{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:33:59Z","timestamp":1789605239716,"version":"build-2803163510"},"reference-count":66,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,10,26]],"date-time":"2023-10-26T00:00:00Z","timestamp":1698278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["BE2376\/8-1"],"award-info":[{"award-number":["BE2376\/8-1"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["CA1708\/1-1"],"award-info":[{"award-number":["CA1708\/1-1"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["P35271"],"award-info":[{"award-number":["P35271"]}]},{"name":"Herzfelder Family Foundation\/Austrian Science Fund FWF","award":["BE2376\/8-1"],"award-info":[{"award-number":["BE2376\/8-1"]}]},{"name":"Herzfelder Family Foundation\/Austrian Science Fund FWF","award":["CA1708\/1-1"],"award-info":[{"award-number":["CA1708\/1-1"]}]},{"name":"Herzfelder Family Foundation\/Austrian Science Fund FWF","award":["P35271"],"award-info":[{"award-number":["P35271"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>L-Citrulline (L-Cit) is discussed to possess a protective effect on intestinal barrier dysfunction but also to diminish aging-associated degenerative processes. Here, the effects of L-Cit on lifespan were assessed in C. elegans, while the effects of L-Cit on aging-associated decline were determined in C57BL\/6J mice. For lifespan analysis, C. elegans were treated with \u00b15 mM L-Cit. Twelve-month-old male C57BL\/6J mice (n = 8\u201310\/group) fed a standard chow diet received drinking water \u00b1 2.5 g\/kg\/d L-Cit or 5 g\/kg\/d hydrolyzed soy protein (Iso-N-control) for 16 or 32 weeks. Additionally, 4-month-old C57BL\/6J mice were treated accordingly for 8 weeks. Markers of senescence, glucose tolerance, intestinal barrier function, and intestinal microbiota composition were analyzed in mice. L-Cit treatment significantly extended the lifespan of C. elegans. The significant increase in markers of senescence and signs of impaired glucose tolerance found in 16- and 20-month-old control mice was attenuated in L-Cit-fed mice, which was associated with protection from intestinal barrier dysfunction and a decrease in NO2\u2212 levels in the small intestine, while no marked differences in intestinal microbiota composition were found when comparing age-matched groups. Our results suggest that pharmacological doses of L-Cit may have beneficial effects on lifespan in C. elegans and aging-associated decline in mice.<\/jats:p>","DOI":"10.3390\/biom13111579","type":"journal-article","created":{"date-parts":[[2023,10,26]],"date-time":"2023-10-26T06:20:16Z","timestamp":1698301216000},"page":"1579","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Supplementing L-Citrulline Can Extend Lifespan in C. elegans and Attenuate the Development of Aging-Related Impairments of Glucose Tolerance and Intestinal Barrier in Mice"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6844-8878","authenticated-orcid":false,"given":"Dragana","family":"Rajcic","sequence":"first","affiliation":[{"name":"Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Kromm","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9980-4695","authenticated-orcid":false,"given":"Ang\u00e9lica","family":"Hern\u00e1ndez-Arriaga","sequence":"additional","affiliation":[{"name":"Institute of Animal Science, University of Hohenheim, 70593 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3934-747X","authenticated-orcid":false,"given":"Annette","family":"Brandt","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Baumann","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphaela","family":"Staltner","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7814-6569","authenticated-orcid":false,"given":"Am\u00e9lia","family":"Camarinha-Silva","sequence":"additional","affiliation":[{"name":"Institute of Animal Science, University of Hohenheim, 70593 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ina","family":"Bergheim","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,26]]},"reference":[{"key":"ref_1","unstructured":"Geneva: World Health Organization (2023, March 14). Decade of Healthy Ageing: Baseline Report. Available online: https:\/\/www.who.int\/publications\/i\/item\/9789240017900."},{"key":"ref_2","unstructured":"GBD 2019 Demographics Collaborators (2020). Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019: A comprehensive demographic analysis for the Global Burden of Disease Study 2019. Lancet, 396, 1160\u20131203."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"R741","DOI":"10.1016\/j.cub.2012.07.024","article-title":"Ageing as a risk factor for disease","volume":"22","author":"Niccoli","year":"2012","journal-title":"Curr. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s41582-019-0244-7","article-title":"Ageing as a risk factor for neurodegenerative disease","volume":"15","author":"Hou","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_5","unstructured":"Geneva: World Health Organization (2023, March 02). World Health Statistics 2022. Available online: https:\/\/www.who.int\/news\/item\/20-05-2022-world-health-statistics-2022."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3685","DOI":"10.2174\/0929867326666190717152739","article-title":"From Healthy Aging to Frailty: In Search of the Underlying Mechanisms","volume":"26","author":"Brivio","year":"2019","journal-title":"Curr. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"Blasco","year":"2013","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1093\/gerona\/glu057","article-title":"Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases","volume":"69","author":"Franceschi","year":"2014","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1055\/s-0034-1384635","article-title":"Plasminogen activator inhibitor-1 in aging","volume":"40","author":"Yamamoto","year":"2014","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.arr.2008.07.002","article-title":"Molecular inflammation: Underpinnings of aging and age-related diseases","volume":"8","author":"Chung","year":"2009","journal-title":"Ageing Res. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"586","DOI":"10.3389\/fimmu.2018.00586","article-title":"Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines","volume":"9","author":"Rea","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Baumann, A., Hernandez-Arriaga, A., Brandt, A., Sanchez, V., Nier, A., Jung, F., Kehm, R., Hohn, A., Grune, T., and Frahm, C. (2021). Microbiota profiling in aging-associated inflammation and liver degeneration. Int. J. Med. Microbiol., 311.","DOI":"10.1016\/j.ijmm.2021.151500"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Odamaki, T., Kato, K., Sugahara, H., Hashikura, N., Takahashi, S., Xiao, J.Z., Abe, F., and Osawa, R. (2016). Age-related changes in gut microbiota composition from newborn to centenarian: A cross-sectional study. BMC Microbiol., 16.","DOI":"10.1186\/s12866-016-0708-5"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Brandt, A., Baumann, A., Hernandez-Arriaga, A., Jung, F., Nier, A., Staltner, R., Rajcic, D., Schmeer, C., Witte, O.W., and Wessner, B. (2022). Impairments of intestinal arginine and NO metabolisms trigger aging-associated intestinal barrier dysfunction and \u2018inflammaging\u2019. Redox Biol., 58.","DOI":"10.1016\/j.redox.2022.102528"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"134049","DOI":"10.1172\/jci.insight.134049","article-title":"Intestinal alkaline phosphatase targets the gut barrier to prevent aging","volume":"5","author":"Kuhn","year":"2020","journal-title":"JCI Insight"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"G736","DOI":"10.1152\/ajpgi.00345.2018","article-title":"Aging-related liver degeneration is associated with increased bacterial endotoxin and lipopolysaccharide binding protein levels","volume":"318","author":"Jin","year":"2020","journal-title":"Am. J. Physiol. Gastrointest Liver Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1128\/cdli.1.6.684-688.1994","article-title":"Endotoxin levels in sera of elderly individuals","volume":"1","author":"Goto","year":"1994","journal-title":"Clin. Diagn. Lab. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"111036","DOI":"10.1016\/j.exger.2020.111036","article-title":"High intensity interval training combined with L-citrulline supplementation: Effects on physical performance in healthy older adults","volume":"140","author":"Buckinx","year":"2020","journal-title":"Exp. Gerontol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.clnu.2011.06.005","article-title":"Oral citrulline does not affect whole body protein metabolism in healthy human volunteers: Results of a prospective, randomized, double-blind, cross-over study","volume":"30","author":"Thibault","year":"2011","journal-title":"Clin. Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"E71","DOI":"10.1152\/ajpendo.00096.2014","article-title":"Citrulline does not enhance blood flow, microvascular circulation, or myofibrillar protein synthesis in elderly men at rest or following exercise","volume":"307","author":"Cotie","year":"2014","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.3945\/jn.114.200626","article-title":"Citrulline Supplementation Induces Changes in Body Composition and Limits Age-Related Metabolic Changes in Healthy Male Rats","volume":"145","author":"Moinard","year":"2015","journal-title":"J. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.biochi.2016.10.020","article-title":"Nitric oxide production by peritoneal macrophages from aged rats: A short term and direct modulation by citrulline","volume":"133","author":"Breuillard","year":"2017","journal-title":"Biochimie"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Maric, S., Restin, T., Muff, J.L., Camargo, S.M., Guglielmetti, L.C., Holland-Cunz, S.G., Crenn, P., and Vuille-Dit-Bille, R.N. (2021). Citrulline, Biomarker of Enterocyte Functional Mass and Dietary Supplement. Metabolism, Transport, and Current Evidence for Clinical Use. Nutrients, 13.","DOI":"10.3390\/nu13082794"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1007\/s00394-016-1287-9","article-title":"Oral citrulline supplementation protects female mice from the development of non-alcoholic fatty liver disease (NAFLD)","volume":"56","author":"Sellmann","year":"2017","journal-title":"Eur. J. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1017\/S0007114516001793","article-title":"Preventive effects of citrulline on Western diet-induced non-alcoholic fatty liver disease in rats","volume":"116","author":"Jegatheesan","year":"2016","journal-title":"Br. J. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Edwards, C., Canfield, J., Copes, N., Brito, A., Rehan, M., Lipps, D., Brunquell, J., Westerheide, S.D., and Bradshaw, P.C. (2015). Mechanisms of amino acid-mediated lifespan extension in Caenorhabditis elegans. BMC Genet., 16.","DOI":"10.1186\/s12863-015-0167-2"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"155233","DOI":"10.1016\/j.metabol.2022.155233","article-title":"GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease","volume":"133","author":"Baumann","year":"2022","journal-title":"Metabolism"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Rajcic, D., Baumann, A., Hernandez-Arriaga, A., Brandt, A., Nier, A., Jin, C.J., Sanchez, V., Jung, F., Camarinha-Silva, A., and Bergheim, I. (2021). Citrulline supplementation attenuates the development of non-alcoholic steatohepatitis in female mice through mechanisms involving intestinal arginase. Redox Biol., 41.","DOI":"10.1016\/j.redox.2021.101879"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1038\/labinvest.2012.75","article-title":"Metformin protects against the development of fructose-induced steatosis in mice: Role of the intestinal barrier function","volume":"92","author":"Spruss","year":"2012","journal-title":"Lab. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1002\/elps.202200222","article-title":"Western blot normalization: Time to choose a proper loading control seriously","volume":"44","author":"Wang","year":"2023","journal-title":"Electrophoresis"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Jung, F., Burger, K., Staltner, R., Brandt, A., Mueller, S., and Bergheim, I. (2021). Markers of Intestinal Permeability Are Rapidly Improved by Alcohol Withdrawal in Patients with Alcohol-Related Liver Disease. Nutrients, 13.","DOI":"10.3390\/nu13051659"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6668","DOI":"10.1038\/s41598-019-43228-0","article-title":"Metformin attenuates the onset of non-alcoholic fatty liver disease and affects intestinal microbiota and barrier in small intestine","volume":"9","author":"Brandt","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5112","DOI":"10.1128\/AEM.01043-13","article-title":"Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform","volume":"79","author":"Kozich","year":"2013","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_34","unstructured":"Clarke, K., and Gorley, R. (2015). PRIMER-E192, PRIMER-E Ltd."