Metabolic and physical decline that occurs during aging promoted by a DNA repair enzyme.

Damage to our DNA accumulates during our aging, and Park et al. show a link between this damage and the loss of metabolic function associated with physical decline and aging-associated diseases. They show that DNA breaks activate the repair promoting enzyme DNA-dependent protein kinase (DNA-PK) in skeletal muscle, but the kinase also suppresses mitochondrial function, energy metabolism, and physical fitness. A small-molecule inhibitor of DNA-PK improves the physical fitness of young obese mice and older mice. Whether there is therapeutic potential in such small inhibitors depends on whether inhibition of DNA repair has deleterious effects, such as increasing the potential for cancer. Here is the abstract:

Hallmarks of aging that negatively impact health include weight gain and reduced physical fitness, which can increase insulin resistance and risk for many diseases, including type 2 diabetes. The underlying mechanism(s) for these phenomena is poorly understood. Here we report that aging increases DNA breaks and activates DNA-dependent protein kinase (DNA-PK) in skeletal muscle, which suppresses mitochondrial function, energy metabolism, and physical fitness. DNA-PK phosphorylates threonines 5 and 7 of HSP90α, decreasing its chaperone function for clients such as AMP-activated protein kinase (AMPK), which is critical for mitochondrial biogenesis and energy metabolism. Decreasing DNA-PK activity increases AMPK activity and prevents weight gain, decline of mitochondrial function, and decline of physical fitness in middle-aged mice and protects against type 2 diabetes. In conclusion, DNA-PK is one of the drivers of the metabolic and fitness decline during aging, and therefore DNA-PK inhibitors may have therapeutic potential in obesity and low exercise capacity.