Longitudinal RNA-Seq Analysis of Vertebrate Aging Identifies Mitochondrial Complex I as a Small-Molecule-Sensitive Modifier of Lifespan.


Type
Article
Change log
Authors
Baumgart, Mario 
Priebe, Steffen 
Groth, Marco 
Hartmann, Nils 
Menzel, Uwe 
Abstract

Mutations and genetic variability affect gene expression and lifespan, but the impact of variations in gene expression within individuals on their aging-related mortality is poorly understood. We performed a longitudinal study in the short-lived killifish, Nothobranchius furzeri, and correlated quantitative variations in gene expression during early adult life with lifespan. Shorter- and longer-lived individuals differ in their gene expression before the onset of aging-related mortality; differences in gene expression are more pronounced early in life. We identified mitochondrial respiratory chain complex I as a hub in a module of genes whose expression is negatively correlated with lifespan. Accordingly, partial pharmacological inhibition of complex I by the small molecule rotenone reversed aging-related regulation of gene expression and extended lifespan in N. furzeri by 15%. These results support the use of N. furzeri as a vertebrate model for identifying the protein targets, pharmacological modulators, and individual-to-individual variability associated with aging.

Description
Keywords
GAGE, Nothobranchius furzeri, RNA transport, RNA-seq, aging, history trait, hormesis, hourglass, life ribosome, lifespan regulation, longevity, longitudinal study, mitohormesis, rejuvenation, weighted gene coexpression network analysis (WGCNA), zebrafish, Animals, Cyprinodontiformes, Longitudinal Studies, RNA, Sequence Analysis, RNA, Vertebrates
Journal Title
Cell Syst
Conference Name
Journal ISSN
2405-4712
2405-4720
Volume Title
2
Publisher
Elsevier BV
Sponsorship
We thank Sabine Matz, Christin Hahn, Ivonne Heinze, and Ivonne Goerlich for technical assistance and Giorgio Bianchini for drawing. This work was partially supported by the German Ministry for Education and Research (JenAge; BMBF, support codes: 0315581A and 0315581C) and by intramural grant of Scuola Normale Superiore.