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.
Highlights
Human lifespan continues to increase at, on average, two years per decade (Kirkwood, 2008)
12- and 24-h ad libitum access to food (12AL and 24AL, respectively) were used, plus four levels of calorie restriction (CR); 10, 20, 30 and 40% restriction from baseline food intake. 12AL was used as the control group for all comparisons, food was given at 1830 h and removed 12 h later to alleviate the ‘time since last meal’ effect, as all mice had been food deprived for at least 7.5 h before culling
No direct relationship between leptin signalling and S1P or ceramide has yet been discovered, and we found the relationship between these metabolites and leptin may be completely explained by adiposity, low levels of ceramide have been associated previously with reduced mass and improved insulin signalling in the liver and muscle tissue in ob/ob and obese mice (Yang et al, 2009)
Summary
Human lifespan continues to increase at, on average, two years per decade (Kirkwood, 2008). This increase in lifespan has persisted over the last two centuries and has resulted in age becoming a major risk factor in the most prevalent clinical conditions, which include cancer, cardiovascular disease and dementia. To attenuate these age-associated clinical conditions, many approaches, in a variety of model organisms, have been investigated (reviewed in Fontana et al, 2010). The beneficial effects of CR are observed in many other species, ranging from nematode worms to nonhuman primates (Speakman & Mitchell, 2011; Colman et al, 2014)
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