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1161\/ATVBAHA.117.309451","article-title":"Plasminogen Activator Inhibitor-1 Is a Marker and a Mediator of Senescence","volume":"37","author":"Vaughan","year":"2017","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"S58","DOI":"10.1123\/ijsnem.11.s1.s58","article-title":"Overview of glucose metabolism and aging","volume":"11","author":"Holloszy","year":"2001","journal-title":"Int. J. Sport Nutr. Exerc. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Brandt, A., Kromm, F., Hernandez-Arriaga, A., Martinez Sanchez, I., Bozkir, H.O., Staltner, R., Baumann, A., Camarinha-Silva, A., Heijtz, R.D., and Bergheim, I. (2023). Cognitive Alterations in Old Mice Are Associated with Intestinal Barrier Dysfunction and Induced Toll-like Receptor 2 and 4 Signaling in Different Brain Regions. Cells, 12.","DOI":"10.3390\/cells12172153"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Uyanga, V.A., Amevor, F.K., Liu, M., Cui, Z., Zhao, X., and Lin, H. (2021). Potential Implications of Citrulline and Quercetin on Gut Functioning of Monogastric Animals and Humans: A Comprehensive Review. Nutrients, 13.","DOI":"10.3390\/nu13113782"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.ebiom.2019.04.005","article-title":"The impact of dietary protein intake on longevity and metabolic health","volume":"43","author":"Kitada","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Pervin, M., Unno, K., Konishi, T., and Nakamura, Y. (2021). L-Arginine Exerts Excellent Anti-Stress Effects on Stress-Induced Shortened Lifespan, Cognitive Decline and Depression. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020508"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"582155","DOI":"10.3389\/fphar.2020.582155","article-title":"Detrimental Effects of Chronic L-Arginine Rich Food on Aging Kidney","volume":"11","author":"Huang","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2147\/JHC.S239039","article-title":"Exploring Metabolic Consequences of CPS1 and CAD Dysregulation in Hepatocellular Carcinoma by Network Reconstruction","volume":"7","author":"Dumenci","year":"2020","journal-title":"J. Hepatocell. Carcinoma"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"596","DOI":"10.3945\/jn.116.240382","article-title":"Supplemental Citrulline Is More Efficient Than Arginine in Increasing Systemic Arginine Availability in Mice","volume":"147","author":"Agarwal","year":"2017","journal-title":"J. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Nyawose, S., Naidoo, R., Naumovski, N., and McKune, A.J. (2022). The Effects of Consuming Amino Acids L-Arginine, L-Citrulline (and Their Combination) as a Beverage or Powder, on Athletic and Physical Performance: A Systematic Review. Beverages, 8.","DOI":"10.3390\/beverages8030048"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Khalaf, D., Kruger, M., Wehland, M., Infanger, M., and Grimm, D. (2019). The Effects of Oral l-Arginine and l-Citrulline Supplementation on Blood Pressure. Nutrients, 11.","DOI":"10.3390\/nu11071679"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Vigne, P., and Frelin, C. (2008). The role of polyamines in protein-dependent hypoxic tolerance of Drosophila. BMC Physiol., 8.","DOI":"10.1186\/1472-6793-8-22"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.mad.2007.05.008","article-title":"Diet dependent longevity and hypoxic tolerance of adult Drosophila melanogaster","volume":"128","author":"Vigne","year":"2007","journal-title":"Mech. Ageing Dev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1002\/jcsm.12435","article-title":"Citrulline stimulates muscle protein synthesis, by reallocating ATP consumption to muscle protein synthesis","volume":"10","author":"Goron","year":"2019","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1017\/thg.2017.36","article-title":"Plasminogen Activator Inhibitor-1 is Regulated through Dietary Fat Intake and Heritability: Studies in Twins","volume":"20","author":"Engstler","year":"2017","journal-title":"Twin Res. Hum. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1038\/ejcn.2011.102","article-title":"A diet rich in oat bran improves blood lipids and hemostatic factors, and reduces apparent energy digestibility in young healthy volunteers","volume":"65","author":"Kristensen","year":"2011","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Martinez-Garcia, M.A., Moncayo, S., Insenser, M., Alvarez-Blasco, F., Luque-Ramirez, M., and Escobar-Morreale, H.F. (2019). Metabolic Cytokines at Fasting and During Macronutrient Challenges: Influence of Obesity, Female Androgen Excess and Sex. Nutrients, 11.","DOI":"10.3390\/nu11112566"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s12979-016-0076-x","article-title":"Interleukin-6 and C-reactive protein, successful aging, and mortality: The PolSenior study","volume":"13","author":"Owczarz","year":"2016","journal-title":"Immun. Ageing"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"14799","DOI":"10.1021\/bi970946u","article-title":"A unique transcription factor for the A alpha fibrinogen gene is related to the mitochondrial single-stranded DNA binding protein P16","volume":"36","author":"Liu","year":"1997","journal-title":"Biochemistry"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1014661","DOI":"10.3389\/fonc.2022.1014661","article-title":"Associations between exercise capacity, p16(INK4a) expression and inflammation among adult survivors of childhood cancer","volume":"12","author":"Goodenough","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"679492","DOI":"10.3389\/fendo.2021.679492","article-title":"Aging Reduces Insulin Clearance in Mice","volume":"12","author":"Marmentini","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.1096\/fasebj.2.12.3044905","article-title":"Aging and glucose homeostasis in C57BL\/6J male mice","volume":"2","author":"Leiter","year":"1988","journal-title":"FASEB J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1113\/EP088109","article-title":"l-Citrulline supplementation improves glucose and exercise tolerance in obese male mice","volume":"105","author":"Eshreif","year":"2020","journal-title":"Exp. Physiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/s13098-021-00669-w","article-title":"The effects of citrulline supplementation on meta-inflammation and insulin sensitivity in type 2 diabetes: A randomized, double-blind, placebo-controlled trial","volume":"13","author":"Abbaszadeh","year":"2021","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1016\/j.celrep.2015.08.004","article-title":"Distinct Shifts in Microbiota Composition during Drosophila Aging Impair Intestinal Function and Drive Mortality","volume":"12","author":"Clark","year":"2015","journal-title":"Cell Rep."},{"key":"ref_60","first-page":"7404","article-title":"Gut microbiota and aging","volume":"22","author":"Mangiola","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1093\/gerona\/glz263","article-title":"Aging Increases the Severity of Colitis and the Related Changes to the Gut Barrier and Gut Microbiota in Humans and Mice","volume":"75","author":"Liu","year":"2020","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Parker, A., Romano, S., Ansorge, R., Aboelnour, A., Le Gall, G., Savva, G.M., Pontifex, M.G., Telatin, A., Baker, D., and Jones, E. (2022). Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain. Microbiome, 10.","DOI":"10.1186\/s40168-022-01243-w"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1177\/0148607111414024","article-title":"Pretreatment with citrulline improves gut barrier after intestinal obstruction in mice","volume":"36","author":"Batista","year":"2012","journal-title":"J. Parenter. Enteral. Nutr."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1007\/s00421-017-3582-4","article-title":"Intestinal fatty acid-binding protein and gut permeability responses to exercise","volume":"117","author":"March","year":"2017","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e13572","DOI":"10.1111\/apha.13572","article-title":"Endogenous flux of nitric oxide: Citrulline is preferred to Arginine","volume":"231","author":"Bahadoran","year":"2021","journal-title":"Acta Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Wijnands, K.A., Vink, H., Briede, J.J., van Faassen, E.E., Lamers, W.H., Buurman, W.A., and Poeze, M. (2012). Citrulline a more suitable substrate than arginine to restore NO production and the microcirculation during endotoxemia. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037439"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/11\/1579\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:12:04Z","timestamp":1760130724000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/11\/1579"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,26]]},"references-count":66,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["biom13111579"],"URL":"https:\/\/doi.org\/10.3390\/biom13111579","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,26]]}}}