Oxidative Damage of Telomeres Induces Cellular Senescence
The accumulation of senescent cells is a contributing cause of degenerative aging. Researchers are very interested in better understanding the processes by which cells are pushed into the senescent state, as this knowledge might lead to better approaches to prevention of senescence. It remains an open question as to the degree to which prevention of senescence via any specific mechanism is beneficial versus harmful. Will it primarily allow cells on the edge of senescence due to transient circumstances, or circumstances that otherwise have little effect on cell viability, to recover and be productive in tissues? Will it allow damaged and potentially cancerous cells to continue their activities unimpeded? These questions remain to be answered on a case by case basis.
When a healthy human cell divides to form two identical cells, a small piece of DNA is shaved off each chromosome's tip, so that telomeres become gradually shorter with each division. However, it remains unclear whether over a person's lifetime, a cell may divide so often that its telomeres erode completely, prompting transition to a senescent state. Researchers have known for decades that telomere shortening triggers senescence in lab-grown cells, but they could only hypothesize that DNA damage at telomeres could make cells senescent.
Until now, testing this hypothesis had not been possible because the tools used to damage DNA were non-specific, causing lesions across the whole chromosome. A new tool uses a special protein that binds exclusively to telomeres. This protein acts like a catcher's mitt, grabbing hold of light-sensitive dye "baseballs" that researchers tossed into the cell. When activated with light, the dye produces DNA-damaging reactive oxygen molecules. Because the dye-catching protein binds only to telomeres, the tool creates DNA lesions specifically at chromosome tips.
Using human cells grown in a dish, the researchers found that damage at telomeres sent the cells into a senescent state after just four days - much faster than the weeks or months of repeated cell divisions that it takes to induce senescence by telomere shortening in the lab. "We found a new mechanism for inducing senescent cells that is completely dependent on telomeres. These findings also solve the puzzle of why dysfunctional telomeres are not always shorter than functional ones. Now that we understand this mechanism, we can start to test interventions to prevent senescence. For example, maybe there are ways to target antioxidants to the telomeres to protect them from oxidative damage."