Researchers here identify one of the mechanisms linking severe forms of DNA damage and cellular senescence. DNA damage accumulates with age, and so too do senescent cells: falling into a senescent state is an evolved response to damage or potentially damaging tissue environments, and at least initially reduces cancer risk by preventing these cells from dividing. Senescent cells are not idle, however: they release all sorts of harmful signals that alter the behavior of surrounding cells, promote inflammation, remodel tissue structure, and otherwise harm tissue function. Too many senescent cells actually promote cancer formation via these mechanisms even as they degrade the normal operation of tissues.
The researchers have found that they can block some of these consequences of DNA damage, preventing cells from reacting by becoming senescent. The risk here would be a greater incidence of cancer and other issues due to very damaged cells remaining active, but in mice altered to have a greatly accelerated rate of DNA damage the outcome of reducing the growth in senescent cells in this way is a net benefit. It remains to be seen whether the same is true in normal mice, however:
Human DNA accumulates damage over time, and older people's bodies can't repair it as well. Many scientists believe a build up of damage can cause cells to enter an irreversible dormant state known as senescence. Cellular senescence is believed to be responsible for some of the telltale signs of aging, such as weakened bones, less resilient skin and slow-downs in organ function. Researchers have now pinpointed a molecular link between DNA damage, cellular senescence and premature aging. Finding the key players could lead to therapeutic targets for counteracting some of the negative effects of progerias and perhaps even forestalling the effects of natural aging.
The study took a closer look at the chemical messenger interferon, a molecule that is naturally produced by the body in response to invading pathogens such as viruses. The team found that interferon signaling ramps up in response to double-stranded DNA breaks and that this signaling prompts cells to enter senescence. One of the reasons senescence is believed to lead to the characteristic changes of aging is that it affects stem cells, which normally serve to replenish populations of healthy cells. Earlier studies had shown that mice lacking the Terc gene, which is key to DNA repair, have lower stem cell function and age prematurely, losing fertility and developing scaly skin, gray fur and shrunken, hunched bodies. These mice also have abnormalities in their intestinal tissues, a site known to be greatly affected by stem cell failure.
The researchers bred Terc-deficient mice to animals also lacking an interferon receptor. These animals had reduced signs of premature aging; they were more fertile, had less gray hair, were larger and lived longer on average than mice lacking only Terc. "We could rescue the majority of these phenotypes by abolishing interferon signaling, showing that there is a substantial role of interferon in aging that is caused by persistent DNA damage." For people who suffer from the effects of accelerated aging after undergoing treatments such as radiation that damage DNA or who suffer from acute radiation poisoning these findings hint at novel therapies. While the current study doesn't pertain directly to normal aging in healthy individuals, future studies could shed light on ways to mitigate its negative effects. "Since natural aging is connected with the DNA damage we accumulate over our lifetime and with decline in the stem cell functions, our skin is not repairing as well, our bones are not holding as well as they used to. There is rationale for the future studies on the role of interferon in normal aging."