Regenerative capacity declines throughout evolution and with age. In this study, we asked whether metabolic programs underlying regenerative capability might be conserved across species, and if so, whether such metabolic drivers might be harnessed to promote tissue repair. To this end, we conducted metabolomic analyses in two vertebrate organ regeneration models: the axolotl limb blastema and antler stem cells. To further reveal why young individuals have higher regenerative capacity than the elderly, we also constructed metabolic profiles for primate juvenile and aged tissues, as well as young and aged human stem cells. In joint analyses, we uncovered that active pyrimidine metabolism and fatty acid metabolism correlated with higher regenerative capacity. Furthermore, we identified a set of regeneration-related metabolite effectors conserved across species. One such metabolite is uridine, a pyrimidine nucleoside, which can rejuvenate aged human stem cells and promote regeneration of various tissues in vivo. These observations will open new avenues for metabolic intervention in tissue repair and regeneration.

Microbial conversion of renewable carbon sources to free fatty acids has attracted significant attention in recent years. Accumulation of free fatty acids in Escherichia coli by overexpression of an acyl-ACP thioesterase which can break the fatty acid elongation has been well established. Various efforts have been made to increase fatty acid production in E. coli by enhancing the enzymes involved in the fatty acid synthesis cycle or host strain manipulations. The current study focused on the effect of NADPH availability on free fatty acids (FFAs) productivity. There are two reduction steps in the fatty acid elongation cycle which are catalyzed by beta keto-ACP reductase (FabG) and enoyl-ACP reductase (FabI), respectively. It is reported that FabI can use either NADH or NADPH as cofactor, while FabG only uses NADPH in E. coli. Fatty acid production dropped dramatically in the glucose-6-phosphate dehydrogenase (encoded by the zwf gene) deficient strain. Similarly, the pntB (which encodes one of the subunit of proton-translocating membrane bounded transhydrogenase PntAB) and udhA (which encodes the energy dependent cytoplasmic transhydrogenase UdhA) double mutant strain also showed an 88.8% decrease in free fatty acid production. Overexpression of PntAB and NadK restored the fatty acid production capability of these two mutant strains. These results indicated that the availability of NADPH played a very important role in fatty acid production.

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Evidence indicates that both S-adenosylmethionine (SAMe) metabolism and intramuscular fat are associated with insulin resistance and type II diabetes. However, it is still unknown whether SAMe have effects on intramuscular adipogenesis. The present study investigated the roles of SAMe in the adipogenic differentiation of porcine muscle satellite cells. Cells isolated from neonatal pig muscle were treated with different concentrations of SAMe (0, 0.5 and 1.0 mM) for 24 h, induced for a 9-day adipogenic differentiation and were finally stained by oil red O staining. The adipocyte determination and differentiation factor-1 (ADD1) and peroxisome proliferator-activated receptor gamma (PPARγ) mRNA and protein were stimulated by SAMe treatment in a dose-dependent manner. Lipoprotein lipase (LPL) mRNA and protein were enhanced in 1.0 mM treatment group, compared with the control. No significant difference was observed in the intracellular lipid content among treatments. These results provide evidence that SAMe may be associated with intramuscular adipogenesis and indicate a novel action of SAMe in fat metabolism.

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