Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys

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

doi:10.1016/j.cmet.2018.01.014

Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys

Cell Metab. 2018 Mar 6;27(3):677-688.e5. doi: 10.1016/j.cmet.2018.01.014.

Authors

Timothy W Rhoads¹, Maggie S Burhans¹, Vincent B Chen², Paul D Hutchins³, Matthew J P Rush³, Josef P Clark¹, Jaime L Stark², Sean J McIlwain⁴, Hamid R Eghbalnia², Derek M Pavelec⁵, Irene M Ong⁴, John M Denu⁶, John L Markley², Joshua J Coon⁷, Ricki J Colman⁸, Rozalyn M Anderson⁹

Affiliations

¹ Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
² National Magnetic Resonance Facility at Madison and Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
³ Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁴ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53792, USA.
⁵ University of Wisconsin Biotechnology Center, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁶ Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53715, USA.
⁷ Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53715, USA.
⁸ Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53715, USA.
⁹ Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; Geriatric Research, Education, and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA. Electronic address: [email protected].

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.

Keywords: RNA processing; aging; caloric restriction; lipid metabolism; metabolism; rhesus macaque.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging / metabolism
Animals
Caloric Restriction*
Gene Expression
Liver / metabolism*
Macaca mulatta
Male
RNA / metabolism*
RNA Processing, Post-Transcriptional*

Substances

RNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding