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Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice

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Abstract

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.

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Figure 1: Heterochronic parabiosis enhances dendritic spine number and synaptic plasticity in the aged hippocampus and elicits a plasticity-related expression profile.
Figure 2: Administration of young blood plasma improves hippocampal-dependent learning and memory in aged mice.
Figure 3: Creb mediates the enhancements in dendritic spine number and hippocampal-dependent learning and memory elicited by young blood in aged mice.

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Acknowledgements

We thank A. Eggel, K. Lucin and N. Woodling for critical review and advice, and D. Jing and F. Lee (Cornell University) for Golgi stain reagents. This work was funded by California Institute for Regenerative Medicine (CIRM) fellowships (K.E.P. and K.L.), a Netherlands Organization for Scientific Research (NWO) Rubicon fellowship (J.M.), a Child Health Research Institute fellowship (Stanford National Institutes of Health (NIH)/National Center for Research Resources CTSA-UL1-RR025744, J.M.C.), a Jane Coffin Childs fellowship (J.M.C.), National Science Foundation fellowships (K.I.M. and J.U.), a National Research Service Award fellowship (1F31-AG034045-01, S.A.V.), anonymous (T.W.-C.), Veterans Affairs (T.W.-C.), the National Institute on Aging (AG045034, AG03144, T.W.-C.), CIRM (T.W.-C.), the University of California San Francisco (UCSF) Program for Breakthrough Biomedical Research, the Sandler Foundation (S.A.V.), the UCSF Clinical and Translational Science Institute (UL1-TR000004, S.A.V.) and an NIH Director's Independence Award (DP5-OD12178, S.A.V.).

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Contributions

S.A.V., K.E.P., J.M., J.M.C., K.I.M., J.L., L.K.S. and K.L. performed parabiosis. S.A.V., K.I.M., G.B. and D.B. performed and/or analyzed microarray. S.A.V., K.E.P., R.W. and E.G.W. performed histological studies. J.M. and D.A.S. performed Golgi studies. B.Z. and X.S.X. performed electrophysiological studies. S.A.V., K.E.P., J.M.C., J.L., L.K.S., G.B., K.L. and J.U. performed plasma cognitive studies. J.M.C. performed maintenance and stress studies. J.M.C. and S.A.V. performed the denaturation study. K.E.P. and G.B. generated viral constructs. K.E.P. performed viral studies. F.M.L. provided reagents. S.A.V. and T.W.-C. designed and supervised the study and wrote the manuscript.

Corresponding authors

Correspondence to Saul A Villeda or Tony Wyss-Coray.

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T.W.-C. has formed a company that follows up on the work described here.

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Villeda, S., Plambeck, K., Middeldorp, J. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 20, 659–663 (2014). https://doi.org/10.1038/nm.3569

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