{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:32:33Z","timestamp":1786627953672,"version":"build-2736575974"},"reference-count":55,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004564","name":"Ministry of Education, Science and Technological Development of the Republic of Serbia","doi-asserted-by":"publisher","award":["451-03-33\/2026-03\/200007"],"award-info":[{"award-number":["451-03-33\/2026-03\/200007"]}],"id":[{"id":"10.13039\/501100004564","id-type":"DOI","asserted-by":"publisher"}]},{"award":["451-03-33\/2026-03\/200007"],"award-info":[{"award-number":["451-03-33\/2026-03\/200007"]}],"id":[{"id":"https:\/\/ror.org\/01znas443","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Caloric restriction (CR) is among the most effective nutritional interventions for promoting healthy aging, yet the influence of intervention duration and age at initiation on its efficacy remains incompletely understood. This study investigated the effects of short-term caloric restriction (STCR) and long-term caloric restriction (LTCR) on frailty and brain redox homeostasis in male Wistar rats. Animals were maintained under ad libitum (AL) feeding, or subjected to LTCR initiated at 6 months of age or STCR initiated at 15 or 21 months, and were sacrificed at 18 or 24 months. Frailty, brain oxidative damage, antioxidant defense, systemic redox status, and the protein expression of key redox-related enzymes were evaluated. Both LTCR and STCR improved frailty and enhanced antioxidant defenses in 18-month-old rats. In contrast, in 24-month-old rats STCR was associated with a pronounced glutathione-related antioxidant response and reduced macromolecular oxidation without improving frailty. Systemic redox indices further supported age-dependent metabolic adaptation rather than a uniform antioxidant effect of CR. Overall, these findings demonstrate that CR is associated with age- and duration-dependent differences in redox-related parameters in the brain tissue. The results indicate differential regulation of antioxidant responses under the experimental conditions applied, while the underlying mechanisms and their functional significance require further investigation.<\/jats:p>","DOI":"10.3390\/ijms27167229","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T12:47:11Z","timestamp":1786625231000},"page":"7229","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Duration of Caloric Restriction Modulates Brain Redox Adaptation and Frailty During Aging"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9799-0335","authenticated-orcid":false,"given":"Desanka","family":"Milanovic","sequence":"first","affiliation":[{"name":"Department of Neurobiology, Institute for Biological Research \u201cSinisa Stankovic\u201d-National Institute of Republic of Serbia, University of Belgrade, Bul. D. Stefana 142, 11060 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5651-7178","authenticated-orcid":false,"given":"Sladjan","family":"Pavlovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Physiology, Institute for Biological Research \u201cSinisa Stankovic\u201d-National Institute of Republic of Serbia, University of Belgrade, Bul. D. Stefana 142, 11060 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milica","family":"Prvulovic","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Institute for Biological Research \u201cSinisa Stankovic\u201d-National Institute of Republic of Serbia, University of Belgrade, Bul. D. Stefana 142, 11060 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4895-9985","authenticated-orcid":false,"given":"Slavica Borkovi\u0107","family":"Miti\u0107","sequence":"additional","affiliation":[{"name":"Department of Physiology, Institute for Biological Research \u201cSinisa Stankovic\u201d-National Institute of Republic of Serbia, University of Belgrade, Bul. D. Stefana 142, 11060 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srdjan","family":"Sokanovic","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Institute for Biological Research \u201cSinisa Stankovic\u201d-National Institute of Republic of Serbia, University of Belgrade, Bul. D. Stefana 142, 11060 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7155-4914","authenticated-orcid":false,"given":"Smilja","family":"Pracer","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Institute for Biological Research \u201cSinisa Stankovic\u201d-National Institute of Republic of Serbia, University of Belgrade, Bul. D. Stefana 142, 11060 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Mladenovic","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Institute for Biological Research \u201cSinisa Stankovic\u201d-National Institute of Republic of Serbia, University of Belgrade, Bul. D. Stefana 142, 11060 