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Research Paper|Volume 9, Issue 7|pp 1770—1824

The effects of graded levels of calorie restriction: XI. Evaluation of the main hypotheses underpinning the life extension effects of CR using the hepatic transcriptome

Davina Derous1,2, Sharon E. Mitchell1, Lu Wang3, Cara L. Green1, Yingchun Wang3, Luonan Chen4, Jing-Dong J. Han5, Daniel E.L. Promislow6,7, David Lusseau1, Alex Douglas1,2, John R. Speakman1,3
  • 1Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, Scotland, UK
  • 2Centre for Genome Enabled Biology and Medicine, University of Aberdeen, Aberdeen, Scotland, UK
  • 3State Key laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Chaoyang, Beijing, China
  • 4Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
  • 5Key laboratory of Systems Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
  • 6Department of Pathology, University of Washington, Seattle, WA 98195, USA
  • 7Department of Biology, University of Washington, Seattle, WA 98195, USA
Received: April 27, 2017Accepted: July 27, 2017Published: July 31, 2017
https://doi.org/10.18632/aging.101269

Copyright: © 2017 Derous et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Calorie restriction (CR) may extend longevity by modulating the mechanisms involved in aging. Different hypotheses have been proposed for its main mode of action. We quantified hepatic transcripts of male C57BL/6 mice exposed to graded levels of CR (0% to 40% CR) for three months, and evaluated the responses relative to these various hypotheses. Of the four main signaling pathways implied to be linked to the impact of CR on lifespan (insulin/insulin like growth factor 1 (IGF-1), nuclear factor-kappa beta (NF-ĸB), mechanistic target of rapamycin (mTOR) and sirtuins (SIRTs)), all the pathways except SIRT were altered in a manner consistent with increased lifespan. However, the expression levels of SIRT4 and SIRT7 were decreased with increasing levels of CR. Changes consistent with altered fuel utilization under CR may reduce reactive oxygen species production, which was paralleled by reduced protection. Downregulated major urinary protein (MUP) transcription suggested reduced reproductive investment. Graded CR had a positive effect on autophagy and xenobiotic metabolism, and was protective with respect to cancer signaling. CR had no significant effect on fibroblast growth factor-21 (FGF21) transcription but affected transcription in the hydrogen sulfide production pathway. Responses to CR were consistent with several different hypotheses, and the benefits of CR on lifespan likely reflect the combined impact on multiple aging related processes.