Hydroxy and keto acids are important intermediates in central carbon metabolism and redox regulation, yet their comprehensive quantitative analysis remains challenging because of high polarity, poor chromatographic retention, and substantial concentration variation in biological matrices. Here, we develop an orthogonal chemical encoding strategy coupled with LC-MS/MS for simultaneous and quantitative profiling of hydroxy and keto acids. Keto acids are selectively modified at carbonyl groups using O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine (PFBHA), followed by carboxyl-directed derivatization of both keto and hydroxy acids with 3-nitrophenylhydrazine (3-NPH). This sequential labeling approach introduces complementary chemical signatures for distinct metabolite classes, improving keto acid detectability while preserving broad coverage of hydroxy acids. The analytical performance of the method was systematically evaluated, demonstrating wide linear dynamic ranges, subnanomolar detection limits, high precision, and minimal matrix effects for 20 hydroxy and keto acids. Furthermore, isotope-coded derivatization using 13C6-3-NPH enabled accurate isotope-based internal standardization without requiring individual isotope-labeled standards for each analyte. The applicability of the method was demonstrated by profiling serum samples from diabetic mice, revealing altered ketone body metabolism, branched-chain amino acid-derived keto acid pathways, and hydroxy/keto acid interconversion. This orthogonal chemical encoding approach provides a robust analytical strategy for quantitative characterization of structurally related polar metabolites in complex biological matrices.

The metabolic response to dietary fat intake and its association with prediabetes are unclear. We aimed to identify the plasma metabolite profiles related to dietary fats and test if they are associated with prediabetes risk. Within the Precision Nutrition and Food Safety for Dietary Prevention of Chronic Disease cohort, we analyzed plasma metabolites from 207 participants (comprising 102 prediabetes cases and 105 controls) via untargeted metabolomics. Dietary fat intakes were assessed using a validated food frequency questionnaire. Metabolic signatures related to dietary fats were identified using elastic net regression and 10-fold cross-validation. The associations of metabolic signatures with prediabetes were evaluated using Poisson regression. We identified multi-metabolite profiles comprising 26 metabolites for intake of saturated fatty acids (SFAs), 32 metabolites for monounsaturated fatty acids (MUFAs), 27 metabolites for polyunsaturated fatty acids (PUFAs), 24 metabolites for n-3 PUFAs, and 25 metabolites for n-6 PUFAs. These metabolic signatures were robustly correlated with corresponding dietary fats intakes (Pearson r = 0.42-0.61; P < 0.001). After adjusting for potential risk factors, metabolic signatures of PUFAs (ORQ4 vs. Q1 = 0.57, 95% CI: 0.35-0.93) and n-3 PUFAs (ORQ4 vs. Q1 = 0.56, 95% CI: 0.34-0.92) were inversely associated with prediabetes prevalence but no significant associations were found for metabolic signatures of dietary SFAs, MUFAs, and n-6 PUFAs. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that dietary PUFAs and n-3 PUFAs promoted the pentose phosphate pathway and glycerolipid metabolism. Moreover, key metabolites related to PUFA/n-3 PUFA consumption were correlated with prediabetes. Our findings reveal the plasma metabolic signatures characterizing typical dietary fat intake and support the beneficial role of PUFAs, especially n-3 PUFAs, in prediabetes prevention by modulating the pentose phosphate pathway and glycerolipid metabolism.

The rapid loss of tissue viability during hypothermic storage frequently results in organ failure and high discard rates in transplantation. In contrast, ectothermic animals can tolerate prolonged exposure to low temperatures in their natural environments. Elucidating the mechanisms underlying this cold tolerance may therefore inform improved strategies for tissue preservation. Here, we investigate proteomic and metabolomic responses to cold exposure in the livers of two frog species from distinct habitats: the cold-sensitive African clawed frog ( Xenopus laevis ) and the cold-tolerant Northeastern Asian brown frog ( Rana dybowskii ). Cold exposure induced lipid mobilization in X. laevis , whereas it promoted phospholipid mono-unsaturation in R. dybowskii . Notably, treatment with monounsaturated fatty acids (MUFAs) or overexpression of stearoyl-CoA desaturase (SCD) reduced cell death during cold storage. Moreover, MUFA infusion significantly improved cell viability in mouse liver tissue under hypothermic conditions. Together, these findings suggest that lipid mono-unsaturation, an adaptive feature of cold-tolerant frogs, can be leveraged to enhance tissue preservation during cold storage. ### Competing Interest Statement The authors have declared no competing interest. National Natural Science Foundation of China, T2293763, 82301607 Beijing Natural Science Foundation, IS24040 State Key Laboratory of Complex, Severe, and Rare Diseases, 2025-I-PY-001 China Postdoctoral Science Foundation, 2024M751632

Cisplatin-based chemotherapy is the first-line treatment for lung cancer. However, cisplatin resistance (CR) remains a major challenge, leading to treatment failure. A key driver of CR is enhanced DNA damage repair. Although males absent on the first (MOF) participate in DNA repair, their specific role in mediating CR remains unclear. In this study, CR models were established in PC9 and A549 lung cancer cell lines. Our results showed that high expression of Williams syndrome transcription factor (WSTF) in lung cancer cells was associated with CR. WSTF knockdown inhibited proliferation and promoted apoptosis, DNA damage, and γ-H2AX levels in CR cells. Moreover, MOF was highly expressed in lung cancer cells and regulated by WSTF acetylation. Furthermore, MOF knockdown downregulated H4K16ac levels in CR cells. MOF overexpression significantly upregulated H4K16ac levels, enhanced proliferation, and suppressed apoptosis in CS cells, concomitant with DNA damage repair and reduced γ-H2AX expression. Notably, transfection with the K46R attenuated these MOF-mediated effects in CS cells. Collectively, our study demonstrates that MOF promotes DNA damage repair and enhances CR in lung cancer cells via H4K16ac-mediated WSTF acetylation. These findings provide valuable insights for overcoming chemoresistance and improving patient outcomes.

Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by genetic heterogeneity. Despite significant progress in understanding the BBSome-coding genes associated with ciliopathies, the pathogenesis linked to mutations in chaperonin-coding genes (BBS6, BBS10, and BBS12) remains poorly defined. This study aims to confirm the genetic diagnosis of BBS and elucidate the pathological mechanisms in causative genes of BBS10 and BBS12. Clinical evaluations were performed on BBS patients, followed by targeted next-generation sequencing (NGS) to identify disease-causing variants. Pathogenicity was assessed using computational prediction tools. Mutant BBS10 and BBS12 constructs were transfected into HEK293T cells for protein stability (Western blot) and interaction analyses (co-immunoprecipitation). Ciliogenesis was evaluated in hTERT-RPE1 cell model via immunofluorescence. The results identified novel compound heterozygous mutants in BBS10 (c. 1391G > C, c.2056 G > A) and BBS12 (c.590-591del AT, c.2102 C > G) in probands from two families. These mutations correlated with the classical BBS features: obesity, polydactyly, and retinal dystrophy. Ophthalmic examinations revealed bone spicule-like deposits, macular outer nuclear layer thinning, and photoreceptor loss in the retina. Comparative analysis across species revealed that these mutations occurred at conserved residues. Structural predictions indicated truncation at the protein's C-terminus. Transfection studies in HEK293T and hTERT-RPE1 cells showed that although the mutant protein localized to primary cilia similar to their wild-type counterparts, their stability was compromised, leading to accelerated degradation through ubiquitin-proteasome pathway. Our findings showed that C-terminal deletions in chaperonin-like BBS proteins significantly impaired their function, particularly affecting protein-protein interactions with each other and with the core BBSome subcomplex protein BBS7. The identified novel compound heterozygous mutations in BBS10 and BBS12 significantly affected ciliary length and protein-protein interactions critical for BBSome assembly, contributing to the manifestation of BBS symptoms.

