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.
journal_name
Cell Metabjournal_title
Cell metabolismauthors
Park SJ,Gavrilova O,Brown AL,Soto JE,Bremner S,Kim J,Xu X,Yang S,Um JH,Koch LG,Britton SL,Lieber RL,Philp A,Baar K,Kohama SG,Abel ED,Kim MK,Chung JHdoi
10.1016/j.cmet.2017.04.008subject
Has Abstractpub_date
2017-05-02 00:00:00pages
1135-1146.e7issue
5eissn
1550-4131issn
1932-7420pii
S1550-4131(17)30213-9journal_volume
25pub_type
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