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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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.).

Author information

Author notes

    • Kristopher E Plambeck
    • , Jinte Middeldorp
    • , Joseph M Castellano
    •  & Kira I Mosher

    These authors contributed equally to this work.


  1. Department of Anatomy, University of California San Francisco, San Francisco, California, USA.

    • Saul A Villeda
    • , Kristopher E Plambeck
    • , Lucas K Smith
    • , Gregor Bieri
    • , Karin Lin
    • , Joe Udeochu
    •  & Elizabeth G Wheatley
  2. The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA.

    • Saul A Villeda
    • , Kristopher E Plambeck
    • , Lucas K Smith
    • , Gregor Bieri
    • , Karin Lin
    • , Joe Udeochu
    •  & Elizabeth G Wheatley
  3. Neuroscience Graduate Program, University of California San Francisco, San Francisco, California, USA.

    • Saul A Villeda
    •  & Karin Lin
  4. Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, California, USA.

    • Saul A Villeda
    •  & Joe Udeochu
  5. Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, California, USA.

    • Saul A Villeda
    •  & Elizabeth G Wheatley
  6. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.

    • Saul A Villeda
    • , Jinte Middeldorp
    • , Joseph M Castellano
    • , Kira I Mosher
    • , Jian Luo
    • , Gregor Bieri
    • , Daniela Berdnik
    • , Rafael Wabl
    • , Danielle A Simmons
    • , Frank M Longo
    •  & Tony Wyss-Coray
  7. Neuroscience Graduate Program, Stanford University School of Medicine, Stanford, California, USA.

    • Kira I Mosher
    • , Gregor Bieri
    •  & Tony Wyss-Coray
  8. AfaSci Research Laboratory, Redwood City, California, USA.

    • Bende Zou
    •  & Xinmin S Xie
  9. Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System, Palo Alto, California, USA.

    • Tony Wyss-Coray


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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.

Competing interests

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

Corresponding authors

Correspondence to Saul A Villeda or Tony Wyss-Coray.

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