Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria

As cells live and divide, their genetic material gets damaged. The DNA damage response is a network of proteins that monitor, recognize and fix the damage, which is also called DNA lesions. For example, an enzyme called ATM senses when DNA is broken and then begins a process that will get it repaired, while another enzyme known as SIRT6 participates in the actual mending process. When organisms get older, the repair machinery becomes less efficient, and the number of DNA lesions and errors increases. The accumulation of DNA damage may cause the ‘symptoms’ of old age – from cancer, to wrinkles and the slowing down of the body’s chemical processes. In fact, individuals with defective ATMs (who thus struggle to repair their DNA) age abnormally fast; conversely, SIRT6 promotes longevity. If declining repair mechanisms cause aging, would boosting the DNA damage response slow down this process? Chloroquine is a drug used to combat malaria, but it can also enhance the activity of ATM without damaging DNA. Qian, Liu et al. show that chloroquine helps cells remove broken DNA and keep dividing for longer. In animals, the drug increases the lifespan of worms and prolongs the lives of mice who have mutations that make them age quicker. Qian, Liu et al. also demonstrate that ATM works by chemically altering the pro-longevity enzyme SIRT6. These changes make SIRT6 more stable, and keep it safe from cellular processes that destroy it. In addition, mice that are genetically engineered to lack ATM can survive for longer if they also produce extra SIRT6. These experiments show that enhancing the DNA damage response can slow down aging, thus linking the DNA repair machinery to longevity. Progeria is a group of rare genetic conditions with inefficient DNA repair; people with progeria age fast and die young. The results by Qian, Liu et al., if confirmed in humans, could provide a new way of treating these diseases.