bims-polyam 2022-12-25 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2022–12–25
thirteen papers selected by
Sebastian J. Hofer, University of Graz

Polyamines conjugated to deoxyribonucleic acid-protein in cell nucleus from filling grain embryos were involved in tolerance of wheat to drought.
Polyamine Oxidase-Generated Reactive Oxygen Species in Plant Development and Adaptation: The Polyamine Oxidase-NADPH Oxidase Nexus.
Thermal tolerance role of novel polyamine, caldopentamine, identified in fifth instar Bombyx mori.
One-Carbon and Polyamine Metabolism as Cancer Therapy Targets.
Spermidine exogenous application mollifies reproductive stage heat stress ramifications in rice.
The Polyamine Spermine Potentiates the Propagation of Negatively Charged Molecules through the Astrocytic Syncytium.
Supplementation of L-Ornithine Could Increase Sleep-like Behavior in the Mouse Pups.
Overexpression of SMS in the tumor microenvironment is associated with immunosuppression in hepatocellular carcinoma.
Diagnostic metabolomic profiling of Parkinson's disease biospecimens.
Spatially resolved transcriptomics reveals innervation-responsive functional clusters in skeletal muscle.
Biomaterial mediated simultaneous delivery of spermine and alpha ketoglutarate modulate metabolism and innate immune cell phenotype in sepsis mouse models.
Spermine synthase (SMS) serves as a prognostic biomarker in head and neck squamous cell carcinoma: a bioinformatics analysis.
The Aging Process: A Metabolomics Perspective.

J Biosci. 2022 ;pii: 85. [Epub ahead of print]47

Polyamines conjugated to deoxyribonucleic acid-protein in cell nucleus from filling grain embryos were involved in tolerance of wheat to drought.

H Y DU, H L Liu, D X Liu, H P Liu, R Kurtenbach.

Deoxyribonucleic acid-protein (DNAP) of the cell nucleus was purified from developing wheat (Triticum aestivum L.) embryo cells under drought stress, with two cultivars differing in drought tolerance as experimental materials - Longmai No. 079 (drought-tolerant) and Wanmai No. 52 (drought-sensitive). Levels of polyamines (PAs) non-covalently conjugated to the DNA and covalently conjugated to the proteins of DNAP were detected. After soil drought treatment for 10 days, in drought-tolerant Longmai No. 079, the increases in the levels of spermine and spermidine non-covalently conjugated to DNA of DNAP were more statistically significant (P<0.05) than in drought-sensitive Wanmai No. 52. Treatment of Wanmai No. 52 with exogenous Spm could not only enhance the tolerance of the cultivar to drought stress, as judged by flag leaf water content, plasma membrane permeability and grain growth, but also elevate the levels of spermine and spermidine noncovalently conjugated to the DNA of the cultivar. On the contrary, treatment of Longmai No. 079 with methylglyoxyl-bis guanylhydrazone, an inhibitor of S-adenosylmethionine decarboxylase, could significantly (P<0.05) aggravate the drought stress to this cultivar, accompanied by a marked decreases in the levels of spermine and spermidine non-covalently conjugated to the DNA of the cultivar. On the other hand, the content of putrescine covalently conjugated to the proteins of DNAP rose more markedly (P<0.05) in Longmai No. 079 than in Wanmai No. 52. The transglutaminase inhibitor, o-phenanthrolin, could markedly reduce the drought-induced increase in the level of putrescine covalently conjugated to the proteins of DNAP and aggravate drought stress to the two cultivars. Collectively, it could be inferred that spermine and spermidine non-covalently conjugated to the DNA and putrescine covalently conjugated to the proteins of DNAP in the developing grain embryo cell nucleus might enhance the tolerance of wheat plants to soil drought.
Antioxidants (Basel). 2022 Dec 17. pii: 2488. [Epub ahead of print]11(12):

Polyamine Oxidase-Generated Reactive Oxygen Species in Plant Development and Adaptation: The Polyamine Oxidase-NADPH Oxidase Nexus.

