Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2018 Mar 8

PMID 29514073

Citations 42

Authors

Timothy W Rhoads

Maggie S Burhans

Vincent B Chen

Paul D Hutchins

Matthew J P Rush

Josef P Clark

Jaime L Stark

Sean J Mcilwain

Hamid R Eghbalnia

Derek M Pavelec

Irene M Ong

John M Denu

John L Markley

Joshua J Coon

Ricki J Colman

Rozalyn M Anderson

Affiliations

Soon will be listed here.

Abstract

Caloric restriction (CR) extends lifespan and delays the onset of age-related disorders in diverse species. Metabolic regulatory pathways have been implicated in the mechanisms of CR, but the molecular details have not been elucidated. Here, we show that CR engages RNA processing of genes associated with a highly integrated reprogramming of hepatic metabolism. We conducted molecular profiling of liver biopsies collected from adult male rhesus monkeys (Macaca mulatta) at baseline and after 2 years on control or CR (30% restricted) diet. Quantitation of over 20,000 molecules from the hepatic transcriptome, proteome, and metabolome indicated that metabolism and RNA processing are major features of the response to CR. Predictive models identified lipid, branched-chain amino acid, and short-chain carbon metabolic pathways, with alternate transcript use for over half of the genes in the CR network. We conclude that RNA-based mechanisms are central to the CR response and integral in metabolic reprogramming.

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References

Geer L, Markey S, Kowalak J, Wagner L, Xu M, Maynard D . Open mass spectrometry search algorithm. J Proteome Res. 2004; 3(5):958-64. DOI: 10.1021/pr0499491. View

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Armstrong V, Rakoczy S, Rojanathammanee L, Brown-Borg H . Expression of DNA methyltransferases is influenced by growth hormone in the long-living Ames dwarf mouse in vivo and in vitro. J Gerontol A Biol Sci Med Sci. 2013; 69(8):923-33. PMC: 4111294. DOI: 10.1093/gerona/glt133. View

Newman J, Verdin E . Ketone bodies as signaling metabolites. Trends Endocrinol Metab. 2013; 25(1):42-52. PMC: 4176946. DOI: 10.1016/j.tem.2013.09.002. View

Phanstiel D, Brumbaugh J, Wenger C, Tian S, Probasco M, Bailey D . Proteomic and phosphoproteomic comparison of human ES and iPS cells. Nat Methods. 2011; 8(10):821-7. PMC: 3432645. DOI: 10.1038/nmeth.1699. View

Wang J, Duncan D, Shi Z, Zhang B . WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucleic Acids Res. 2013; 41(Web Server issue):W77-83. PMC: 3692109. DOI: 10.1093/nar/gkt439. View

Fontana L, Partridge L . Promoting health and longevity through diet: from model organisms to humans. Cell. 2015; 161(1):106-118. PMC: 4547605. DOI: 10.1016/j.cell.2015.02.020. View

Calvo S, Clauser K, Mootha V . MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res. 2015; 44(D1):D1251-7. PMC: 4702768. DOI: 10.1093/nar/gkv1003. View

10.

Barger J, Anderson R, Newton M, da Silva C, Vann J, Pugh T . A conserved transcriptional signature of delayed aging and reduced disease vulnerability is partially mediated by SIRT3. PLoS One. 2015; 10(4):e0120738. PMC: 4382298. DOI: 10.1371/journal.pone.0120738. View

11.

Leng N, Dawson J, Thomson J, Ruotti V, Rissman A, Smits B . EBSeq: an empirical Bayes hierarchical model for inference in RNA-seq experiments. Bioinformatics. 2013; 29(8):1035-43. PMC: 3624807. DOI: 10.1093/bioinformatics/btt087. View

12.

Hagopian K, Ramsey J, Weindruch R . Influence of age and caloric restriction on liver glycolytic enzyme activities and metabolite concentrations in mice. Exp Gerontol. 2003; 38(3):253-66. DOI: 10.1016/s0531-5565(02)00203-6. View

13.

Li B, Dewey C . RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011; 12:323. PMC: 3163565. DOI: 10.1186/1471-2105-12-323. View

14.

Hebert A, Dittenhafer-Reed K, Yu W, Bailey D, Selen E, Boersma M . Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol Cell. 2012; 49(1):186-99. PMC: 3704155. DOI: 10.1016/j.molcel.2012.10.024. View

15.

Balasubramanian P, Mattison J, Anderson R . Nutrition, metabolism, and targeting aging in nonhuman primates. Ageing Res Rev. 2017; 39:29-35. PMC: 5563491. DOI: 10.1016/j.arr.2017.02.002. View

16.

Clos 2nd L, Jofre M, Ellinger J, Westler W, Markley J . NMRbot: Python scripts enable high-throughput data collection on current Bruker BioSpin NMR spectrometers. Metabolomics. 2013; 9(3):558-563. PMC: 3651530. DOI: 10.1007/s11306-012-0490-9. View

17.

Durinck S, Moreau Y, Kasprzyk A, Davis S, De Moor B, Brazma A . BioMart and Bioconductor: a powerful link between biological databases and microarray data analysis. Bioinformatics. 2005; 21(16):3439-40. DOI: 10.1093/bioinformatics/bti525. View

18.

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J . STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2014; 43(Database issue):D447-52. PMC: 4383874. DOI: 10.1093/nar/gku1003. View

19.

Hallows W, Yu W, Smith B, Devries M, Devires M, Ellinger J . Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol Cell. 2011; 41(2):139-49. PMC: 3101115. DOI: 10.1016/j.molcel.2011.01.002. View

20.

Dobin A, Davis C, Schlesinger F, Drenkow J, Zaleski C, Jha S . STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2012; 29(1):15-21. PMC: 3530905. DOI: 10.1093/bioinformatics/bts635. View