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Cell Syst. 2016 Feb 24;2(2):122-32. doi: 10.1016/j.cels.2016.01.014. Epub 2016 Feb 24.

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

Author information

1
Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Beutenbergstraße 11, 07745 Jena, Germany.
2
Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Beutenbergstraße 11a, 07745 Jena, Germany.
3
Scuola Normale Superiore, Laboratory of Biology, c/o Istituto di Biofisica del CNR, via Moruzzi 1, 56124 Pisa, Italy.
4
Energy Metabolism Laboratory, ETH Zürich (Swiss Federal Institute of Technology), Schorenstrasse 16, 8603 Schwerzenbach-Zürich, Switzerland.
5
Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Beutenbergstraße 11, 07745 Jena, Germany; Faculty of Biology and Pharmacy, Friedrich Schiller University Jena, 07743 Jena, Germany.
6
Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Beutenbergstraße 11, 07745 Jena, Germany; Scuola Normale Superiore, Laboratory of Biology, c/o Istituto di Biofisica del CNR, via Moruzzi 1, 56124 Pisa, Italy. Electronic address: alessandro.cellerino@sns.it.

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.

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

PMID:
27135165
DOI:
10.1016/j.cels.2016.01.014
[Indexed for MEDLINE]
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