Bacterial cell wall peptidoglycan (PG) consists of alternating β-(1,4) linked N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG). The C-6 hydroxyl group of NAM is acetylated by transmembrane O-acetyltransferases post PG biosynthesis in many pathogenic bacteria. This modification is important for bacterial resistance to lysozyme. It is also known that the extent of NAM O-acetylation varies greatly, depending on genetic background and growth phase. However, it remains unclear if the fluctuation of NAM O-acetylation has any function. In this study, we show that NAM O-acetylation functions as a potential extracellular signal of cellular metabolism for epigenetic response to nutrient conditions in human pathogen Streptococcus pneumoniae (pneumococcus). The O-acetylation was found to control reversible switch between opaque and transparent colony phases by modulating inversion reactions of DNA methyltransferase hsdS genes in the colony opacity determinant (cod) locus, and thereby phase-defining genome methylation pattern. The NAM O-acetylation made S. pneumoniae adopt the HsdSA1 methylome and opaque colony phase, whereas the lack of this modification favored the HsdSA3 methylome and transparent colony phenotype. Further analysis revealed that the major autolysin LytA and multiple other proteins are required for the O-acetylation-dependent control of epigenetic machinery. Lastly, the extent of NAM O-acetylation was found to correlate with the cellular level of the acetyl donor acetyl-CoA and glucose. These data support the postulation that S. pneumoniae uses NAM O-acetylation as an extracellular marker of cellular acetyl-CoA to synchronize nutrient availability with bacterial lifestyle by epigenetic modulation of cellular metabolism.

The association between plasma fatty acid profiles and dementia risk remains debatable, with additional complexity introduced by genetic susceptibility and serum biomarkers. Multivariable-adjusted Cox models were conducted to assess hazard ratios and 95% confidence intervals of dementia. The influences of APOE gene and dementia genetic risk score were investigated by nutrition-genetic interaction analyses. Mediation analyses were performed to assess the role of serum biomarkers. Among 117,884 UK Biobank participants, 1785 cases of dementia emerged after an average follow-up duration of 11.7 years. The highest quartiles of plasma concentrations of monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) were associated with 29% and 28% reduced risk of dementia, respectively. Plasma linolenic acid (LA) and non-docosahexaenoic acid (non-DHA) n-3 PUFAs were also found to be inversely associated with dementia risk, while plasma saturated fatty acids, non-LA n-6 PUFAs, and DHA were not. Among White ethnicity individuals, the protective role of MUFAs was more pronounced in high APOE risk individuals, whereas the influence of PUFAs was marginally stronger in low APOE risk individuals. Non-LA n-6 PUFAs were found to be associated with elevated risk of dementia among White ethnicity individuals with low dementia genetic risk score. Serum triglyceride, glucose, and HbA1c partially mediated these associations. Our research underscores the importance of improving plasma fatty acid profiles based on individual genetic background to effectively prevent dementia.

Accurate detection of lymph node metastasis (LNM) is critical for colorectal cancer (CRC) staging and treatment planning, yet current histopathological assessment based on lymph nodes remains labor-intensive and operator-dependent. Here, we developed a tissue metabolic fingerprinting platform leveraging label-free ferric nanoparticle-enhanced laser desorption/ionization mass spectrometry (FELDI-MS) to directly acquire colorectal cancer tissue metabolic fingerprints (CRC-TMFs) from 276 primary CRC tissue samples (138 non-metastatic/LNM-, 138 metastatic/LNM+). Based on CRC-TMFs, we constructed a machine learning-based diagnostic model for LNM detection, achieving area under the curve (AUC) of 0.914. Furthermore, metabolic profiling revealed cysteine deficiency in LNM+ tissues, concomitant with upregulation of glutamate-cysteine ligase catalytic subunit (GCLC), which catalyzes the rate-limiting step in glutathione biosynthesis from cysteine. Functional validation demonstrated that GCLC knockdown inhibited CRC cell proliferation and migration, underscoring its role in metastatic reprogramming. Our work not only introduces a rapid, operator-independent tool for precise LNM assessment but also highlights dysregulated cysteine-GCLC-glutathione metabolism as a key feature of metastatic reprogramming in CRC.

