Investigators Identify Free Radical-Based Feedback Loop that Triggers Cell Senescence After DNA Damage

Scientists report new insights into the mechanism behind cell senescence that they claim could lead to new approaches to treating age-related diseases. The research, by a team at Newcastle University’s Institute for Ageing and Health, used a systems biology approach to unravel the molecular pathway that occurs when DNA damage triggers cells to shut down their ability to divide and support repair and regeneration.

The work is published in Molecular Systems Biology in a paper titled “Feedback between p21 and reactive oxygen production is necessary for cell senescence.”

Led by Thomas von Zglinicki, Ph.D., professor of cellular gerontology, the Newcastle team found that DNA damage in cells initially impacts mitochondrial function. The mitochodria pump out increased levels of free radicals, which causes further DNA damage. This in turn generates more free radicals until the cell is triggered to go into senescence.

“The pathways leading to the establishment of senescence are proving to be more complex than was previously envisaged,” the researchers state. “Combining in-silico interactome analysis and functional target-gene inhibition, stochastic modeling, and live-cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by DNA damage response (DDR) and which after a delay of several days, locks the cell into an actively maintained state of deep cellular senescence.

“The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signaling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFβ. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR.”

The investigators admit they can’t rule out the existence of other pathways stabilizing ROS production in senescent cells. However, they maintain that signaling through CDKN1A, MAPK14, and TGFβ is the important link between telomere-dependent and -independent DDR and ROS production in primary human and mice fibroblasts.

The Newcastle team further claims its findings were made possible only because a multidisciplinary systems biology approach was used. The work was carried out at the Centre for Integrated Systems Biology of Ageing and Nutrition (CISBAN), which is sited at the Institute for Ageing and Health. “There is no way that this advance could have been made without combining the expertise of experimental biologists, mathematicians, and computer scientists,” comments professor Tom Kirkwood, director of both CISBAN and the Institute for Ageing and Health. “It’s no exaggeration to say that without systems biology, we will not understand something as complicated as the aging process.”