Péter Benkő, Katalin Gémes, Attila Fehér.

  Metabolism and regulation of cellular polyamine levels are crucial for living cells to maintain their homeostasis and function. Polyamine oxidases (PAOs) terminally catabolize polyamines or catalyse the back-conversion reactions when spermine is converted to spermidine and Spd to putrescine. Hydrogen peroxide (H2O2) is a by-product of both the catabolic and back-conversion processes. Pharmacological and genetic approaches have started to uncover the roles of PAO-generated H2O2 in various plant developmental and adaptation processes such as cell differentiation, senescence, programmed cell death, and abiotic and biotic stress responses. Many of these studies have revealed that the superoxide-generating Respiratory Burst Oxidase Homolog (RBOH) NADPH oxidases control the same processes either upstream or downstream of PAO action. Therefore, it is reasonable to suppose that the two enzymes co-ordinately control the cellular homeostasis of reactive oxygen species. The intricate relationship between PAOs and RBOHs is also discussed, posing the hypothesis that these enzymes indirectly control each other's abundance/function via H2O2.

Keywords:  NADPH oxidase; hydrogen peroxide; polyamine catabolism; polyamine oxidase; polyamines; stress response

DOI:  https://doi.org/10.3390/antiox11122488
Amino Acids. 2022 Dec 23.

Thermal tolerance role of novel polyamine, caldopentamine, identified in fifth instar Bombyx mori.

Anugata Lima, Brinda Goda Lakshmi Didugu, Alekhya Rani Chunduri, Resma Rajan, Anjali Jha, Anitha Mamillapalli.

  Silkworms have limited ability to regulate their body temperature; therefore, environmental changes, such as global warming, can adversely affect their viability. Polyamines have shown protection to various organisms against heat stress. This study evaluated the qualitative and quantitative changes in heat-stressed Bombyx mori larvae polyamines. Fifth instar Bombyx mori larvae were divided into two groups; control group, reared at room temperature, i.e., 28 ± 2 °C, and the heat shock group, exposed to 40 °C. Dansylation of the whole worm polyamines and subsequent thin-layer chromatography revealed the presence of components with the same Rf value as dansyl-putrescine, spermidine, and spermine. The dansyl-putrescine, spermidine, and spermine polyamines were identified by mass spectrometric analyses. After heat shock, the thin-layer chromatography of the whole-larvae tissue extracts showed qualitative and quantitative changes in dansylated polyamines. A new polyamine, caldopentamine, was identified, which showed elevated levels in heat-stressed larvae. This polyamine could play a role in helping the larvae tolerate various stress, including thermal stress. No significant changes in silk fiber's economic and mechanical properties were observed in our study. This study indicated that PA, caldopentamine, supplementation could improve heat-stress tolerance in Bombyx mori.

Keywords:  Bombyx mori; Caldopentamine; Heat shock; Polyamine; Putrescine; Sericulture; Spermidine

DOI:  https://doi.org/10.1007/s00726-022-03226-5
Biomolecules. 2022 Dec 19. pii: 1902. [Epub ahead of print]12(12):

One-Carbon and Polyamine Metabolism as Cancer Therapy Targets.

Anowarul Islam, Zeeshan Shaukat, Rashid Hussain, Stephen L Gregory.

  Cancer metabolic reprogramming is essential for maintaining cancer cell survival and rapid replication. A common target of this metabolic reprogramming is one-carbon metabolism which is notable for its function in DNA synthesis, protein and DNA methylation, and antioxidant production. Polyamines are a key output of one-carbon metabolism with widespread effects on gene expression and signaling. As a result of these functions, one-carbon and polyamine metabolism have recently drawn a lot of interest for their part in cancer malignancy. Therapeutic inhibitors that target one-carbon and polyamine metabolism have thus been trialed as anticancer medications. The significance and future possibilities of one-carbon and polyamine metabolism as a target in cancer therapy are discussed in this review.

