In recent years, the science of aging has developed rapidly, and many substances with potential anti-aging effects are being gradually excavated and further studied, such as uridine. In early February, uridine was first found to reverse human stem cell aging and promote the repair of a variety of tissues, and since then it has been a concern for the academic community, and on the 5th of this month, a new study once again demonstrated the anti-aging effect of uridine.
Through in vitro cell experiments, the researchers found that uridine significantly downregulated the proportion of senescent cells in intestinal cells, as well as levels of inflammation and oxidative stress, and enhanced intestinal barrier function, and that when elderly mice were fed uridine, their intestinal levels of biomarkers associated with aging (such as intestinal SA-β-gal staining) decreased significantly, and the intestinal fibrosis status with aging was significantly improved [1].
Uridine research frequently spread the news, when it really earned enough attention from readers and all members of the time school, after a comprehensive investigation, we decided to write a period of uridine substance science, let's see, is it really the next star substance on our life extension road?
A thousand turns,
What exactly is uridine sacred?
Uridine, full name uracil nucleoside, is a small molecule metabolite composed of uracil and ribose, commonly found in foods such as vegetable broccoli, tomatoes, mushrooms, animal livers, dairy products, etc., and its derivatives (a variety of pyrimidine nucleotides) can be used to synthesize genetic material such as RNA and DNA, and participate in the synthesis of glycogen and biofilm phospholipids [2]. It looks like this:
Figure note: Structure of uridine
As an endogenous substance in the living body, our body is always synthesizing and decomposing uridine, coming and going, building an internal balance.
No.1
Synthesis of uridine
In cells, uridine is synthesized primarily through de novo synthesis pathways and remedial pathways [3, 4], in the following steps:
(1) De novo synthesis pathway: Glutamine as raw material, catalyzed by the rate-limiting enzyme CAD protein (composed of CPS II, ATCase, DHO enzyme), the formation of whey acid (i.e., vitamin B13) through intermediate metabolites, and finally the formation of uracil nucleotide (UMP, also known as uridine monophosphate), UMP is dephosphorylated to generate uridine.
The speed-limiting step of this pathway is the conversion of glutamine to vitamin B13 precursor (dihydroorotate), which consumes a large amount of ATP[5], and the CAD enzyme (DHO fraction) that catalyzes this speed-limiting process is a mitochondrial respiratory chain coupling enzyme that links pyrimidine biosynthesis and mitochondrial energy metabolism [3].
(2) Remediation synthesis pathway: Compared with the "long" of the de novo synthesis pathway, the chain of synthetic uridine in the remedial pathway appears to be much shorter - both through exogenous vitamin B13 supplementation, and the de novo synthesis pathway "special way to the same destination" (generation of UMP, and then phosphorylation to generate uridine), but also with the help of nucleic acids or nucleotide hydrolysis products derived from the body itself or food decomposition, directly generated. Moreover, it is still a "power saving mode" with low energy consumption.
Figure note: Uridine synthesis pathway. Sources[3]
No.2
Breakdown of uridine
The liver is the main site of uridine catabolism, where uridine is broken down into β-alanine and acetyl-CoA [6, 7]. Subsequently, β-alanine can enter other tissues (such as the brain and muscles) or be excreted, while acetyl-CoA plays an important role in cellular energy metabolism and the synthesis of the neurotransmitter acetylcholine.
Note: Uridine decomposition to form β-alanine process. The Time Faction sorts itself out
Love and kill each other,
"Duplicitous" uridine regulates body metabolism
Then, this innate substance that is synthesized-decomposed all the time must also participate in the great carnival of biological metabolism regulation. In recent years, it has been found that uridine regulates overall metabolism through enzymes or intermediates that regulate metabolic pathways (UTP triphosphate, uridine phosphorylase, etc.) [3], especially closely related to glucose and lipid metabolism.
No.1
Uridine and glucose metabolism: the first sight is happy, and the two are tired for a long time
Maintaining the body's normal glucose metabolism is of great significance for improving the energy homeostasis that is deteriorating due to aging. In the presence of leptin, an amino acid product that can be involved in the regulation of multiple processes such as neuroendocrine and glucose metabolism [8]), uridine can improve the glucose tolerance of mice in high-fat diets or aging-induced, but once leptin is missing, oral uridine not only fails to improve glucose metabolism, but also leads to a decrease in blood glucose regulation [9].
