Metabolic Phenotype Modulation by Caloric Restriction in a Lifelong

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Metabolic Phenotype Modulation by Caloric Restriction in a Lifelong Dog Study Selena E. Richards,*,†,∥ Yulan Wang,†,⊥ Sandrine P. Claus,†,▽ Dennis Lawler,‡ Sunil Kochhar,§ Elaine Holmes,† and Jeremy K. Nicholson*,† †

Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, South Kensington, London, SW7 2AZ, U.K. ‡ The Nestle Research CentreSt. Louis, St. Louis, Missouri 63164, United States § Nestle Research Centre, Lausanne, NESTEC Limited, Vers-Chez-Les-Blanc, 1000 Lausanne 26, Switzerland S Supporting Information *

ABSTRACT: Modeling aging and age-related pathologies presents a substantial analytical challenge given the complexity of gene−environment influences and interactions operating on an individual. A top-down systems approach is used to model the effects of lifelong caloric restriction, which is known to extend life span in several animal models. The metabolic phenotypes of caloric-restricted (CR; n = 24) and pair-housed control-fed (CF; n = 24) Labrador Retriever dogs were investigated by use of orthogonal projection to latent structures discriminant analysis (OPLS-DA) to model both generic and age-specific responses to caloric restriction from the 1H NMR blood serum profiles of young and older dogs. Three aging metabolic phenotypes were resolved: (i) an aging metabolic phenotype independent of diet, characterized by high levels of glutamine, creatinine, methylamine, dimethylamine, trimethylamine N-oxide, and glycerophosphocholine and decreasing levels of glycine, aspartate, creatine and citrate indicative of metabolic changes associated largely with muscle mass; (ii) an aging metabolic phenotype specific to CR dogs that consisted of relatively lower levels of glucose, acetate, choline, and tyrosine and relatively higher serum levels of phosphocholine with increased age in the CR population; (iii) an aging metabolic phenotype specific to CF dogs including lower levels of liproprotein fatty acyl groups and allantoin and relatively higher levels of formate with increased age in the CF population. There was no diet metabotype that consistently differentiated the CF and CR dogs irrespective of age. Glucose consistently discriminated between feeding regimes in dogs (≥312 weeks), being relatively lower in the CR group. However, it was observed that creatine and amino acids (valine, leucine, isoleucine, lysine, and phenylalanine) were lower in the CR dogs (468 weeks. Choline metabolism is implicated in the aging serum and urine metabolic profile and points to involvement of both mammalian and microbial metabolism. H

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Analysis of the longitudinal 1H NMR serum profiles has enabled unbiased evaluation of the metabolic markers modulated by lifetime CR. Since many studies conclude that the mechanisms of aging are likely to be multifaceted, caloric restriction is likely to contribute only partially to understanding of etiopathogenic mechanisms of chronic disease. Nevertheless, modeling of these data has provided a framework such that significant metabolites relating to life extension could be differentiated and/or integrated with aging processes. Although these results have specific implications with respect to caloric restriction and the impact of diet on late-life diseases, the approach is generic and can, in principle, be applied to any system in which multiple factors contribute uniquely or in combination to the metabolic phenotype.

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ASSOCIATED CONTENT

S Supporting Information *

One table listing the strength of independent contributions of significant metabolites (468 vs 13 weeks for CR and CF dogs) and diet models at 13, 28−312, 312, 416, and 468 weeks. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail [email protected] (S.E.R.), hod.surgery. [email protected] (J.K.N.); tel +44(0)20 7594 3195; fax +44 (0)20 7594 3226. Present Addresses ∥

S.E.R.: School of Science and Technology, Nottingham Trent University, Erasmus Darwin Building, Clifton Campus, Nottingham NG11 8NS, U.K. ⊥ Y.W.: State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, The Chinese Academy of Sciences, Wuhan, 430071, PR China. ▽ S.P.C.: Department of Food and Nutritional Sciences, The University of Reading, Reading, U.K. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the Nestle Research Centre, St. Louis, MO (NRC-STL). S.E.R. and Y.W. thank Nestlé Research Centre, Switzerland, for funding. We acknowledge Richard Barton, Andrew Clayton, and Marc Dumas for spectral assignments and helpful comments.

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