Saul A Villeda1–6, Kristopher E Plambeck1,2,10, Jinte Middeldorp6,10, Joseph M Castellano6,10, Kira I Mosher6,7,10, Jian Luo6, Lucas K Smith1,2, Gregor Bieri1,2,6,7, Karin Lin1–3, Daniela Berdnik6, Rafael Wabl6, Joe Udeochu1,2,4, Elizabeth G Wheatley1,2,5, Bende Zou8, Danielle A Simmons6, Xinmin S Xie8, Frank M Longo6 & Tony Wyss-Coray6,7,9
As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging1,2. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts—in which circulatory systems of young and aged animals are connected—identified synaptic plasticity–related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function. Aging drives cognitive impairments and susceptibility to degenerative disorders in healthy individuals3–6 by structurally and functionally changing the adult brain3,7–13. Considering the increase in the proportion of elderly humans1,2, it is important to identify a means for maintaining cognitive integrity by protecting against, or even counteracting, the aging process. In aged animals, exposure to young blood through heterochronic parabiosis improves stem cell function in muscle14,15, liver14, spinal cord16 and the brain12 and ameliorates cardiac hypertrophy17. However, whether enhancements of young blood extend beyond regeneration in the aged brain is unknown, raising the question of whether young blood can counteract aging and rejuvenate cognitive processes. In humans and mice, the hippocampus is particularly vulnerable to aging, exhibiting downregulation of plasticity-related genes, reduced spine density, decreased synaptic plasticity and impairments in associated cognitive functions3–13,18–20. We first performed genome-wide microarray analysis of hippocampi from aged (18 months) isochronic (aged-aged) and aged (18 months) heterochronic (aged-young) parabionts (Fig. 1a). We observed a distinct gene expression profile between the two parabiont groups (Fig. 1c and Supplementary Table 1) and identified synaptic plasticity regulation as one of the top gene ontology enrichment categories associated with heterochronic parabiosis. Furthermore, Ingenuity Pathway Analysis (IPA) detected prominent involvement of plasticity-related signaling pathways, including Creb21, in the top-signaling network (Fig. 1b). Together our data reveal a transcriptional profile that is indicative of plasticity changes in heterochronic parabionts. We then used immunohistochemistry to examine a subset of identified genes in a second cohort of parabionts (Fig. 1d–g). We observed increased numbers of cells expressing the immediate early genes Egr1 (Fig. 1d,e) and c-Fos (Fig. 1d,f) and a corresponding increase in phosphorylated Creb (Fig. 1d,g) in the dentate gyrus (DG) of heterochronic compared to isochronic parabionts. Although we observed increased phosphorylated Creb in the CA1 region, we detected no changes in immediate early genes in heterochronic parabionts (Supplementary Fig. 1a–c). We confirmed age-related differences in immediate early gene expression and Creb phosphorylation between young and aged unpaired animals (Supplementary Fig. 2). Molecular changes were not elicited by the parabiosis procedure (Supplementary Fig. 1d–i), and we observed no differences in general health, maintenance behavior or stress responses between.
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