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1038\/s41591-019-0673-2","article-title":"Undulating changes in human plasma proteome profiles across the lifespan","volume":"25","author":"Lehallier","year":"2019","journal-title":"Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1038\/s43587-024-00692-2","article-title":"Nonlinear dynamics of multi-omics profiles during human aging","volume":"4","author":"Shen","year":"2024","journal-title":"Nat. Aging"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5763","DOI":"10.1016\/j.cell.2025.06.047","article-title":"Comprehensive human proteome profiles across a 50-year lifespan reveal aging trajectories and signatures","volume":"188","author":"Ding","year":"2025","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/s41586-023-06802-1","article-title":"Organ aging signatures in the plasma proteome track health and disease","volume":"624","author":"Oh","year":"2023","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"14063","DOI":"10.1038\/ncomms14063","article-title":"Caloric restriction improves health and survival of rhesus monkeys","volume":"8","author":"Mattison","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1111\/joim.13530","article-title":"Does diet influence aging? Evidence from animal studies","volume":"295","author":"Raubenheimer","year":"2024","journal-title":"J. Intern. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/s41586-024-08026-3","article-title":"Dietary restriction impacts health and lifespan of genetically diverse mice","volume":"634","author":"Deighan","year":"2024","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Draicchio, F., and Axen, K.V. (2025). Does Energy Restriction and Loss of Body Fat Account for the Effect of Intermittent Fasting on Cognitive Function?. Nutrients, 17.","DOI":"10.3390\/nu17152407"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e13942","DOI":"10.1111\/acel.13942","article-title":"Interactions between mitochondrial dysfunction and other hallmarks of aging: Paving a path toward interventions that promote healthy old age","volume":"23","author":"Li","year":"2024","journal-title":"Aging Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"fcad356","DOI":"10.1093\/braincomms\/fcad356","article-title":"Role of oxidative stress in neurodegenerative disorders: A review of reactive oxygen species and prevention by antioxidants","volume":"6","author":"Houldsworth","year":"2024","journal-title":"Brain Commun."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Trofin, D.M., Sardaru, D.P., Trofin, D., Onu, I., Tutu, A., Onu, A., Onit\u0103, C., Galaction, A.I., and Matei, D.V. (2025). Oxidative Stress in Brain Function. Antioxidants, 14.","DOI":"10.3390\/antiox14030297"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/j.cmet.2018.05.011","article-title":"Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States","volume":"27","author":"Mattson","year":"2018","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.clnesp.2024.06.046","article-title":"Clinical implications of nutritional interventions reducing calories, a systematic scoping review","volume":"63","author":"Oudmaijer","year":"2024","journal-title":"Clin. Nutr. ESPEN"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s10522-021-09918-x","article-title":"Middle aged turn point in parameters of oxidative stress and glucose catabolism in mouse cerebellum during lifespan: Minor effects of every-other-day fasting","volume":"22","author":"Bayliak","year":"2021","journal-title":"Biogerontology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"111182","DOI":"10.1016\/j.exger.2020.111182","article-title":"Middle age as a turning point in mouse cerebral cortex energy and redox metabolism: Modulation by every-other-day fasting","volume":"145","author":"Bayliak","year":"2021","journal-title":"Exp. Gerontol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Teofilovi\u0107, A., Vratari\u0107, M., Veli\u010dkovi\u0107, N., Vojnovi\u0107 Milutinovi\u0107, D., Mladenovic, A., Prvulovic, M., and Djordjevic, A. (2022). Late-Onset Calorie Restriction Improves Lipid Metabolism and Aggravates Inflammation in the Liver of Old Wistar Rats. