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Numerous studies have supported its protective role in neurodegenerative diseases, yet the research for its therapeutic utility in D-galactose (D-gal)-induced brain ageing is still lacking. In this study, the potential neuroprotective impact of luteolin against D-gal-induced brain ageing was explored. Forty rats were randomly divided into four groups: control, luteolin, D-gal, and luteolin-administered D-gal groups. All groups were subjected to behavioural, cholinergic function, and hippocampal mitochondrial respiration assessments. Hippocampal oxidative, neuro-inflammatory, senescence and apoptotic indicators were detected. Gene expressions of SIRT1, BDNF, and RAGE were assessed. Hippocampal histopathological studies, along with GFAP and Ki67 immunoreactivity, were performed. Our results demonstrated that luteolin effectively alleviated D-gal-induced cognitive impairment and reversed cholinergic abnormalities. Furthermore, luteolin administration substantially mitigated hippocampus oxidative stress, mitochondrial dysfunction, neuro-inflammation, and senescence triggered by D-gal. Additionally, luteolin treatment considerably attenuated neuronal apoptosis and upregulated hippocampal SIRT1 mRNA expression. In conclusion, our findings revealed that luteolin administration attenuated D-gal-evoked brain senescence, improving mitochondrial function and enhancing hippocampal neuroregeneration in an ageing rat model through its antioxidant, senolytic, anti-inflammatory, and anti-apoptotic impacts, possibly due to upregulation of SIRT1. Luteolin could be a promising therapeutic modality for brain aging-associated abnormalities.<\/jats:p>","DOI":"10.1007\/s11064-024-04203-y","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T02:01:42Z","timestamp":1720663302000},"page":"2803-2820","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Luteolin Mitigates D-Galactose-Induced Brain Ageing in Rats: SIRT1-Mediated Neuroprotection"],"prefix":"10.1007","volume":"49","author":[{"given":"Reham L","family":"Younis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6106-3051","authenticated-orcid":false,"given":"Rehab M","family":"El-Gohary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5075-7624","authenticated-orcid":false,"given":"Asmaa A","family":"Ghalwash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1469-1941","authenticated-orcid":false,"given":"Islam Ibrahim","family":"Hegab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7609-6817","authenticated-orcid":false,"given":"Maram M","family":"Ghabrial","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azza M","family":"Aboshanady","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9316-8758","authenticated-orcid":false,"given":"Raghad A","family":"Mostafa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9209-3432","authenticated-orcid":false,"given":"Alaa H. 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