Keywords:  autophagy; cancer; metabolic therapy; methionine; one-carbon metabolism; polyamines; reactive oxygen species

DOI:  https://doi.org/10.3390/biom12121902
Front Plant Sci. 2022 ;13 1027662

Spermidine exogenous application mollifies reproductive stage heat stress ramifications in rice.

Sourabh Karwa, Jyoti Taunk, Sadhana Maurya, Adhip Das, G K Krishna, Sunder Singh Arya, Awadhesh Kumar, Sudhir Kumar, Pramod Kumar, Viswanathan Chinnusamy, Madan Pal.

   Introduction: Rice productivity is severely hampered by heat stress (HS) which induces oxidative stress in this crop. This oxidative stress can be alleviated using various exogenous chemicals, including spermidine (Spd). Therefore, the present study was carried out to characterize HS components and to elucidate the role of exogenous Spd application in rice at the flowering stage.
Methods: Two contrasting rice genotypes, i.e. Nagina22 (N22) and Pusa Basmati-1121 (PB-1121) were placed in temperature tunnels and exposed to HS (38-43°C) with and without Spd (1.5 mM) foliar application during the heading stage till the end of the anthesis stage.
Result: Heat stress induced the production of H2O2 and thiobarbituric acid reactive substances, which resulted in lower photosynthesis, spikelet sterility, and reduced grain yield. Interestingly, foliar application of Spd induced antioxidant enzyme activities and thus increased total antioxidant capacity resulting in higher photosynthesis, spikelet fertility, and improved grain yield under HS in both genotypes. Under HS with Spd, higher sugar content was recorded as compared to HS alone, which maintained the osmotic equilibrium in leaf and spikelets. Spd application initiated in vivo polyamine biosynthesis, which increased endogenous polyamine levels.
Discussion: This study corroborates that the exogenous application of Spd is promising in induction of antioxidant defence and ameliorating HS tolerance in rice via improved photosynthesis and transpiration. Thereby, the study proposes the potential application of Spd to reduce HS in rice under current global warming scenario.

Keywords:  Antioxidant enzymes; flowering; heat stress; polyamine; rice; spermidine; spikelet fertility

DOI:  https://doi.org/10.3389/fpls.2022.1027662
Biomolecules. 2022 Dec 05. pii: 1812. [Epub ahead of print]12(12):

The Polyamine Spermine Potentiates the Propagation of Negatively Charged Molecules through the Astrocytic Syncytium.

Jan Benedikt, Christian J Malpica-Nieves, Yomarie Rivera, Miguel Méndez-González, Colin G Nichols, Rüdiger W Veh, Misty J Eaton, Serguei N Skatchkov.

  The interest in astrocytes, the silent brain cells that accumulate polyamines (PAs), is growing. PAs exert anti-inflammatory, antioxidant, antidepressant, neuroprotective, and other beneficial effects, including increasing longevity in vivo. Unlike neurons, astrocytes are extensively coupled to others via connexin (Cx) gap junctions (GJs). Although there are striking modulatory effects of PAs on neuronal receptors and channels, PA regulation of the astrocytic GJs is not well understood. We studied GJ-propagation using molecules of different (i) electrical charge, (ii) structure, and (iii) molecular weight. Loading single astrocytes with patch pipettes containing membrane-impermeable dyes, we observed that (i) even small molecules do not easily permeate astrocytic GJs, (ii) the ratio of the charge to weight of these molecules is the key determinant of GJ permeation, (iii) the PA spermine (SPM) induced the propagation of negatively charged molecules via GJs, (iv) while no effects were observed on propagation of macromolecules with net-zero charge. The GJ uncoupler carbenoxolone (CBX) blocked such propagation. Taken together, these findings indicate that SPM is essential for astrocytic GJ communication and selectively facilitates intracellular propagation via GJs for negatively charged molecules through glial syncytium.