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.899255"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1097\/WNR.0000000000000107","article-title":"The effects of dietary restriction and aging on amyloid precursor protein and presenilin-1 mRNA and protein expression in rat brain","volume":"25","author":"Perovic","year":"2014","journal-title":"Neuroreport"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s10522-014-9537-9","article-title":"Long-term dietary restriction differentially affects the expression of BDNF and its receptors in the cortex and hippocampus of middle-aged and aged male rats","volume":"16","author":"Smiljanic","year":"2015","journal-title":"Biogerontology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1093\/gerona\/gly015","article-title":"Effects of Different Dietary Protocols on General Activity and Frailty of Male Wistar Rats During Aging","volume":"73","author":"Todorovic","year":"2018","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1093\/gerona\/glab353","article-title":"Late-Onset Calorie Restriction Worsens Cognitive Performances and Increases Frailty Level in Female Wistar Rats","volume":"77","author":"Prvulovic","year":"2022","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"111666","DOI":"10.1016\/j.mad.2022.111666","article-title":"Calorie restriction changes the anxiety-like behaviour of ageing male Wistar rats in an onset- and duration-dependent manner","volume":"204","author":"Prvulovic","year":"2022","journal-title":"Mech. Ageing Dev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"111992","DOI":"10.1016\/j.mad.2024.111992","article-title":"Mitigating the effects of time in the heart and liver: The variable effects of short- and long-term caloric restriction","volume":"222","author":"Prvulovic","year":"2024","journal-title":"Mech. Ageing Dev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1093\/eurheartj\/ehr304","article-title":"Nitric oxide synthases: Regulation and function","volume":"33","author":"Sessa","year":"2012","journal-title":"Eur. Heart J."},{"key":"ref_24","first-page":"4128152","article-title":"Oxidative Stress Indexes for Diagnosis of Health or Disease in Humans","volume":"2019","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.freeradbiomed.2013.05.037","article-title":"The effects of dietary restriction on oxidative stress in rodents","volume":"66","author":"Walsh","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.molcel.2018.03.029","article-title":"SOD1 Phosphorylation by mTORC1 Couples Nutrient Sensing and Redox Regulation","volume":"70","author":"Tsang","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"107485","DOI":"10.1016\/j.cdnut.2025.107485","article-title":"Nutrition and Aging Biology: Summary of a Research Centers Collaborative Network Workshop and Research Needs","volume":"9","author":"Shea","year":"2025","journal-title":"Curr. Dev. Nutr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.neuint.2009.10.008","article-title":"Long-term dietary restriction modulates the level of presynaptic proteins in the cortex and hippocampus of the aging rat","volume":"56","author":"Perovic","year":"2010","journal-title":"Neurochem. Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1111\/acel.12601","article-title":"Molecular and physiological manifestations and measurement of aging in humans","volume":"16","author":"Khan","year":"2017","journal-title":"Aging Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1146\/annurev-nutr-122319-034601","article-title":"Calorie Restriction and Aging in Humans","volume":"40","author":"Flanagan","year":"2020","journal-title":"Annu. Rev. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/s41574-025-01111-1","article-title":"Potential downsides of calorie restriction","volume":"21","author":"Wang","year":"2025","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"B20","DOI":"10.1093\/gerona\/52A.1.B20","article-title":"Influence of fat intake and caloric restriction on bone in aging male rats","volume":"52","author":"Sanderson","year":"1997","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1111\/j.1365-201X.2004.01281.x","article-title":"Effects of ageing on the energy balance of food-restricted rats","volume":"181","author":"Passadore","year":"2004","journal-title":"Acta Physiol. Scand."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.neurobiolaging.2016.03.006","article-title":"The impact of aging, hearing loss, and body weight on mouse hippocampal redox state, measured in brain slices using fluorescence imaging","volume":"42","author":"Stebbings","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1038\/s43587-025-00929-8","article-title":"Dietary patterns and accelerated multimorbidity in older adults","volume":"5","year":"2025","journal-title":"Nat. Aging"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.mad.2019.01.002","article-title":"Brain region-specific effects of long-term caloric restriction on redox balance of the aging rat","volume":"179","author":"Moyse","year":"2019","journal-title":"Mech. Ageing Dev."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kolb, H., Kempf, K., R\u00f6hling, M., Lenzen-Schulte, M., Schloot, N.C., and Martin, S. (2021). Ketone bodies: From enemy to friend and guardian angel. BMC Med., 19.","DOI":"10.1186\/s12916-021-02185-0"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: An expanding universe","volume":"186","author":"Blasco","year":"2023","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1134\/S1819712423030157","article-title":"Metabolic Plasticity in Developing and Aging Brain","volume":"17","author":"Salmina","year":"2023","journal-title":"Neurochem. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.freeradbiomed.2019.10.411","article-title":"INOS as a metabolic enzyme under stress conditions","volume":"146","author":"Anavi","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"105359","DOI":"10.1016\/j.neubiorev.2023.105359","article-title":"The impact of life stress on hallmarks of aging and accelerated senescence: Connections in sickness and in health","volume":"153","author":"Lyons","year":"2023","journal-title":"Neurosci. Biobehav Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1080\/1028415X.2025.2533967","article-title":"Different intermittent fasting regimens decrease anxious and depressive-like behaviour, but show damage to brain tissues in healthy Wistar rats","volume":"28","author":"Soares","year":"2025","journal-title":"Nutr. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"321213","DOI":"10.1155\/2013\/321213","article-title":"Acetylcholinesterase as a biomarker in environmental and occupational medicine: New insights and future perspectives","volume":"2013","author":"Lionetto","year":"2013","journal-title":"BioMed Res. Int."},{"key":"ref_44","first-page":"805","article-title":"Glutathione-peroxidase, glutathione-reductase and glutathione transferase in 2 different hepatomas and in normal liver","volume":"11","author":"Rossi","year":"1983","journal-title":"IRCS Med. Sci.-Biochem."},{"key":"ref_45","first-page":"4233","article-title":"Superoxide dismutase in various tissues from ratbits bearing the Vx-2 carcinoma in the maxillary sinus","volume":"42","author":"Takada","year":"1982","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1093\/clinchem\/46.4.560d","article-title":"Effect of prolonged storage on the activities of superoxide dismutase, glutathione reductase, and glutathione peroxidase","volume":"46","author":"Abiaka","year":"2000","journal-title":"Clin. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1111\/j.1471-4159.1992.tb10990.x","article-title":"Reactive oxygen species and the central nervous system","volume":"59","author":"Halliwell","year":"1992","journal-title":"J. Neurochem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.1016\/S0021-9258(19)45228-9","article-title":"The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase","volume":"247","author":"Misra","year":"1972","journal-title":"J. Biol. Chem."},{"key":"ref_49","unstructured":"Greenwald, R.A. (1985). Catalase activity. Handbook of Methods for Oxygen Radical Research, CRC Press Inc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1093\/oxfordjournals.jbchem.a134017","article-title":"Some characteristics of hydrogen- and alkylhydroperoxides metabolizing systems in cardiac tissue","volume":"92","author":"Tamura","year":"1982","journal-title":"J. Biochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/BF01921531","article-title":"Glutathione reductase test with whole blood, a convenient procedure for the assessment of the riboflavin status in humans","volume":"30","author":"Glatzle","year":"1974","journal-title":"Experientia"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"7130","DOI":"10.1016\/S0021-9258(19)42083-8","article-title":"Glutathione S-transferases. The first enzymatic step in mercapturic acid formation","volume":"249","author":"Habig","year":"1974","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1111\/j.1471-4159.1980.tb11254.x","article-title":"Peroxidative changes in brain cortical fatty acids and phospholipids, as characterized during Fe2+- and ascorbic acid-stimulated lipid peroxidation in vitro","volume":"34","author":"Rehncrona","year":"1980","journal-title":"J. Neurochem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ab.2014.04.034","article-title":"Simplified 2,4-dinitrophenylhydrazine spectrophotometric assay for quantification of carbonyls in oxidized proteins","volume":"458","author":"Mesquita","year":"2014","journal-title":"Anal. Biochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"113608","DOI":"10.1016\/j.ab.2020.113608","article-title":"A systematic approach to quantitative Western blot analysis","volume":"593","author":"Harford","year":"2020","journal-title":"Anal. Biochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7229\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T12:47:28Z","timestamp":1786625248000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7229"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":55,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27167229"],"URL":"https:\/\/doi.org\/10.3390\/ijms27167229","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]}}}