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. 2021 Aug 3;118(31):e2101977118.
doi: 10.1073/pnas.2101977118.

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  1 , Cara L Green  2 , Sharon E Mitchell  2 , Daniel E L Promislow  3   4 , David Lusseau  2 , Alex Douglas  2 , John R Speakman  5   2   6   7
Affiliations

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 et al. Proc Natl Acad Sci U S A. .

Abstract

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.

Keywords: aging; calorie restriction; evolution; life span; metabolomics.

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Conflict of interest statement

The authors declare no competing interest.

Figures

Fig. 1.
Fig. 1.
Numbers of significantly differentially expressed (SDE) metabolites in response to graded CR in the liver, BAT, brain, and plasma relative to the number of metabolites in mice exposed to the 12AL treatment. The top plot shows the number of increased and the other plot the number of decreased metabolites.
Fig. 2.
Fig. 2.
Orthogonal partial least-square discriminate analysis (OPLS-DA) demonstrates the differentiation effect of each diet group (12-h ad libitum fed: 12AL; 24-h ad libitum fed: 24AL; 10–40% calorie-restricted: 10CR, 20CR, 30CR, 40CR) on the filtered and normalized metabolites extracted from each tissue. The OPLS-DA plot showed significant separation among samples in the first two principal components (comp.1 and comp.2) based on the model quality parameters that are under each plot.
Fig. 3.
Fig. 3.
(A) Venn diagram of all detected metabolites in the four different matrices using only two decimals. (B) Categories of metabolites in the second, third, and fourth patterns. Fourteen classes according to the information in the HMDB, KEGG, and PubChem were found.
Fig. 4.
Fig. 4.
Pie graphs show the metabolite categories and their respective percent and number of metabolites by tissue group and pattern.
Fig. 5.
Fig. 5.
NAD biosynthesis from 2-amino-3-carboxymuconate semialdehyde pathway together with some metabolites from the other four canonical pathways. The second pattern metabolites (except niacinamide of the fourth pattern) were colored based on the correlation coefficient. Brighter red means more up-regulation, and blue, more colorful, more down-regulation. Metabolites shown in triangle symbols were detected in individual tissue, except NADPH, caught in BAT and CER. One-way ANOVA P values are shown next to the symbol (P value with an asterisk indicates the BAT result), and red arrows means a positive increase in the CR groups compared to AL. White metabolites indicate those not identified. Abbreviations: AMP, adenosine monophosphate; ATP, adenosine triphosphate; CP, canonical pathways; CO2, carbon dioxide; H+, hydron; NAD, nicotinamide adenine dinucleotide; NAD+, nicotinamide adenine dinucleotide, oxidized form; NADH, nicotinamide adenine dinucleotide, its reduced form; NADP, nicotinamide adenine dinucleotide phosphate; and NADPH, reduced nicotinamide adenine dinucleotide phosphate.
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