Cell sub-journal | Multiomics reveals glycine-serine-threonine metabolic axis to resist mouse aging mechanisms
The effects of chronic calorie restriction (CR) on health and survival are complex, and little is known about its underlying molecular mechanisms. A recent study in mice on diets used in non-human primate CR studies found that while diet structure does not affect longevity, fasting time and total calorie intake are decisive factors in improving survival. In this study, through the combined analysis and comprehensive pathway enrichment of transcription +protein+metabolism multiomics, the metabolic hub of lifespan and health of mice with two diets and different feeding strategies was explored, and it was found that the glycine-serine-threonine metabolic axis may be involved in longevity and its related molecular mechanisms. Direct comparisons of different feeding strategies reveal a common metabolic pattern that improves health and increases longevity, including metabolism of short-chain fatty acids and essential polyunsaturated fatty acids.
● Journal: cell metab.
● if=22.415
● Publication time: 2020-05
Research routes
Research results
>> 1. Effects of NIA or WIS diet feeding patterns on the health of male mice
The authors conducted a series of longitudinal studies on the effects of diet composition and feeding patterns on mouse physiology (Figure 1a). 292 4-month-old male c57bl/6j mice were randomly divided into NIA and WIS diet groups under the AL (free-eating), CR (calorie restriction) or MF (one meal a day) regimens. CR and mf mice receive a single meal daily at 3:00 PM. The nmr results showed that the obesity rates of CR and mf mice were significantly reduced compared to the AL group (Figure 1b, above); the lean-to-fat ratios of MF and AL mice were similar and significantly lower compared to CR mice (Figure 1b, figure below). Fasting blood glucose testing found that fasting blood glucose (FBG) levels were relatively stable in all mice under both diets, and slightly higher levels of FBG in the WIS diet (Figure 1c). Oral glucose tolerance tests (ogtts) were performed on mice aged 10 and 14 months, and the glucose clearance in CR mice was higher than al (Figure 1d). A comprehensive laboratory animal monitoring system (clams) that monitors metabolic rhythms in three light/dark cycles in 10-month-old mice by breath assays. The circadian respiration exchange rate (RER) rhythm of al mice was weak, and the circadian rhythm of both mf and CR mice was obvious, indicating a higher metabolic dependence on the oxidation of fatty acids (fa).
>> 2. Liver transcriptome and metabolomics response to dietary composition and feeding paradigms
CDNA microarray analysis was performed on the livers of mice fed NIA or WIS diets to determine transcriptional responses. At the same time, non-targeted mass spectrometry metabolomics was performed on the livers of mice. Principal component analysis (PCA) (Figure 2a) and partial least squares discriminant analysis (plsda) analysis showed a clear separation between al and cr, but the overlap between the mf group and al was greater, especially in the WIS diet (Figure 2b). Independent of diet (nia or wis), CR (700 genes, 19 metabolites) and mf (69 genes, 17 metabolites) show significant upregulation or downregulation compared to al (Figure 2c). The mf pathway focuses on the central catabolic and anabolic pathways synthesized by amino acids, fa, and protein precursors (purine and pyrimidine) (Figure 2e). CR-specific pathways include detoxification, maintenance of molecular renewal, and provision of energy (Figure 2d). These data suggest that, relative to AL, CR increases body longevity through liver protection mechanisms for detoxification and maintaining redox balance.
Figure 2 Multi-omics analysis of liver extracts: specific pathways of lifespan
>> 3. The monocarbon, methionine and sulfur pathways of glycine, serine and threonine metabolism are the main pathways of life
To gain insight into pathways of action that may contribute to lifespan, the analysis found a total of 21 genes (Table S1) and 10 metabolites between cr and mf (Figure 3a), the most enriched pathway being aminoacyl t-RNA biosynthesis. The metabolic pathways of glycine (gly), serine (ser) and threonine (THR), glutathione, taurine-haurine, and cysteine-methionine are the highest ranked catabolic and redox-related pathways according to the enrichment score (Figure 3b). Topological analysis showed that interactions between gly-ser-thr are associated with several highly important biological pathways (Figures 3c and 3d). gly-ser-thr can be reversibly converted to each other by the action of two enzymes, serine hydroxymethyltransferase (shmt) and threonine aldera (Figure 3c). SER is a source of a carbon pool for nucleotide synthesis directly related to the methionine cycle (Figure 3d).