Peptides are molecules composed of two or more amino acids linked by peptide bonds, and they play essential biological roles. In recent decades, peptides have become pivotal bioactive ingredients in pharmaceuticals and cosmetics due to their unique features. Originally developed for therapeutic purposes, peptides have gained popularity in the cosmetic field, providing solutions for anti-aging, whitening, moisturizing, and skin repair. Moreover, innovations such as artificial intelligence-assisted peptide design, efficient delivery systems, and the integration of multifunctional ingredients have significantly contributed to the industry’s rapid evolution. This review explores the historical milestones of peptides in medicine and cosmetics, delves into cutting-edge synthesis technologies, and dissects the molecular mechanisms behind their cosmetic properties. Research in medicinal peptides has promoted the development of cosmetic peptides. Despite their potential, challenges such as stability, bioavailability, and cost-effective production remain barriers to widespread adoption. Future studies should focus on enhancing peptide stability, developing synergistic formulations, and conducting large-scale clinical trials to validate long-term efficacy. With continuous innovation, peptides are poised to redefine the cosmetic industry, bridging the gap between pharmaceuticals and skincare for safer and more effective solutions.

Oxidative stress plays a crucial role in organ aging and related diseases, yet the endogenous regulators involved remain largely unknown. This work highlights the importance of metabolic homeostasis in protecting against oxidative stress in the large intestine. By developing a low-input and user-friendly pipeline for the simultaneous profiling of five distinct cysteine (Cys) states, including free SH, total Cys oxidation (Sto), sulfenic acid (SOH), S-nitrosylation (SNO), and S-glutathionylation (SSG), we shed light on Cys redox modification stoichiometries and signaling with regional resolution in the aging gut of monkeys. Notably, the proteins modified by SOH and SSG were associated primarily with cell adhesion. In contrast, SNO-modified proteins were involved in immunity. Interestingly, we observed that the Sto levels ranged from 0.97% to 99.88%, exhibiting two distinct peaks and increasing with age. Crosstalk analysis revealed numerous age-related metabolites potentially involved in modulating oxidative stress and Cys modifications. Notably, we elucidated the role of fumarate in alleviating intestinal oxidative stress in a dextran sulfate sodium (DSS)-induced colitis mouse model. Our findings showed that fumarate treatment promotes the recovery of several cell types, signaling pathways, and genes involved in oxidative stress regulation. Calorie restriction (CR) is a known strategy for alleviating oxidative stress. Two-month CR intervention led to the recovery of many antioxidative metabolites and reshaped the Cys redoxome. This work decodes the complexities of redoxomics during the gut aging of non-human primates and identifies key metabolic regulators of oxidative stress and redox signaling.

JOURNAL/nrgr/04.03/01300535-202606000-00069/figure1/v/2026-02-11T151048Z/r/image-tiff Alzheimer's disease is the most common cause of dementia. Although increasing evidence suggests that disruptions in lipid metabolism are closely associated with the disease, the overall profile of lipid and sterol changes that occur in the brain during Alzheimer's disease remains unclear. In this study, we compared brain tissues extracted from 32-week-old male wild-type mice and 5×FAD transgenic Alzheimer's disease model mice, which carry mutations in the amyloid precursor protein ( APP ) and presenilin 1 ( PS1 ) genes. Using untargeted lipidomics and sterolomics techniques, we investigated the metabolic profiles of lipids, with a focus on sterols specifically, in three brain regions: cerebellum, hippocampus, and olfactory bulb. Our results revealed significant alterations in various lipids, particularly in the hippocampus and olfactory bulb, suggesting changes in energy levels in these regions. Further pathway analysis indicated notable disruptions in key metabolic processes, particularly those related to fatty acids and cell membrane components. Additionally, we observed decreased expression of 15 genes involved in lipid and sterol regulation. Collectively, these findings provide new insights into how imbalances in lipid and sterol metabolism may contribute to the progression of Alzheimer's disease, highlighting potential metabolic pathways involved in the development of this debilitating disease.