Keywords:  astrocytes; connexin; glial syncytium; polyamines

DOI:  https://doi.org/10.3390/biom12121812
Metabolites. 2022 Dec 09. pii: 1241. [Epub ahead of print]12(12):

Supplementation of L-Ornithine Could Increase Sleep-like Behavior in the Mouse Pups.

Mayumi Takakura, Satsuki Nagamachi, Takuma Nishigawa, Yoshihiro Takahashi, Mitsuhiro Furuse.

  Along the maternal-fetal-neonatal axis, one of the problems relating to the maternal-neonatal axis is infant sleep problems including nighttime crying. One possible solution could be to provide the newborn with sleep-promoting ingredients through breast milk or formula. So far, it has been reported that L-ornithine has a sleep-related effect. Therefore, we investigated the effect of dietary L-ornithine on maternal mouse plasma and milk L-ornithine levels in Experiment 1. In Experiment 2, a single dose of L-ornithine was applied to know the time-course changes in plasma, mammary gland and milk L-ornithine levels. Experiment 3 was conducted to confirm sleep behavior as well as changes in polyamine levels in milk. L-Ornithine levels in maternal plasma significantly increased by both dietary regimen and single oral administration in Experiments 1 and 2. Both L-ornithine treatments also increased its levels in milk, although not to a concentration as high as in plasma. In Experiment 3, the level of polyamines, which are metabolized from L-ornithine, did not significantly differ after L-ornithine administration. In sleep-like behavior observations, the average concentration of L-ornithine in milk did not increase the sleep-like behavior of mouse pups. However, more concentrated L-ornithine solutions can significantly increase sleep-like behavior. These results revealed that even if mothers ingested L-ornithine to increase L-ornithine levels in breast milk, it is difficult to promote sleep in newborns. Because it is difficult to raise L-ornithine in breast milk to sleep-inducing levels, L-ornithine added formula may partially improve infant sleep and has the potential for preventing infant sleep problems such as nighttime crying.

Keywords:  L-ornithine; breast milk; mouse; polyamine; pups; sleep-like behavior

DOI:  https://doi.org/10.3390/metabo12121241
Front Immunol. 2022 ;13 974241

Overexpression of SMS in the tumor microenvironment is associated with immunosuppression in hepatocellular carcinoma.

Lin Xiang, Longhuan Piao, Dong Wang, Li-Feng-Rong Qi.

  Disorders of polyamine metabolism may contribute to the development of hepatocellular carcinoma (HCC), but the precise mechanism remains unknown. This study reports that spermine synthase (SMS), an enzyme involved in polyamine biosynthesis, is overexpressed in HCC and not associated with hepatitis virus infection in HCC patients. The results of analyzing the clinical data of HCC patients showed that SMS level as a categorical dependent variable was related to clinicopathological features of poor prognosis. Furthermore, the Kaplan-Meier survival analysis and ROC curve indicated that increased SMS level is associated with poor survival rate in HCC and may be a potential biomarker to discriminate HCC tissues. However, SMS overexpression limited the therapeutic effect of immune checkpoint blockade (ICB), which seemed to be related to the immunosuppressive effect of the HCC immune microenvironment formed by higher mRNA transcript levels of immune checkpoints and higher infiltration levels of immunosuppressive cells. In samples with high and low SMS expression, functional enrichment analysis of the differentially expressed genes (DEGs) showed that SMS may be linked to the occurrence and development of HCC by affecting a variety of immune-related pathways, such as Intestinal immune network for IgA production, Fc gamma R-mediated phagocytosis, Antigen processing and presentation, Th1 and Th2 cell differentiation. Subsequently, analysis of the co-expression network of SMS in the liver hepatocellular carcinoma (LIHC) cohort revealed that SMS has a broad impact on multiple important immune- and metabolic-related processes in HCC. In summary, SMS is a promising biomarker to differentiate the prognosis, immune characteristics, and holds promise as a potential target for ICB therapy to improve HCC.

