The effects of graded levels of calorie restriction: IX. Global metabolomic screen reveals modulation of carnitines, sphingolipids and bile acids in the liver of C57BL/6 mice

Abstract

SummaryCalorie restriction (CR) remains the most robust intervention to extend lifespan and improve health span. Using a global mass spectrometry‐based metabolomic approach, we identified 193 metabolites that were significantly differentially expressed (SDE) in the livers of C57BL/6 mice, fed graded levels of CR (10, 20, 30 and 40% CR) compared to mice fed ad libitum for 12 h a day. The differential expression of metabolites also varied with the different feeding groups. Pathway analysis revealed that graded CR had an impact on carnitine synthesis and the carnitine shuttle pathway, sphingosine‐1‐phosphate (S1P) signalling and methionine metabolism. S1P, sphingomyelin and L‐carnitine were negatively correlated with body mass, leptin, insulin‐like growth factor‐ 1 (IGF‐1) and major urinary proteins (MUPs). In addition, metabolites which showed a graded effect, such as ceramide, S1P, taurocholic acid and L‐carnitine, responded in the opposite direction to previously observed age‐related changes. We suggest that the modulation of this set of metabolites may improve liver processes involved in energy release from fatty acids. S1P also negatively correlated with catalase activity and body temperature, and positively correlated with food anticipatory activity. Injecting mice with S1P or an S1P receptor 1 agonist did not precipitate changes in body temperature, physical activity or food intake suggesting that these correlations were not causal relationships.

Male lifespan extension with 17‐α estradiol is linked to a sex‐specific metabolomic response modulated by gonadal hormones in mice

“…Elevations of hepatic amino acid levels are also observed with other lifespan extending manipulations in rodents, including calorie restriction (CR) and treatment with acarbose (Gibbs, Brewer, Miyasaki, Patki & Smith, 2017; Green et al., 2017). Acarbose extends lifespan to a much greater degree in male than in female mice (Harrison et al., 2014), while CR works equally in both sexes (Simons, Koch & Verhulst, 2013).…”

“…Indeed, while long lifespan has been associated with elevations in selected amino acids in previous studies, the published work has sometimes documented a lack of concordance in BCAA responses. With CR, for example, elevations in leucine are observed in liver without changes in valine or isoleucine (Green et al., 2017), and cells from long‐lived species have higher levels of valine and leucine but not isoleucine (Ma et al., 2016). …”

“…In this study, we used untargeted metabolomic analysis of liver tissue to identify metabolite responses that occur in mice treated with 17aE2 at the concentration previously shown to extend male but not female lifespan. The liver is a key tissue involved in regulation of glucose, carbohydrate, and protein metabolism, with previous research showing that the metabolite profile of the liver changes in response to lifespan extending manipulations in line with expected alterations in energy utilization (e.g., calorie restriction (Green et al., 2017)). We focused our investigation on liver metabolites that show a sex‐specific response to 17aE2 and may underlie the male‐specific lifespan response.…”

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

“…Furthermore, based on a global mass spectrometry-based metabolomics study, graded CR (10, 20, 30, 40% CR) modulated metabolic signaling pathways, including the carnitine synthesis and shuttle pathway and sphingosine-1-phosphate and methionine metabolism, in a graded manner. The expression of various metabolites was modulated by CR, indicating that CR could ameliorate the energy release process of hepatic fatty acids [79]. In addition, augmented gene-gene network connectivity analysis has shown that CR changed the network arrangement and biological gene centrality in a CR level-dependent manner.…”

Lipid metabolism and transport define longevity of the yeast Saccharomyces cerevisiae

“…The essential mechanistic role of lipid metabolism and transport in defining longevity of this unicellular eukaryote further supports the notion that some aspects of the maintenance of lipid homeostasis are essential for healthy aging in evolutionarily distant organisms. These eukaryotic organisms include not only laboratory strains of budding yeast, roundworms (15,, fruit flies (214)(215)(216)(217)(218)(219)(220)(221)(222)(223) and mammals (208,(224)(225)(226)(227)(228)(229)(230)(231)(232)(233)(234)(235)(236)(237)(238)(239)(240)(241), but also humans (208,(232)(233)(234)(235)(241)(242)(243)(244)(245)(246). The major challenge now is to get a greater insight into the mechanisms through which lipid metabolism and transport define lifespan and healthspan in multicellular model organisms and humans.…”