Purpose:The aetiology of colorectal cancer (CRC) is attributed to the intrinsic malignant cell transformation and the extrinsic tumor microenvironment (TME). Within the TME, M2-like tumor-associated macrophages (TAMs) play a pivotal role in promoting CRC malignancy. Although the interaction between tumor cells and TAMs has been studied, the mechanism underlying the polarization of M2-like TAMs directed by CRC cells remains unclear. Materials and Methods:Macrophage polarization was analyzed by flow cytometry. Cytokine production was quantified by qPCR. EVs were identified by transmission electron microscopy and western blotting. CRC cell apoptosis and viability were measured by flow cytometry and CCK8 assay, respectively. Results:The results showed that CRC cells have high expression of HMGCS1, the enzyme responsible for catalyzing the synthesis of HMG-CoA during cholesterol biosynthesis. The increased expression of HMGCS1 resulted in an excess of cholesterol in CRC patients. The excess cholesterol derived from CRC cells was released via extracellular vesicles (EVs) and taken up by surrounding macrophages via the CD36 receptor. Macrophages that took up CRC cell-derived cholesterol showed a preferential polarization towards M2-like TAMs, which produced large amounts of pro-tumor cytokines. The production of these cytokines further accelerated the progression of the surrounding CRC. Conclusion:Our findings revealed a mutual stimulatory effect between CRC cells and M2-like TAMs. CRC cells with hyper-expressed HMGCS1 facilitated M2-like TAM polarization by releasing cholesterol-rich EVs, and M2-like TAMs in turn promoted CRC malignancy. These findings suggest that inhibiting excessive cholesterol production may be a promising strategy for the treatment of advanced CRC.

Age-related changes in circulating metabolites influence systemic physiology and may contribute to diseases such as sarcopenia. Although metabolic dysregulation is closely linked to sarcopenia, the roles of specific metabolites remain unclear. In this study, we performed comprehensive plasma metabolomic and lipidomic analyses across two cohorts comprising 1,013 individuals, uncovering the metabolic characteristics of sarcopenia, including a notable decline in plasma sarcosine levels in both aging patients and those with sarcopenia. Functional studies in mice showed that sarcosine helps maintain muscle mass homeostasis during aging, promotes adipose thermogenesis and enhances muscle regeneration. We demonstrate here that sarcosine activated the GCN2 signaling pathway to enhance anti-inflammatory macrophage polarization, promoting adipose thermogenesis and muscle regeneration. These effects may increase energy expenditure and restore metabolic balance to reduce chronic inflammation and improve insulin sensitivity, which are crucial for managing sarcopenia. This study underscores the potential of sarcosine supplementation as an adjunctive strategy via macrophage modulation for preventing sarcopenia in older adults. Using two cohorts, Liu, Ge, Xiao, Lu and colleagues perform plasma metabolomics and lipidomics, linking reduced sarcosine to sarcopenia diagnosis. In mice, they demonstrate that sarcosine enhances muscle repair, boosts adipose thermogenesis and preserves muscle mass via macrophage modulation.