Keywords:  hepatocellular carcinoma; immune checkpoint blockade (ICB); polyamine metabolism; spermine synthase; tumor immune microenvironment (TIME)

DOI:  https://doi.org/10.3389/fimmu.2022.974241
Neurobiol Dis. 2022 Dec 20. pii: S0969-9961(22)00354-0. [Epub ahead of print] 105962

Diagnostic metabolomic profiling of Parkinson's disease biospecimens.

Peter A LeWitt, Jia Li, Kuan-Han Wu, Mei Lu.

   BACKGROUND: Reliable and sensitive biomarkers are needed for enhancing and predicting Parkinson's disease (PD) diagnosis.
OBJECTIVE: To investigate comprehensive metabolomic profiling of biochemicals in CSF and serum for determining diagnostic biomarkers of PD.
METHODS: Fifty subjects, symptomatic with PD for ≥5 years, were matched to 50 healthy controls (HCs). We used ultrahigh-performance liquid chromatography linked to tandem mass spectrometry (UHPLC-MS/MS) for measuring relative concentrations of ≤1.5 kDalton biochemicals. A reference library created from authentic standards facilitated chemical identifications. Analytes underwent univariate analysis for PD association, with false discovery rate-adjusted p-value (≤0.05) determinations. Multivariate analysis (for identifying a panel of biochemicals discriminating PD from HCs) used several biostatistical methods, including logistic LASSO regression.
RESULTS: Comparing PD and HCs, strong differentiation was achieved from CSF but not serum specimens. With univariate analysis, 21 CSF compounds exhibited significant differential concentrations. Logistic LASSO regression led to selection of 23 biochemicals (11 shared with those determined by the univariate analysis). The selected compounds, as a group, distinguished PD from HCs, with Area-Under-the-Receiver-Operating-Characteristic (ROC) curve of 0.897. With optimal cutoff, logistic LASSO achieved 100% sensitivity and 96% specificity (and positive and negative predictive values of 96% and 100%). Ten-fold cross-validation gave 84% sensitivity and 82% specificity (and 82% positive and 84% negative predictive values). From the logistic LASSO-chosen regression model, 2 polyamine metabolites (N-acetylcadaverine and N-acetylputrescine) were chosen and had the highest fold-changes in comparing PD to HCs. Another chosen biochemical, acisoga (N-(3-acetamidopropyl)pyrrolidine-2-one), also is a polyamine metabolism derivative.
CONCLUSIONS: UHPLC-MS/MS assays provided a metabolomic signature highly predictive of PD. These findings provide further evidence for involvement of polyamine pathways in the neurodegeneration of PD.

Keywords:  Biomarkers; Diagnosis; Metabolomics; Parkinson's disease; Polyamines

DOI:  https://doi.org/10.1016/j.nbd.2022.105962
Cell Rep. 2022 Dec 20. pii: S2211-1247(22)01757-0. [Epub ahead of print]41(12): 111861

Spatially resolved transcriptomics reveals innervation-responsive functional clusters in skeletal muscle.

Chiara D'Ercole, Paolo D'Angelo, Veronica Ruggieri, Daisy Proietti, Laura Virtanen, Cristina Parisi, Carles Sanchez Riera, Alessandra Renzini, Alberto Macone, Marta Marzullo, Laura Ciapponi, Davide Bonvissuto, Claudio Sette, Lorenzo Giordani, Luca Madaro.

  Striated muscle is a highly organized structure composed of well-defined anatomical domains with integrated but distinct assignments. So far, the lack of a direct correlation between tissue architecture and gene expression has limited our understanding of how each unit responds to physio-pathologic contexts. Here, we show how the combined use of spatially resolved transcriptomics and immunofluorescence can bridge this gap by enabling the unbiased identification of such domains and the characterization of their response to external perturbations. Using a spatiotemporal analysis, we follow changes in the transcriptome of specific domains in muscle in a model of denervation. Furthermore, our approach enables us to identify the spatial distribution and nerve dependence of atrophic signaling pathway and polyamine metabolism to glycolytic fibers. Indeed, we demonstrate that perturbations of polyamine pathway can affect muscle function. Our dataset serves as a resource for future studies of the mechanisms underlying skeletal muscle homeostasis and innervation.

