Abstract

Hallmarks of aging that have critical impact on health include weight gain and reduced physical fitness, usually starting at middle age. These changes lead to insulin resistance and development of many diseases including type-2 diabetes. The molecular events that drive the metabolic and fitness decline in older age are poorly understood. We discovered that DNA-dependent protein kinase (DNA-PK) is a mediator of the aging-associated decline in metabolism and fitness. Aging increases DNA-PK activity, decreasing the ability of HSP90 to chaperone clients such as AMP-activated protein kinase (AMPK). Inhibiting DNA-PK either genetically or with a small molecule inhibitor prevents the weight gain, decline of mitochondrial function and physical fitness in middle age mice and protects against type-2 diabetes in obese mice. We conclude that DNA-PK activates a metabolic brake at older age, which makes staying lean and physically fit difficult at older age and increases susceptibility to metabolic diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAHL006118-06
Application #
9353139
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost

  Institution

Name
U.S. National Heart Lung and Blood Inst
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Kang, Hyeog; Oka, Shinichi; Lee, Duck-Yeon et al. (2017) Sirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins. Nat Commun 8:15560
Park, Sung-Jun; Ahmad, Faiyaz; Um, Jee-Hyun et al. (2017) Specific Sirt1 Activator-mediated Improvement in Glucose Homeostasis Requires Sirt1-Independent Activation of AMPK. EBioMedicine 18:128-138
Mishra, Amarjit; Brown, Alexandra L; Yao, Xianglan et al. (2015) Dendritic cells induce Th2-mediated airway inflammatory responses to house dust mite via DNA-dependent protein kinase. Nat Commun 6:6224
Park, Jun Hong; Kang, Hong-Jun; Lee, Yun Kyung et al. (2015) Inactivation of EWS reduces PGC-1? protein stability and mitochondrial homeostasis. Proc Natl Acad Sci U S A 112:6074-9
Bitterman, Jacob L; Chung, Jay H (2015) Metabolic effects of resveratrol: addressing the controversies. Cell Mol Life Sci 72:1473-88
Maurice, Donald H; Ke, Hengming; Ahmad, Faiyaz et al. (2014) Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov 13:290-314
Um, Jee-Hyun; Brown, Alexandra L; Singh, Samarendra K et al. (2013) Metabolic sensor AMPK directly phosphorylates RAG1 protein and regulates V(D)J recombination. Proc Natl Acad Sci U S A 110:9873-8
Pullikotil, Philomena; Chen, Hui; Muniyappa, Ranganath et al. (2012) Epigallocatechin gallate induces expression of heme oxygenase-1 in endothelial cells via p38 MAPK and Nrf-2 that suppresses proinflammatory actions of TNF-?. J Nutr Biochem 23:1134-45
Chung, Jay H; Manganiello, Vincent; Dyck, Jason R B (2012) Resveratrol as a calorie restriction mimetic: therapeutic implications. Trends Cell Biol 22:546-54
Chung, Jay H (2012) Metabolic benefits of inhibiting cAMP-PDEs with resveratrol. Adipocyte 1:256-258

Showing the most recent 10 out of 15 publications