BACKGROUND:Evidence linking circulating fatty acids (FAs) to mortality from age-related chronic diseases was limited and inconsistent. We aimed to investigate the associations of plasma FAs with total, cardiovascular disease (CVD), and cancer mortality and explore the potential mechanism. METHODS:117,871 individuals were prospectively followed in the UK Biobank. Circulating FAs were measured by a high-throughput NMR-based metabolic platform. Causes and dates of death were collected from death certificates according to the code of International Statistical Classification of Diseases (ICD-10). RESULTS:Over a median follow-up of 11.9 years, 7805 (6.6 %) deaths occurred. Plasma saturated FAs (SFAs) were positively associated with total mortality risk while plasma polyunsaturated FAs (PUFAs) exhibited an inverse association. For cause-specific mortality, circulating PUFAs, linoleic acid (LA), and n-3 PUFAs were associated with 34 %, 30 %, and 37 % lower risk of CVD mortality, respectively. Moreover, plasma n-3 PUFAs were related to a 24 % lower risk of cancer mortality. However, circulating non-LA n-6 PUFAs were associated with 11 % and 22 % higher risk of total and cancer mortality, respectively. Serum levels of C-reactive protein (CRP) and apolipoprotein A (ApoA) had significant mediation effects on these associations. Additionally, the inverse association of plasma n-6 PUFAs with total mortality only existed among carriers of the GG genotype at rs16966952 and the inverse association of plasma PUFAs with CVD mortality was only observed among TT genotype carriers at rs174547. CONCLUSIONS:Circulating PUFAs, particularly n-3 PUFAs and LA, were inversely related to premature death from chronic diseases and longevity. Inflammatory and lipid metabolism partially explained these associations. Genetic interactions with rs16966952 and rs174547 further modified these associations.

Idiopathic pulmonary fibrosis is a high-mortality chronic lung disease, and currently existing medications have limited therapeutic efficacy with noticeable adverse effects, urgently necessitating the exploration of more effective and safer treatment options. Our preliminary studies have demonstrated that the leech extract group with molecular weight greater than 10 kDa (>10 kDa group) exhibited superior anti-idiopathic pulmonary fibrosis efficacy. To trace the active components of > 10 kDa group, it was separated by gel electrophoresis and analyzed by Nano LC-MS/MS. To further analyze the effects of these active components on the regulation of metabolic pathways in fibrotic lung tissue, the metabolites of lung tissue were analyzed by UPLC/MS after administration of > 10 kDa group in bleomycin-induced pulmonary fibrosis (BML-induced PF) mice for 28 days at a 0.179 mg/g per day. A total of 17 proteins were identified in > 10 kDa group and 46 endogenous metabolites were identified in lung tissue, among which 18 significantly differential metabolites were screened as potential metabolomics biomarkers. Metabolic pathway analysis demonstrated that these identified differential metabolites mainly involved biosynthesis of unsaturated fatty acids, phenylalanine-tyrosine and tryptophan biosynthesis and tryptophan metabolism signaling pathway, indicating that the active components of > 10 kDa group mainly regulated the metabolic disorders of lung tissue in BLM-induced mice by up-regulating the biosynthesis of unsaturated fatty acids, down-regulating phenylalanine-tyrosine and tryptophan biosynthesis, and adjusting tryptophan metabolism signaling pathway.

A novel surface molecularly imprinted polymers-based dual-mode nanoprobe, NH2-MIL-53(Al)@PDA-MIPs/ AuNPs, was developed for fluorescence (FL) and surface-enhanced Raman scattering (SERS) detection of 4-Nitro- phenol (4-NP) in real water samples. By integrating the advantage of rapid visual detection in FL mode with the advantage of ultrasensitive sensing in SERS mode, the FL-SERS dual-modal approach offers cross-verification of results and extends the detection range. The incorporation of NH2-MIL-53(Al) as carriers not only improved the MIPs stability and prevented the deformation of the imprinting cavity, but also provided stable emission signals, eliminating the need for complex fluorescence sources preparation. The PDA-based MIPs layer isolated NH2-MIL- 53(Al) from the external interferences, providing selective cavities for improved specificity. Additionally, the functional groups on the surface of PDA-based MIPs facilitated the in-situ reduction of AuNPs to create the SERS substrate. The FL-SERS dual-mode nanoprobe exhibited excellent performance, with limits of detection (LOD) of 2.56 nM for FL mode and 1.3 pM for SERS mode. The imprinting factors were calculated to be 13.15 for FL mode and 6.06 for SERS mode, indicating the strong imprinting efficiency. Moreover, real sample applications demonstrated satisfactory recoveries ranging from 96.38 % to 101.78 %, underscoring the practical utility of the sensor in environmental monitoring. The FL-SERS dual-mode nanoprobe thus holds great potential as a versatile tool for future practical application in the sensitive detection of 4-NP in complex water environment.

