Recently, there has been a substantial use of phytotherapy to attenuate the metabolic disorders associated with aging induced in animal model. The current research aimed to evaluate the anti-aging activity of Citharexylum spinosum leaves in rats' model. Six extracts of C. spinosum leaves were successively obtained to determine the anti-aging activity of the plant. The cytotoxicity of the six extracts was determined to identify the safe extracts that will be further used to determine their effectiveness as anti-aging in experimental animal model. The extracts n-hexane (n-Hex), n-hexane: benzene (n-Hex: Bz) and chloroform (CHCl3) showed cytotoxic effects on human normal skin fibroplast cell line, however, ethyl acetate (EtOAc), n-butanol (n-BuOH) and Ethanol: H2O 50% (EtOH:H2O 50%) extracts were safe. Rats were injected intraperitoneal (ip) with D-galactose (100 mg/kg b.wt. /daily) for two successive months and post one month were treated (200 mg/kg b. wt./daily) by the three safe extracts; EtOAc, n-BuOH and EtOH: H2O 50%. Biochemical parameters of brain derived neurotrophic factor (BDNF), interleukin-6 (IL-6) and capsular polysaccharides (CPS), neurotransmitters [noradrenaline (NA), dopamine (Dopa) and serotonin (Ser)], oxidative stress markers [malodialdehyde (MDA) and nitric oxide (NO)], nonenzymatic antioxidant of glutathione reduced (GSH) as well as histopathological examination in brain tissue were determined. Significant enhancement in all previous parameters besides, histopathological architectures of brain treated-rats were observed. EtOH: H2O 50% extract gave a higher extraction yield percentage and anti-aging activity than the solvents with lower polarities (n-Hex, n-Hex: Bz 1:1 and CHCl3). The most promising n-BuOH extract's profile showed the presence of variant phytoconstituents analyzed by LC-ESI-TOF-MS for the first time. Administration of n-BuOH may has potent ameliorating effects in revealing symptoms and delaying complication of aging that may be related to their bioactive compounds content of of phenolics and flavonoids. All extracts of C. spinosum leaves with the priority of n-BuOH has improved the disorders in inflammatory markers, CPS, neurotransmitters, oxidative stress markers, nonenzymatic activity as well as the brain architectures of aged rats. The present study showed for the first time the anti-aging activity of these extracts and their roles on brain-gut microbiota CPS.