>> 4. Liver pathways involving mf and CR responses
JPA analysis was performed for mice with different dietary strategies, and the top 20 pathways were ranked according to enrichment and topology (Figure 4b). Catalyzed by propionyl-CoA carboxylase (PCC), Propionyl-CoA is carboxylated to produce methylmalonyl-CoA, which enters the tca cycle via succinyl-CoA (Figure 4c). The link between propionic acid metabolism and mitochondrial metabolism (BCAA, FA and ketone body degradation) is produced by the catabolism of cholesterol, valine, odd chain fa, methionine, isoleucine and threonine (Figure 4c). The Wien diagram characterizes genes and metabolites commonly found in three feeding regimens (Figure 4d). According to the combined enrichment and network topology indicators (Figure 4e), four of the six shared pathways (foreign bodies and drugs of cytochrome p450, glutathione, omega-6 linoleic acid metabolism) are at the top of the "core pathway". In addition to the above pathways, taurine-caldurine and cysteine methionine metabolism (via glutathione; see Figure 3d) and lipid metabolism (by α-linolenic acid) are closely related, such as arachidonic acid, glycerol phospholipids (Figure 4f).
The NIA diet is associated with various pathways, such as "metabolism of xenosomes and drugs through cytochrome p450", "u6 pufa linoleic acid" and "nad rescue", while the WIS diet is mainly a pathway that promotes central catabolism, namely carbohydrates, amino acids, and tCA circulation (Figure 5, comparing Figure 5e with 5b). Three dietary regimens demonstrate a high degree of topological connectivity and functional complementarity between processes associated with detoxification, antioxidants, energy, and signaling pathways, including pathways and pathways, which further affect the body's immunity and inflammatory metabolites.
>> 5.Liver factors associated with longevity regulation respond to diet and feeding patterns
Al-mf-cr leads to a gradual prolongation of the fasting period, showing decreased levels of sirt1 and nampt protein, but elevated ampk in the NIA diet (Figures 6a and 6b). Importantly, the ampka expression is specifically related to sirt1 and not to sir6 (Figure 6c). The abundance of nampt is also associated with sirt1, but not with sirt6 or ampk (Figures 6a-6c). Amp content in cr was significantly elevated in both diet types (Figure 6d).
>> 6. Verification test
Fasting time caused similar metabolic remodeling of mice and nhps in the liver. Metabolomics showed that 173 metabolites were identified in serum, of which PLS-DA showed a clear trend of separation between al and cr groups, especially in the NIA cohort (Figure 7a). Using a similar method to analyze the serum of current mice, it was found that 155 metabolites, PLS-DA analysis between al, mf and cr showed good separation (Figure 7b). The overall serum metabolites of the urea cycle in NIA, such as fumarate, citrulline, and n-acetyl glutamic acid (an allosteric effector of carbamoyl phosphatase), are lower in content compared to wis. Among them, the amino acid component (green arrow) is identified as a factor associated with longevity in the liver and serum diet. Liver glyc-ser-thr metabolism is positively correlated with lifespan (Figure 7d, above), while most circulating amino acids are negatively correlated with longevity (Figure 7d, bottom). Of the 34 serum metabolites, 7 respond to CR and belong to metabolic pathways associated with fasting, including amino acid and lipid metabolism, ammonia cycling, urea cycling, fa oxidation, and PUFA (Figures 7e and 7f). Thus, the metabolic remodeling caused by CR is similar between mice and monkeys, suggesting that the potential metabolic response to CR between these fairly distant species is conserved.
Conclusions of the study
Based on the combined analysis of transcription + protein + metabolomics, male c57bl/6j mice fed with nia and wis diets were studied, and multiple omics jointly revealed that the glycine-serine-threonine metabolic axis may be involved in longevity and its related molecular mechanisms. Eventually, it was also validated in monkey species, with similar metabolic remodeling found in monkey livers.
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Wuhan Matwell Biotechnology Co., Ltd. (hereinafter referred to as "Meivei Metabolism"), located in Wuhan National Biological Industry Base - Optics Valley Bio-City, focuses on providing leading metabolomics technology development and services. Maiwei Metabolism innovated the "broadly targeted metabolome" technology, based on the "metabolome + genome + transcriptome" multi-omics research scheme, in recent years as a corresponding author in the international academic journals such as cell, nature communications, nature genetics, pnas and other international academic journals, leading the new direction of metabolic biology research in the genomic era.