Stress response and energy metabolism as a function of aging

National Heart, Lung, And Blood Institute

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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 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.