Young blood exposure reverses age-related cognitive impairments and synaptic plasticity deficits in aged mice. The study demonstrates that exposure of aged animals to young blood can counteract and reverse the effects of brain aging at the molecular, structural, functional, and cognitive levels. Genome-wide microarray analysis of heterochronic parabionts—animals with connected circulatory systems—revealed transcriptional changes in the hippocampus of aged mice related to synaptic plasticity. Dendritic spine density in mature neurons increased, and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. Systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. These effects are partially mediated by the activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Aging leads to cognitive impairments and susceptibility to degenerative disorders by structurally and functionally altering the adult brain. Exposure to young blood through heterochronic parabiosis improves stem cell function in various tissues and ameliorates cardiac hypertrophy in aged animals. However, whether young blood enhances cognitive function beyond regeneration in the aged brain remains unclear. The hippocampus is particularly vulnerable to aging, showing downregulation of plasticity-related genes, reduced spine density, and impaired cognitive functions. Genome-wide microarray analysis of hippocampi from aged isochronic and heterochronic parabionts identified synaptic plasticity regulation as a top gene ontology enrichment category. Ingenuity Pathway Analysis detected prominent involvement of plasticity-related signaling pathways, including Creb, in the top-signaling network. Immunohistochemistry revealed increased expression of immediate early genes Egr1 and c-Fos, and phosphorylated Creb in the dentate gyrus of heterochronic parabionts compared to isochronic parabionts. Structural and functional analyses showed increased dendritic spine density and enhanced synaptic plasticity in the hippocampus of heterochronic parabionts. Functional electrophysiological recordings demonstrated that long-term potentiation (LTP) in the hippocampus of heterochronic parabionts was maintained above baseline levels, indicating enhanced synaptic plasticity. Behavioral tests confirmed that systemic administration of young blood plasma improved hippocampal-dependent learning and memory in aged mice. These cognitive improvements were partially mediated by Creb signaling. Mechanistically, the study identified Creb as a key regulator of structural and cognitive enhancements by young blood. The findings suggest that introducing 'pro-youthful' factors from young blood can reverse age-related impairments in the brain, and abrogating pro-aging factors from aged blood can counteract such impairments. These two possibilities are not mutually exclusive and warrant further investigation. The study highlights the potential of young blood to rejuvenate cognitive function in aged individuals, although results are currently limited to aged mice. Future studies in humans and those with age-related neuroYoung blood exposure reverses age-related cognitive impairments and synaptic plasticity deficits in aged mice. The study demonstrates that exposure of aged animals to young blood can counteract and reverse the effects of brain aging at the molecular, structural, functional, and cognitive levels. Genome-wide microarray analysis of heterochronic parabionts—animals with connected circulatory systems—revealed transcriptional changes in the hippocampus of aged mice related to synaptic plasticity. Dendritic spine density in mature neurons increased, and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. Systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. These effects are partially mediated by the activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Aging leads to cognitive impairments and susceptibility to degenerative disorders by structurally and functionally altering the adult brain. Exposure to young blood through heterochronic parabiosis improves stem cell function in various tissues and ameliorates cardiac hypertrophy in aged animals. However, whether young blood enhances cognitive function beyond regeneration in the aged brain remains unclear. The hippocampus is particularly vulnerable to aging, showing downregulation of plasticity-related genes, reduced spine density, and impaired cognitive functions. Genome-wide microarray analysis of hippocampi from aged isochronic and heterochronic parabionts identified synaptic plasticity regulation as a top gene ontology enrichment category. Ingenuity Pathway Analysis detected prominent involvement of plasticity-related signaling pathways, including Creb, in the top-signaling network. Immunohistochemistry revealed increased expression of immediate early genes Egr1 and c-Fos, and phosphorylated Creb in the dentate gyrus of heterochronic parabionts compared to isochronic parabionts. Structural and functional analyses showed increased dendritic spine density and enhanced synaptic plasticity in the hippocampus of heterochronic parabionts. Functional electrophysiological recordings demonstrated that long-term potentiation (LTP) in the hippocampus of heterochronic parabionts was maintained above baseline levels, indicating enhanced synaptic plasticity. Behavioral tests confirmed that systemic administration of young blood plasma improved hippocampal-dependent learning and memory in aged mice. These cognitive improvements were partially mediated by Creb signaling. Mechanistically, the study identified Creb as a key regulator of structural and cognitive enhancements by young blood. The findings suggest that introducing 'pro-youthful' factors from young blood can reverse age-related impairments in the brain, and abrogating pro-aging factors from aged blood can counteract such impairments. These two possibilities are not mutually exclusive and warrant further investigation. The study highlights the potential of young blood to rejuvenate cognitive function in aged individuals, although results are currently limited to aged mice. Future studies in humans and those with age-related neuro