title: A Systems Approach to Reverse Engineer Lifespan Extension by Dietary Restriction.
abstract: Dietary restriction (DR) is the most powerful natural means to extend lifespan. Although several genes can mediate responses to alternate DR regimens, no single genetic intervention has recapitulated the full effects of DR, and no unified system is known for different DR regimens. Here we obtain temporally resolved transcriptomes during calorie restriction and intermittent fasting in Caenorhabditis elegans and find that early and late responses involve metabolism and cell cycle/DNA damage, respectively. We uncover three network modules of DR regulators by their target specificity. By genetic manipulations of nodes representing discrete modules, we induce transcriptomes that progressively resemble DR as multiple nodes are perturbed. Targeting all three nodes simultaneously results in extremely long-lived animals that are refractory to DR. These results and dynamic simulations demonstrate that extensive feedback controls among regulators may be leveraged to drive the regulatory circuitry to a younger steady state, recapitulating the full effect of DR.
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Hou
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China; Graduate University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China; Beijing Key Lab of Traffic Data Analysis and Mining, School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China; Graduate University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China; Graduate University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Chi
authors.initials: C
authors.lastname: Xu
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
authors.forename: Na
authors.initials: N
authors.lastname: Sun
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
authors.forename: Joseph
authors.initials: J
authors.lastname: McDermott
authors.affiliation: Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Mair
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China. Electronic address: jdhan@picb.ac.cn.
authors.forename: Jing-Dong J
authors.initials: JD
authors.lastname: Han
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D031204:Caloric Restriction; D053263:Gene Regulatory Networks; D017238:Genes, Helminth; D005818:Genetic Engineering; D008136:Longevity / Q000235:genetics*; D059386:Reverse Genetics; D049490:Systems Biology; D059467:Transcriptome
chemical_list: D029742:Caenorhabditis elegans Proteins