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.

Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
U.S. National Heart Lung and Blood Inst
Department
Type
DUNS #
City
State
Country
Zip Code
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