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 HSP90, 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 physical fitness in middle aged mice and protects against type 2 diabetes. Therefore, DNA-PK is one of the drivers of the metabolic and fitness decline during aging, which make staying lean and physically fit difficult and increase susceptibility to metabolic diseases.
|Chung, Jay H (2018) The role of DNA-PK in aging and energy metabolism. FEBS J 285:1959-1972|
|Park, Sung-Jun; Gavrilova, Oksana; Brown, Alexandra L et al. (2017) DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging. Cell Metab 25:1135-1146.e7|