Abstract

Antagonistic pleiotropy is a foundational theory that predicts aging-related diseases are the result of evolved genetic traits conferring advantages early in life. Here we examine CaMKII, a pluripotent signaling molecule that contributes to common aging-related diseases, and find that its activation by reactive oxygen species (ROS) was acquired more than half-a-billion years ago along the vertebrate stem lineage. Functional experiments using genetically engineered mice and flies reveal ancestral vertebrates were poised to benefit from the union of ROS and CaMKII, which conferred physiological advantage by allowing ROS to increase intracellular Ca2+ and activate transcriptional programs important for exercise and immunity. Enhanced sensitivity to the adverse effects of ROS in diseases and aging is thus a trade-off for positive traits that facilitated the early and continued evolutionary success of vertebrates.

Natural selection may favor traits underlying aging-related diseases if they benefit the young. Wang et al. find that oxidative activation of CaMKII provides physiological benefits critical to the initial and continued success of vertebrates but at the cost of disease, frailty, and shortened lifespan.

Details

Title
CaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution
Author
Wang Qinchuan 1   VIAFID ORCID Logo  ; Hernández-Ochoa, Erick O 2 ; Viswanathan, Meera C 1 ; Blum, Ian D 3   VIAFID ORCID Logo  ; Do, Danh C 1 ; Granger, Jonathan M 1 ; Murphy, Kevin R 1   VIAFID ORCID Logo  ; An-Chi, Wei 4 ; Aja, Susan 5 ; Liu Naili 6 ; Antonescu, Corina M 7 ; Florea, Liliana D 7   VIAFID ORCID Logo  ; Conover, Talbot C, Jr 8   VIAFID ORCID Logo  ; Mohr, David 9 ; Wagner, Kathryn R 10 ; Regot Sergi 11   VIAFID ORCID Logo  ; Lovering, Richard M 12 ; Gao Peisong 1   VIAFID ORCID Logo  ; Bianchet, Mario A 13   VIAFID ORCID Logo  ; Wu, Mark N 3 ; Cammarato Anthony 1 ; Schneider, Martin F 2 ; Bever, Gabriel S 14 ; Anderson, Mark E 1   VIAFID ORCID Logo 

1  Johns Hopkins School of Medicine, Department of Medicine, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
2  University of Maryland School of Medicine, Department of Biochemistry and Molecular Biology, Baltimore, USA (GRID:grid.411024.2) (ISNI:0000 0001 2175 4264) 
3  Johns Hopkins School of Medicine, Department of Neurology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
4  National Taiwan University, Department of Electrical Engineering, Graduate Institute of Biomedical Electronics and Bioinformatics, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241) 
5  Johns Hopkins School of Medicine, Department of Neuroscience, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins School of Medicine, Center for Metabolism and Obesity Research, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
6  Kennedy Krieger Institute, Center for Genetic Muscle Disorders, Baltimore, USA (GRID:grid.240023.7) (ISNI:0000 0004 0427 667X) 
7  Johns Hopkins Computational Biology Consulting Core, Baltimore, USA (GRID:grid.240023.7) 
8  Johns Hopkins School of Medicine, Institute for Basic Biomedical Sciences, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
9  Johns Hopkins School of Medicine Genetic Resources Core Facility, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
10  Johns Hopkins School of Medicine, Department of Neurology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Kennedy Krieger Institute, Center for Genetic Muscle Disorders, Baltimore, USA (GRID:grid.240023.7) (ISNI:0000 0004 0427 667X) 
11  Johns Hopkins School of Medicine, Department of Molecular Biology & Genetics, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
12  University of Maryland School of Medicine, Department of Orthopaedics, Baltimore, USA (GRID:grid.411024.2) (ISNI:0000 0001 2175 4264) 
13  Johns Hopkins School of Medicine, Department of Neurology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University, Department of Biophysics and Biophysical Chemistry, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
14  Johns Hopkins School of Medicine, Department of Medicine, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins School of Medicine, Center for Functional Anatomy & Evolution, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-23549-3
ProQuest document ID
2532432096
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.