However, "duplicitous" uridine does not seem to be so simple, when ordinary mice (leptin is present, normal diet) long-term supplementation of uridine, the level of uridine derivatives (UDP-GlcNAc: uridine diphosphate-n-acetylglucosamine) in skeletal muscle increases significantly, which may eventually induce insulin resistance by reducing the expression of important glucose transporters (GLUT4) and stimulating islet hyperplasia [10].
Human clinical studies have also found that plasma uridine concentrations in patients with non-insulin-dependent diabetes mellitus are positively correlated with insulin resistance index [12]. Between uridine and glucose metabolism, it can be described as "love and killing".
No.2
Uridine and lipid metabolism: success is also Xiao He, defeat is also Xiao He
The influence of uridine, which regulates blood glucose metabolism, also radiates lipid metabolism, and the relationship between the two seems to be the same as that between uridine and glucose metabolism—short-term uridine supplementation can reverse fatty liver caused by the side effects of certain drugs (such as fenofibrate and tamoxifen)[13], and long-term intake of uridine may induce fatty liver disease in organisms [6].
The result of such "cloudy and uncertain" may also be attributed to the multiple complex regulation of lipid metabolism by uridine.
For example, the drug tamoxifen, which is used to prevent and treat breast cancer in the long term, increases the risk of nonalcoholic fatty liver disease, but when combined with uridine, the conversion of neutral fat in the body into membrane phospholipids is accelerated, reducing the accumulation of fat in the cytoplasm [13].
However, when organisms ingest uridine for a long time, it not only leads to inhibition of specific fatty acid binding protein (FABP1) expression in the liver, driving fatty liver production, but also promotes excessive accumulation of fatty acids in the liver by inhibiting insulin signaling or glycosylated FOXO1 proteins [14, 15].
Another "immortal medicine"?
Talk about uridine and anti-aging
After introducing the circulatory process of uridine in the body and understanding its regulation of the main metabolic processes, is uridine really magical in interfering with aging? Is there solid scientific evidence to support it?
Based on the current research results, uridine, as a bioactive molecule that can enter the brain region through the blood-brain barrier, can regulate a variety of central system functions, including memory and neuronal plasticity[16], and may play a neuroprotective role in aging-related neurodegenerative diseases such as Alzheimer's disease [17-19].
One of the few reports of "uridine anti-aging potential" suggests that uridine may reverse stem cell senescence, promote tissue repair, and upregulate levels of antioxidant enzymes (e.g., SOD, CAT, GSH), ultimately significantly reducing levels of pro-aging inflammatory factors [20].
In one study, when scholars treated senescent gastric epithelial cells with 0.4 mg of uridine, there were significant reductions in these cells as markers associated with aging (SA-β-gal, p16, and p21), and uridine was hypothesized to promote the expression of fibroblast growth factor (FGF) in senescent gastric cells, stimulating gastric epithelial cell proliferation[21] and damage repair of gastric mucosal cells [22].
But in addition, to ask whether I have data on the intervention of uridine in model organisms, or even in the length of human life, and whether there are high-quality human clinical trials that are underway or are being prepared to be carried out, the author's answer is: really no...
Eat no, eat no? Let's take a look at it together
After chewing on the theory in front, it is finally time for the "big vernacular" to talk about whether we can achieve our life extension wish by supplementing uridine. As a pyrimidine nucleoside, uridine provides a material basis for a variety of metabolic processes in the body, and with the deepening of research, it has been found that it may have neuroprotective and anti-aging effects, but objectively speaking, it is really only "possible".
For example, the discovery of uridine promoting multi-tissue regeneration and reversing stem cell senescence mentioned at the beginning of the article [1], although the study initially obtained positive results, is still only in the stage of phenomenon observation, does not involve internal mechanisms, and the intervention test uses a large dose of uridine (such as the dose of uridine in mouse cartilage repair, which is equivalent to 60 kg of human daily intake of 3 grams), for humans, not only the dose can not be used as a reference, and even the effect can not be guaranteed.
In addition, some studies have found that ingestion of uridine supplementation may induce activation of P2Y2 receptors (a purine receptor) [23-25], alter normal DNA sequence (incorporation of uracil nucleotides) [26], and increase cancer risk.
Based on the current multi-faceted research, coupled with the possible health risks of long-term use of uridine on the liver [14, 15], bone [27, 28], and blood sugar balance [11, 12], at present, Time School does not recommend the deliberate intake of uridine supplements by the general population.
In short, the anti-aging exploration of uridine has just set sail, and we will wait and see where it will go.
—— TIMEPIE ——
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