibility that this suppression was due to problems with their hypothalamus or pituitary glands, which regulate growth hormone secretion. Furthermore, they demonstrated that if normal adult mice were exposed to a drug that causes DNA damage, such as a cancer chemotherapy agent, the growth
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Source:University of Pittsburgh Medical Center


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