Is uridine anti-longevity?

It is good for brain function and tissue repair but bad for longevity? is it worth it?

When we supplemented the culture medium with uridine, we found that uridine treatment was sufficient to reprogram the prematurely and physiologically aged stem cell models (WS/HGPS (Hutchinson-Gilford progeria syndrome)-hMSCs and hPMSCs) into a younger state with a higher regenerative ability (Fig. 3d–f and Supplementary Fig. S4a–f). Specifically, uridine-treated hMSCs achieved a much higher proliferation rate and an enhanced capacity to form cartilage and gained increased genome and epigenome stability (Fig. 3d–g and Supplementary Fig. S4a–f). In accordance, genome-wide RNA-seq analysis showed that upregulated genes were mainly associated with “cell cycle” and “DNA integrity checkpoint” GO terms or pathways (Fig. 3h). Consistent with a previous study reporting that uridine addition rescues pyrimidine biosynthesis deficiency45, we found that the “pyrimidine nucleoside metabolic process” was elevated by uridine supplementation (Fig. 3i). Uridine treatment also appears to have a beneficial role in mitochondrial activity, as we found augmented gene expression associated with “mitochondrial central dogma”, “mtDNA maintenance”, and “mitochondrial gene expression” in uridine-treated hMSCs (Fig. 3i). Taken together, these results showed that uridine supplementation drives broad transcriptional changes associated with improved hMSC activity.

Uridine treatment enhances regeneration and repair in various types of tissues

The extent of tissue repair after injury is limited by organismal intrinsic regenerative capacity46. Next, we asked whether uridine supplementation could promote regeneration or tissue repair in multiple tissues, including skeletal muscle, heart, liver, skin, and articular cartilage (Fig. 4a). Relative to vehicle-treated mice, we observed that uridine treatment promoted tissue repair in both muscular and cardiac injury models (Figs. 4b–j, 5a–f, and Supplementary Fig. S5a–d). For instance, uridine treatment facilitated muscle tissue regeneration, reduced fibrotic or erosion area, decreased proinflammatory cytokine levels, and endowed treated mice with higher grip strength and longer running distance (Fig. 4b–g). We next performed genome-wide RNA-seq analysis in injured muscles with or without uridine treatment (Fig. 4h–j). In line with the decreased levels of proinflammatory cytokines in mouse serum in the uridine-treated groups (Fig. 4e), bulk RNA sequencing showed uridine supplementation antagonized the expression of a panel of the inflammatory genes, the expression of which was elevated in injured muscles (Fig. 4j). In comparison, pathways related to muscle structure development, as well as metabolic pathways, especially in “small-molecule biosynthetic process” and “nucleotide metabolic process” were upregulated in uridine-treated mice (Fig. 4j). These data suggest that uridine supplementation, in turn, may promote regeneration and repair by remodeling metabolic adaptation. We next sought to dissect the cell type-specific effects associated with the regenerative response by constructing a single-nucleus transcriptomic atlas of uridine-treated muscle. We identified 14 muscle cell types, including satellite cells (Pax7+), the rare muscle stem cell population, fibro-adipogenic progenitors (FAPs, Pdgfra+), an interstitial mesenchymal cell population that supports muscle regeneration47, and fast-twitch muscle fibers (Mybpc2+ or Myh1+), that use anaerobic respiration to produce rapid movement bursts (Supplementary Fig. S5a, b). Similar to the bulk RNA-seq results, uridine supplementation restored the expression of genes associated with pyrimidine nucleotide biosynthesis and muscle structure development across cell types, especially in fast-twitch muscle fibers (Supplementary Fig. S5c).

Additionally, the uridine treatment improved the function of the heart underwent myocardial infraction, as evidenced by elevated left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) (Fig. 5a, b). Serum lactate dehydrogenase (LDH) and creatine kinase (CK), leakage of which are indicators of acute myocardial infarction, were also lower in uridine-treated mice than control mice (Fig. 5c). Compared to vehicle-treated mice, global gene expression was also reset to be close to the state before injury in uridine-treated mice, with increased expression of genes related to “heart contraction”, and “cardiac muscle tissue development”, and decreased expression of genes associated with “inflammatory response” (Fig. 5d–f). Altogether, uridine promotes the course of tissue regeneration probably by modulating the metabolic process and suppressing inflammation.