Keywords:  Amd1; Amd2; CP: Molecular biology; Smox; denervation; muscular atrophy; polyamine; putrescin; skeletal muscle; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.celrep.2022.111861
Biomaterials. 2022 Dec 17. pii: S0142-9612(22)00613-5. [Epub ahead of print]293 121973

Biomaterial mediated simultaneous delivery of spermine and alpha ketoglutarate modulate metabolism and innate immune cell phenotype in sepsis mouse models.

Sahil Inamdar, Tina Tylek, Abhirami Thumsi, Abhirami P Suresh, Madhan Mohan Chandra Sekhar Jaggarapu, Michelle Halim, Shivani Mantri, Arezoo Esrafili, Nathan D Ng, Elizabeth Schmitzer, Kelly Lintecum, Camila de Ávila, John D Fryer, Ying Xu, Kara L Spiller, Abhinav P Acharya.

  Although different metabolic pathways have been associated with distinct macrophage phenotypes, the field of utilizing metabolites to modulate macrophage phenotype is in a nascent stage. In this report, we developed microparticles based on polymerization of alpha-ketoglutarate (a Krebs cycle metabolite), with or without encapsulation of spermine (a polyamine metabolite), to modulate cell phenotype that are critical for resolution of inflammation. Poly (alpha-ketoglutarate) microparticles encapsulated and released spermine (spermine (encap)paKG MPs) in vitro, which was accelerated in an acidic environment. When delivered to bone marrow-derived-macrophages, spermine (encap)paKG MPs induced a complex phenotypic profile outside of the typical M1/M2 paradigm, with distinct effects in the presence or absence of the pro-inflammatory stimulus lipopolysaccharide. Of particular interest was the increase in expression of CD163, which has been linked to anti-inflammatory responses in sepsis. Therefore, we systemically administered spermine (encap)paKG MPs to two different murine models of sepsis using acute or chronic injection of LPS. Macrophages and neutrophils in the liver and spleen of animals treated with spermine (encap)paKG MPs increased expression of CD163, concomitant with normalizing of glycolysis and oxidative phosphorylation, in both models. Overall, these results show that spermine (encap)paKG MPs modulate macrophage phenotype in vitro and in vivo, with potential applications in inflammation-associated diseases.

Keywords:  Biomaterials; Immunoengineering; Immunometabolism; Macrophages; Sepsis

DOI:  https://doi.org/10.1016/j.biomaterials.2022.121973
Ann Transl Med. 2022 Nov;10(22): 1213

Spermine synthase (SMS) serves as a prognostic biomarker in head and neck squamous cell carcinoma: a bioinformatics analysis.

Xiaoyu Pan, Lijun Xue, Yihan Sun.

