Chemotherapy May Hasten Aging

It saves patients' lives, but chemotherapy also might hasten their aging, a new study finds. The findings could prove beneficial in the long run by allowing doctors to devise less-harmful chemotherapy combinations and identify patients whose cells are “old” and who are prone to side effects.

Senescent cells have lost the ability to divide, and as people age, these stagnant cells accrue in their bodies. Senescence of stem cells and other proliferating cells may promote physical breakdown late in life by preventing tissues from repairing and renovating themselves. DNA damage such as that induced by chemotherapy can spur cells to senesce, but whether chemotherapy accelerates the accumulation of senescent cells in the body hasn't been clear.

The researchers obtained blood samples from 39 breast cancer patients before and after they underwent the chemotherapy regimen of doxorubicin and cyclophosphamide. The team tested the patients' circulating T cells for indicators of senescence, such as the tumor suppressor proteins p16^INK4a and ARF.

Levels of these two senescence markers shot up after chemotherapy, the team revealed in the April 1 issue in the Journal of the National Cancer Institute. The rise in overall expression was equivalent to what would occur after nearly 15 years of chronological aging, the researchers calculated. “The burden of senescent cells was dramatically increased,” says coauthor Norman Sharpless, MD, director of the Lineberger Comprehensive Cancer Center at the University of North Carolina in Chapel Hill.

Some of the patients had also received radiation or taxanes, but those therapies didn't appear to affect cellular senescence. However, the intensity of chemotherapy did make a difference. Patients treated every 2 weeks—a so-called dose-dense schedule—showed a larger increase in p16^INK4a than did patients treated every 3 weeks.

The researchers confirmed the aging effect by studying a group of 176 breast cancer survivors, 69 of whom who had received chemotherapy between 2 and 18 years earlier. In the chemotherapy group, the level of p16^INK4a was substantially higher than in the patients who hadn't received the treatment, a difference that corresponded to nearly 11 years of chronological aging.

The upsurge in senescent circulating T cells likely reflects senescence of the patients' hematopoietic stem cells, the authors surmise. Sharpless notes that after multiple rounds of chemotherapy, levels of blood and immune cells might not be able to rebound. The study's results explain this so-called hematopoietic exhaustion.

Cancer is more common in older people, some of whom could suffer hematopoietic exhaustion if they have chemotherapy. However, patients' chronological ages provide a poor guide to whether they can tolerate the treatment, Sharpless says. The amount of cellular senescence could be a better predictor.

“The real hope is that you could measure p16 prior to treatment and see how likely they were to have effects from the therapy,” he says. If patients do carry large numbers of senescent cells, that could be another factor for them to consider as they choose a treatment, he says.