In addition to muscular and cardiac injury models, uridine treatment also facilitates the regeneration of the liver after carbon tetrachloride (CCl4) induced injury as evidenced by increased liver-to-body weight ratio and decreased liver fibrosis (Fig. 6a–c). Meanwhile, liver function was restored to a physiological level, such as the total bile acid production (Fig. 6d). In the hair regeneration model, we found that uridine supplementation initiated a new wave of hair growth, as revealed by actively cycling hair follicles with high expression of the proliferation marker Ki67 upon uridine supplementation (Fig. 6e–i). In another tissue injury model, uridine treatment facilitated the regeneration of injured cartilage as assessed by safranin O-fast green staining and further ameliorated functional deterioration, as shown by improved grip strength and athletic ability compared to those of the vehicle-treated group (Fig. 6j–m). Finally, we evaluated the effect of uridine supplementation in physiologically aged mice (22 months old) (Fig. 6n–p) and found improved locomotive activities in the mice with oral administration of uridine for 2 months, as indicated by their enhanced grip strength and exercise endurance (Fig. 6o, p). Overall, by combining systematic metabolomics analysis across multiple models with small-molecule screening for regenerative activity, we identified the endogenous small-molecule metabolite uridine as an effective compound that promotes the repair and regeneration of various tissues and organs, which has the potential to extend the healthspan of aged individuals (Supplementary Fig. S5e).

Uridine treatment of diabetic mice restored the mRNA level of Ppargc1a and enhanced Pink1 gene expression, which may indicate an increase in the intensity of mitochondrial biogenesis and mitophagy, and as a consequence, mitochondrial turnover. Uridine also reduced oxidative phosphorylation dysfunction and suppressed lipid peroxidation, but it had no significant effect on the impaired calcium retention capacity and potassium transport in the heart mitochondria of diabetic mice. Altogether, these findings suggest that, along with its hypoglycemic effect, uridine has a protective action against diabetes-mediated functional and structural damage to cardiac mitochondria and disruption of mitochondrial quality-control systems in the diabetic heart.

meanwhile it may fuel cancer growth and aging.

Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS–MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.

Uridine homeostatic disorder induced by uridine phosphorylase knockout leads to DNA damage and spontaneous tumorigenesis.

Addition of uridine into culture medium causes uracil DNA damage and p53-mediated DNA damage response (DDR).

Pharmacological use of uridine may be carcinogenic, and the far-reaching effects need to be considered.

Uridine is a natural nucleoside precursor of uridine monophosphate in organisms and thus is considered to be safe and is used in a wide range of clinical settings. The far-reaching effects of pharmacological uridine have long been neglected. Here, we report that the homeostatic disorder of uridine is carcinogenic. Targeted disruption (−/−) of murine uridine phosphorylase (UPase) disrupted the homeostasis of uridine and increased spontaneous tumorigenesis by more than 3-fold. Multiple tumors (e.g., lymphoma, hepatoma and lung adenoma) occurred simultaneously in some UPase deficient mice, but not in wild-type mice raised under the same conditions. In the tissue from UPase −/− mice, the 2′-deoxyuridine,5′-triphosphate (dUTP) levels and uracil DNA were increased and p53 was activated with an increased phospho-Ser18 p53 level. Exposing cell lines (e.g., MCF-7, RKO, HCT-8 and NCI-H460) to uridine (10 or 30 µM) led to uracil DNA damage and p53 activation, which in turn triggered the DNA damage response. In these cells, phospho-ATM, phospho-CHK2, and phospho-γH2AX were increased by uridine. These data suggest that uridine homeostatic disorder leads to uracil DNA damage and that pharmacological uridine may be carcinogenic.

studies report conflicting data on mTOR activation.