   Background: Head and neck squamous cell carcinoma (HNSC) is an aggressive type of cancer that lacks early detection, and therefore, has a low 5-year survival rate. The spermine synthase (SMS) gene has been shown to be associated with Snyder-Robinson syndrome and poor prognosis of multiple cancers; however, its regulatory role in HNSC has never been investigated. Therefore, we explored the potential predictive value of SMS in HNSC.
Methods: We explored the association between SMS expression and clinicopathological parameters of HNSC patients by using data from The Cancer Genome Atlas datasets (TCGA). The prognostic value of SMS was evaluated using the Kaplan-Meier plotter, Gene Expression Profiling Interactive Analysis (GEPIA) 2 and univariate and multivariate Cox regression analyses. We further used gene set enrichment analysis (GESA) to investigate the potential roles of SMS in HNSC prognosis and Tumor Immunity Estimation Resource 2.0 (TIMER2.0) to analyze the correlation between immune cell infiltration and SMS expression. Finally, starBase was used to screen out prognosis-associated non-coding RNA genes to constructed the competing endogenous RNA (ceRNA) network. Co-expression and survival analyses were used to identify the ceRNA network's effect on HNSC prognosis.
Results: We found that SMS expression was increased in HNSC compared with normal tissues (P<0.05). In addition, SMS expression was associated with tumor grade (P=0.006), N stage (P=0.001), and prognosis. Survival analysis revealed that high expression of SMS showed worse overall survival (OS) (HR =1.4, P=0.01) and worse disease-free survival (DFS) (HR =1.5, P=0.014). Multivariate Cox analysis further supported the prognostic value of SMS in HNSC (HR =1.006636, P=0.0056). GESA showed that SMS was involved in metabolism- and immune-related pathways. The immune infiltration analyses results showed a decrease in the landscape of immune cell infiltration with high SMS expression and SMS deletion in HNSC. Finally, a ceRNA network (SMS/hsa-miR-23b-3p/KTN1-AS1 and VPS9D1-AS axis) was constructed based on the co-expression and survival analyses in HNSC.
Conclusions: Our findings first revealed that SMS functioned as a potential prognostic biomarker and provide insights into the molecular mechanisms of its function in HNSC. The use of SMS may be powerful for determining worse prognosis HNSC patients.

Keywords:  Head and neck squamous cell carcinoma (HNSC); bioinformatics analysis; biomarker; prognosis; spermine synthase (SMS)

DOI:  https://doi.org/10.21037/atm-22-5014
Molecules. 2022 Dec 07. pii: 8656. [Epub ahead of print]27(24):

The Aging Process: A Metabolomics Perspective.

Alex Castro, Étore F Signini, Juliana Magalhães De Oliveira, Maria Carolina Bezerra Di Medeiros Leal, Patrícia Rehder-Santos, Juliana C Millan-Mattos, Vinicius Minatel, Camila B F Pantoni, Regina V Oliveira, Aparecida M Catai, Antônio G Ferreira.

  Aging process is characterized by a progressive decline of several organic, physiological, and metabolic functions whose precise mechanism remains unclear. Metabolomics allows the identification of several metabolites and may contribute to clarifying the aging-regulated metabolic pathways. We aimed to investigate aging-related serum metabolic changes using a metabolomics approach. Fasting blood serum samples from 138 apparently healthy individuals (20-70 years old, 56% men) were analyzed by Proton Nuclear Magnetic Resonance spectroscopy (1H NMR) and Liquid Chromatography-High-Resolution Mass Spectrometry (LC-HRMS), and for clinical markers. Associations of the metabolic profile with age were explored via Correlations (r); Metabolite Set Enrichment Analysis; Multiple Linear Regression; and Aging Metabolism Breakpoint. The age increase was positively correlated (0.212 ≤ r ≤ 0.370, p < 0.05) with the clinical markers (total cholesterol, HDL, LDL, VLDL, triacylglyceride, and glucose levels); negatively correlated (-0.285 ≤ r ≤ -0.214, p < 0.05) with tryptophan, 3-hydroxyisobutyrate, asparagine, isoleucine, leucine, and valine levels, but positively (0.237 ≤ r ≤ 0.269, p < 0.05) with aspartate and ornithine levels. These metabolites resulted in three enriched pathways: valine, leucine, and isoleucine degradation, urea cycle, and ammonia recycling. Additionally, serum metabolic levels of 3-hydroxyisobutyrate, isoleucine, aspartate, and ornithine explained 27.3% of the age variation, with the aging metabolism breakpoint occurring after the third decade of life. These results indicate that the aging process is potentially associated with reduced serum branched-chain amino acid levels (especially after the third decade of life) and progressively increased levels of serum metabolites indicative of the urea cycle.

Keywords:  liquid chromatography-high-resolution mass spectrometry; metabolism; metabolome; nuclear magnetic resonance

DOI:  https://doi.org/10.3390/molecules27248656