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Hepatic Metabolic Reprogramming by Caloric Restriction in Rhesus Monkeys
Author(s) -
Rhoads Timothy W.,
Burhans Maggie S.,
McIlwain Sean J.,
Hutchins Paul D.,
Chen Vincent B.,
Eghbalnia Hamid R.,
Ong Irene M.,
Markley John L.,
Coon Joshua J.,
Anderson Rozalyn M.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.941.5
Subject(s) - longevity , ketone bodies , biology , citric acid cycle , downregulation and upregulation , medicine , caloric theory , metabolism , endocrinology , metabolomics , biochemistry , bioinformatics , gene , genetics
Caloric Restriction (CR) without malnutrition delays aging and the incidence of age‐related diseases. Adult‐onset CR enhances survival and reduces age‐related mortality in rhesus monkey ( Macaca mulatta ) compared to ad libitum fed controls, suggesting that the longevity benefits of CR can apply to primates, including humans; however, the mechanisms responsible for the longevity benefits of CR are to date unknown. We used five high‐throughput, high‐resolution techniques to generate hepatic molecular profiles for monkeys at baseline and 2 years after introduction of the CR diet. Approximately 20,000 biological molecules were detected and quantified across two time points, enabling us to determine the trajectory of response to CR. We find that CR upregulated many metabolic pathways, including fatty acid metabolism, the citric acid cycle, and branched chain amino acid degradation, and downregulated immune and inflammation pathways at the transcriptional and proteomic levels. Our data are suggestive of a novel role for the processing of mRNA in the mechanisms of CR. We report significant remodeling of the non‐histone acetylome, especially on proteins localized to the mitochondria. Hepatic lipid composition analysis showed increased levels of highly unsaturated trigylcerides and increased prevalence of odd‐chain phospholipids as a result of CR, while metabolomics analysis revealed increases in aspartate and 3‐hydroxybutyrate, the first ketone body to be synthesized under fasting conditions. These data reveal that CR activates a distinct hepatic metabolic program, suggesting that the metabolic adaptation to CR sets the stage for downstream longevity benefits. Support or Funding Information This work was supported by NIH grants R01AG040178, R56AG047358, and R01AG037000.