@article{ee940b69a49f425e9babf224d31cc12f,
title = "DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging",
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.",
keywords = "AMPK, DNA-PK, HSP90α, aging, calorie restriction, exercise, insulin sensitivity, mitochondria, obesity, skeletal muscle, type 2 diabetes",
author = "Park, {Sung Jun} and Oksana Gavrilova and Brown, {Alexandra L.} and Soto, {Jamie E.} and Shannon Bremner and Jeonghan Kim and Xihui Xu and Shutong Yang and Um, {Jee Hyun} and Koch, {Lauren G.} and Britton, {Steven L.} and Lieber, {Richard L.} and Andrew Philp and Keith Baar and Kohama, {Steven G.} and Abel, {E. Dale} and Kim, {Myung K.} and Chung, {Jay H.}",
note = "Funding Information: This work was supported by the Intramural Research Program of the National Heart Lung and Blood Institute in the National Institutes of Health. E.D.A. was supported by NIH grant HL73167. The LCR-HCR rat model system was funded by Office of Research Infrastructure Programs grant P40OD021331 (to L.G.K. and S.L.B.) from the NIH. This research was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), which is funded by the Ministry of Health & Welfare of the Republic of Korea (grant number HI14C1176). We acknowledge the expert care of the rat colony provided by Molly Kalahar and Lori Heckenkamp. L.G.K. (lgkoch@umich.edu) or S.L.B. (brittons@umich.edu) may be contacted for information on the LCR and HCR rats; these rat models are maintained as an international resource with support from the Department of Anesthesiology at the University of Michigan in Ann Arbor, Michigan. We thank Benoit Viollet for AMPKα2-KO mice, Dalton Saunders for his help with drug studies, and Zu-Xi Yu for assistance with electron microscopy. We also thank Adam Weidenhammer and Yiying Tsai for their technical assistance. Publisher Copyright: {\textcopyright} 2017",
year = "2017",
month = may,
day = "2",
doi = "10.1016/j.cmet.2017.04.008",
language = "English (US)",
volume = "25",
pages = "1135--1146.e7",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "5",
}