Monocarboxylate transporter 1 (MCT1) exhibits essential roles in cellular metabolism and energy supply. Although MCT1 is highly expressed in activated B cells, it is not clear how MCT1-governed monocarboxylates transportation is functionally coupled to antibody production during the glucose metabolism. Here, we report that B cell-lineage deficiency of MCT1 significantly influences the class-switch recombination (CSR), rendering impaired IgG antibody responses in Mct1 f/f Mb1 Cre mice after immunization. Metabolic flux reveals that glucose metabolism is significantly reprogrammed from glycolysis to oxidative phosphorylation in Mct1 -deficient B cells upon activation. Consistently, activation-induced cytidine deaminase (AID), is severely suppressed in Mct1 -deficient B cells due to the decreased level of pyruvate metabolite. Mechanistically, MCT1 is required to maintain the optimal concentration of pyruvate to secure the sufficient acetylation of H3K27 for the elevated transcription of AID in activated B cells. Clinically, we found that MCT1 expression levels are significantly upregulated in systemic lupus erythematosus patients, and Mct1 deficiency can alleviate the symptoms of bm12-induced murine lupus model. Collectively, these results demonstrate that MCT1-mediated pyruvate metabolism is required for IgG antibody CSR through an epigenetic dependent AID transcription, revealing MCT1 as a potential target for vaccine development and SLE disease treatment.

The incidence of intestinal diseases increases with age, yet the mechanisms governing gut aging and its link to diseases, such as colorectal cancer (CRC), remain elusive. In this study, while considering age, sex and proximal–distal variations, we used a multi-omics approach in non-human primates ( Macaca fascicularis ) to shed light on the heterogeneity of intestinal aging and identify potential regulators of gut aging. We explored the roles of several regulators, including those from tryptophan metabolism, in intestinal function and lifespan in Caenorhabditis elegans . Suggesting conservation of region specificity, tryptophan metabolism via the kynurenine and serotonin (5-HT) pathways varied between the proximal and distal colon, and, using a mouse colitis model, we observed that distal colitis was more sensitive to 5-HT treatment. Additionally, using proteomics analysis of human CRC samples, we identified links between gut aging and CRC, with high HPX levels predicting poor prognosis in older patients with CRC. Together, this work provides potential targets for preventing gut aging and associated diseases.

AbstractThe metabolic response to dietary fat intake and its relation with metabolic syndrome (MetS) remains unclear. Here, we identified dietary fat related signature metabolites and characterized their associations with MetS prevalence. We enrolled 236 participants from the Precision Nutrition and Food Safety for Dietary Prevention of Chronic Disease study in China. Nontargeted metabolomics was conducted to investigate plasma metabolome. The signature metabolites in relation to dietary fat intake were assessed using elastic net regression with a 10‐fold cross‐validation. We identified multi‐metabolite profiles comprising of 28, 19, 23, 31, and 25 metabolites, which were robustly correlated with dietary intake of saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids (PUFAs), n − 3 PUFAs, and n − 6 PUFAs, respectively (r = .47–.54; p < .001). After adjustment for potential risk factors, metabolic signatures of PUFAs and n − 3 PUFAs were inversely associated with 31% and 48% lower MetS prevalence, respectively. Dietary intake of n − 3 and n − 6 PUFAs ameliorates key metabolites involved in the glyoxylate and dicarboxylate metabolism, arginine biosynthesis, and tricarboxylic acid cycle. Our findings revealed plasma metabolic signatures characterizing dietary fat intake and supported the beneficial role of PUFAs especially n − 3 PUFAs in MetS prevention.