|A neuron transfected with GFP (source)|
In vertebrates, DSBs are repaired by non-homologous end-joining (NHEJ), a process that sticks the broken ends back together. When NHEJ is impaired in humans and mice, we see premature and accelerated aging including cardiovascular disease, osteoporosis, cancer, atrophy, and alopecia. Because of these studies we know that NHEJ is involved in aging, but we don't quite know how it is affected by aging.
Since NHEJ efficiency decreases with age, the authors wanted to find out which of the two NHEJ pathways was primarily affected. There are two NHEJ pathways: canonical NHEJ (cNHEJ) and microhomology-mediated end joining (MMEJ). The authors found that the use of MMEJ to repair DSBs actually increases with age in several mouse tissues, possibly to compensate for the decline in cNHEJ function (right, bottom). MMEJ glues the broken ends back together, but create an overlap between homologous sequences - something that NHEJ does not do. The downside is that the MMEJ pathway is more error-prone, which leads to the accumulation of mutations that ultimately age the cell and cause cell death. Interestingly, many cancer tissues exhibit high levels of MMEJ, including bladder cancer and myeloid leukemia.
Using the genetically modified line of mice from this study, the researchers now plan to look at the effects of diet, medicines, and genetic factors affect aging in mice. They hope to provide information that will help us fight age-related illnesses in the future.