The effects of graded calorie restriction XVII: Multitissue metabolomics reveals synthesis of carnitine and NAD, and tRNA charging as key pathways

Libia Alejandra García-Flores, Cara L. Green, Sharon E. Mitchell, Daniel E.L. Promislow, David Lusseau, Alex Douglas, John R. Speakman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


The evolutionary context of why caloric restriction (CR) activates physiological mechanisms that slow the process of aging remains unclear. The main goal of this analysis was to identify, using metabolomics, the common pathways that are modulated across multiple tissues (brown adipose tissue, liver, plasma, and brain) to evaluate two alternative evolutionary models: the “disposable soma” and “clean cupboards” ideas. Across the four tissues, we identified more than 10,000 different metabolic features. CR altered the metabolome in a graded fashion. More restriction led to more changes. Most changes, however, were tissue specific, and in some cases, metabolites changed in opposite directions in different tissues. Only 38 common metabolic features responded to restriction in the same way across all four tissues. Fifty percent of the common altered metabolites were carboxylic acids and derivatives, as well as lipids and lipid-like molecules. The top five modulated canonical pathways were L-carnitine biosynthesis, NAD (nicotinamide adenine dinucleotide) biosynthesis from 2-amino-3-carboxymuconate semialdehyde, S-methyl-5′-thioadenosine degradation II, NAD biosynthesis II (from tryptophan), and transfer RNA (tRNA) charging. Although some pathways were modulated in common across tissues, none of these reflected somatic protection, and each tissue invoked its own idiosyncratic modulation of pathways to cope with the reduction in incoming energy. Consequently, this study provides greater support for the clean cupboards hypothesis than the disposable soma interpretation.

Original languageEnglish
Article numbere2101977118
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number31
Early online date30 Jul 2021
Publication statusPublished - 3 Aug 2021

Bibliographical note

ACKNOWLEDGMENTS. Our work on graded calorie restriction has been funded by the United Kingdom Biotechnology and Biological Sciences Research Council (BBSRC) (BB/G009953/1, BB/P009875/1, and BB/J020029/1) and the K. C. Wong Foundation. J.R.S. was supported by a President’s International Fellowship Initiative (PIFI) professorial fellowship from the Chinese Academy of Sciences (CAS), and a Royal Society Wolfson merit award. L.A.G.-F. was supported by a PIFI postdoctoral fellowship from CAS. C.L.G. was supported by a BBSRC EastBio doctoral training partnership award (1438803). D.E.L.P. was supported in part by NIH Grant AGO49494. D.L. was supported by Office of Naval Research Grant N000141512377. We thank Dean Jones, Quinlyn Soltow, and Karl Burgess for technical assistance with the original metabolomics analysis, and the Biological Services Unit staff for caring for the animals.


  • Aging
  • Calorie restriction
  • Evolution
  • Life span
  • Metabolomics


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