Researchers at the Abramson Family Cancer Research Institute of the University of Pennsylvania have found that deleting a gene important in embryo development leads to premature aging and loss of stem cell reservoirs in adult mice. This gene, ATR, is essential for the body’s response to damaged DNA, and mutations in proteins in the DNA damage response underlie certain types of cancer and other disorders in humans.
ATR deletion leads to trabecular (left; the spongy inner cavity of long bones) and cortical (right; dense surface areas) bone loss. Credit: Ruzankina et al., University of Pennsylvania School of Medicine; Cell Stem Cell
“The reason we’re seeing the early signs of aging in these mice is that we’re exhausting their ability to renew tissues,” says Eric J. Brown, PhD, Assistant Professor of Cancer Biology. “We believe these findings may be helpful to the aging and oncology fields since premature aging syndromes and many cancers involve the loss of DNA repair genes.”
When the researchers deleted ATR in the tissues of adult mice, they noticed that the mice showed signs of premature aging, such as hair graying, hair loss, and osteoporosis, within three to four months.
To be able to renew itself, most tissues have a reservoir of specific adult stem cells. These stem cells don’t divide as frequently as other cell types since they need to maintain the integrity of their DNA, and multiple divisions lead to natural breaks in DNA. But when these stem cells are needed, their progeny can rapidly divide and are able to replenish the tissue with new cells.
Brown explains that in the current study the mouse cells without ATR had an overwhelming amount of DNA damage and could not contribute to tissue renewal; nevertheless, the 10 to 20 percent of cells that escaped ATR deletion were able to reconstitute tissues in the engineered mice, at least initially.
Hair follicle stem cells (green) are lost from resting follicles (left) during hair regeneration (right) leading to alopecia, or hair loss. Credit: Ruzankina et al., University of Pennsylvania School of Medicine; Cell Stem Cell
“Think of aging as a slow loss of stem cells, a deterioration of pools of cells that reside in each tissue type,” says Brown. We accelerated the aging process by wiping out a large fraction of these cells prematurely, in one fell swoop. Essentially, these mice start their young adulthood with two strikes against them in terms of long-term tissue maintenance, and so, they subsequently age before their time.”
With this new knowledge of how DNA repair, stem cells, and the aging process interconnect, Brown, first author Yaroslava Ruzankina, and Amma Asare are currently using this mouse model to discover compounds that preserve stem cells and may, consequentially, suppress aging.
This work was funded in part by the National Institute on Aging, the Abramson Family Cancer Research Institute, and the General Motors Cancer Research Scholars Program. Co-authors in addition to Brown are Ruzankina, Asare, Carolina Pinzon-Guzman, Tony Ong, Laura Pontano, George Cotsarelis, Valerie Zediak, Marielena Velez, and Avinash Bhandoola, all from Penn.