Diverse Metabolic Reactions Activated During 58-hr Fasting are Revealed by Non-Targeted Metabolomic Analysis of Human Blood

Abstract

During human fasting, metabolic markers, including butyrates, carnitines, and branched-chain amino acids, are upregulated for energy substitution through gluconeogenesis and use of stored lipids. We performed non-targeted, accurate semiquantitative metabolomic analysis of human whole blood, plasma, and red blood cells during 34-58 hr fasting of four volunteers. During this period, 44 of ~130 metabolites increased 1.5~60-fold. Consistently fourteen were previously reported. However, we identified another 30 elevated metabolites, implicating hitherto unrecognized metabolic mechanisms induced by fasting. Metabolites in pentose phosphate pathway are abundant, probably due to demand for antioxidants, NADPH, gluconeogenesis and anabolic metabolism. Global increases of TCA cyclerelated compounds reflect enhanced mitochondrial activity in tissues during fasting. Enhanced purine/ pyrimidine metabolites support RNA/protein synthesis and transcriptional reprogramming, which is promoted also by some fasting-related metabolites, possibly via epigenetic modulations. Thus diverse, pronounced metabolite increases result from greatly activated catabolism and anabolism stimulated by fasting. Anti-oxidation may be a principal response to fasting.

Modulating pyrimidine ribonucleotide levels for the treatment of cancer

“…A recent study on mice, rats, and humans reported that fasting increases plasma uridine through a mechanism that involves uridine biosynthesis by adipocytes, whereas, in the postprandial state, liverinduced bile excretion results in plasma uridine clearance [54]. In support of this study, longer starvation times in human volunteers led to even more prominent increases in uridine plasma levels that were accompanied by a smaller rise in plasma cytidine and CTP [55]. Further confirmation came from a study where uridine as well as uracil and dihydrouracil levels in human plasma were observed to drop after food intake [56] and were also seen to be affected by circadian rhythms [56,57].…”

The biology of ergothioneine, an antioxidant nutraceutical

“…While most ERG is inside erythrocytes in whole blood (6,121,122,129,387) , there have been a number of measurements of ERG concentrations in serum. Unsurprisingly it varies with diet (388,389) , starvation (390) , age (391,392) and other factors, including diseases of oxidative stress (393) , with typical values of 20-100 μg/ml. A detailed list is provided by Cheah & Halliwell (4) ; a smaller listing is given in Table 3.…”

Aging markers in human urine: A comprehensive, non‐targeted LC‐MS study

“…Standards for metabolite identification were purchased from commercial sources as described previously 12,26‐28 …”

“…Peak detection and identification of metabolites were performed using MZmine 2 software 29 . Detailed data analytical procedures and parameters have been described previously 26 . Normalized peak area was calculated from the following formula: Normalized peak area = (Raw peak area of each metabolite/Raw peak area of creatinine) × 1000.…”

“…We analyzed 99 urine metabolites that were confirmed using standards or MS/MS analysis 12,26‐28 . Metabolite abundances were classified into 3 groups (H, M, and L), according to their peak areas.…”