Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys

• Published in: Cell metabolism Vol. 27; no. 3; pp. 677 - 688.e5
• Main Authors: Rhoads, Timothy W., Burhans, Maggie S., Chen, Vincent B., Hutchins, Paul D., Rush, Matthew J.P., Clark, Josef P., Stark, Jaime L., McIlwain, Sean J., Eghbalnia, Hamid R., Pavelec, Derek M., Ong, Irene M., Denu, John M., Markley, John L., Coon, Joshua J., Colman, Ricki J., Anderson, Rozalyn M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.03.2018
• Subjects: aging; caloric restriction; lipid metabolism; metabolism; rhesus macaque; RNA processing; rhesus macaque; metabolism; caloric restriction; aging; RNA processing; lipid metabolism
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2018.01.014

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. [Display omitted] •Caloric restriction reprograms hepatic metabolism in monkeys independently of aging•The response to CR involves recruitment of RNA processing mechanisms•Integrative analysis reveals a multi-pathway core CR metabolic network•The core CR metabolic network is regulated at the level of RNA processing Rhoads et al. use multi-platform high-resolution molecular profiling to demonstrate that caloric restriction (CR) reprograms hepatic metabolism in rhesus monkeys. They identify a role for RNA processing in the mechanisms of CR and show that the CR metabolic network is subject to substantial regulation at the RNA level.