Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , , & Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch. Neurol. 60, 1119–1122 (2003).

  2. 2.

    , & Neural mechanisms of ageing and cognitive decline. Nature 464, 529–535 (2010).

  3. 3.

    & Insights into the ageing mind: a view from cognitive neuroscience. Nat. Rev. Neurosci. 5, 87–96 (2004).

  4. 4.

    , , , & Neuroanatomical correlates of cognitive aging: evidence from structural magnetic resonance imaging. Neuropsychology 12, 95–114 (1998).

  5. 5.

    & Ageing and neuronal vulnerability. Nat. Rev. Neurosci. 7, 278–294 (2006).

  6. 6.

    & Memory systems in normal and pathological aging. Curr. Opin. Neurol. 7, 294–298 (1994).

  7. 7.

    et al. Disruption of large-scale brain systems in advanced aging. Neuron 56, 924–935 (2007).

  8. 8.

    , , , & Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68, 1501–1508 (2007).

  9. 9.

    , , , & Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments. J. Neurosci. 24, 7648–7653 (2004).

  10. 10.

    , , , & Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats. J. Neurosci. 20, 6587–6593 (2000).

  11. 11.

    & The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat. Rev. Neurosci. 13, 240–250 (2012).

  12. 12.

    et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011).

  13. 13.

    et al. Molecular mechanism for age-related memory loss: the histone-binding protein RbAp48. Sci. Transl. Med. 5, 200ra115 (2013).

  14. 14.

    et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005).

  15. 15.

    et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007).

  16. 16.

    et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10, 96–103 (2012).

  17. 17.

    et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153, 828–839 (2013).

  18. 18.

    , & Loss of perforated synapses in the dentate gyrus: morphological substrate of memory deficit in aged rats. Proc. Natl. Acad. Sci. USA 83, 3027–3031 (1986).

  19. 19.

    & Impact of aging on hippocampal function: plasticity, network dynamics, and cognition. Prog. Neurobiol. 69, 143–179 (2003).

  20. 20.

    , , , & A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat. Rev. Neurosci. 12, 585–601 (2011).

  21. 21.

    Transcription factors in long-term memory and synaptic plasticity. Physiol. Rev. 89, 121–145 (2009).

  22. 22.

    & A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).

  23. 23.

    & Synaptic tagging and long-term potentiation. Nature 385, 533–536 (1997).

  24. 24.

    et al. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat. Med. 18, 159–165 (2012).

  25. 25.

    , , , & Hippocampal cell genesis does not correlate with spatial learning ability in aged rats. J. Comp. Neurol. 459, 201–207 (2003).

  26. 26.

    & Production of new cells in the rat dentate gyrus over the lifespan: relation to cognitive decline. Eur. J. Neurosci. 18, 215–219 (2003).

  27. 27.

    et al. Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc. Natl. Acad. Sci. USA 100, 14385–14390 (2003).

  28. 28.

    et al. Analysis of grooming behavior and its utility in studying animal stress, anxiety, and depression. in Mouse Models of Mood and Anxiety Disorders (ed. Gould, T.) 21–36 (Humana Press, NY, 2009).

  29. 29.

    Mood and Anxiety Related Phenotypes in Mice: Characterization Using Behavioral Tests (Humana Press, New York, 2009).

  30. 30.

    et al. Glia-dependent TGF-β signaling, acting independently of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis. J. Clin. Invest. 117, 3306–3315 (2007).

  31. 31.

    & Modulation of long-term potentiation in rat hippocampal pyramidal neurons by zinc. Pflugers Arch. 427, 481–486 (1994).

  32. 32.

    et al. In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J. Virol. 82, 5887–5911 (2008).

  33. 33.

    et al. Distinct neuronal coding schemes in memory revealed by selective erasure of fast synchronous synaptic transmission. Neuron 73, 990–1001 (2012).

  34. 34.

    et al. Irradiation enhances hippocampus-dependent cognition in mice deficient in extracellular superoxide dismutase. Hippocampus 21, 72–80 (2011).

  35. 35.

    , , , & Two-day radial-arm water maze learning and memory task; robust resolution of amyloid-related memory deficits in transgenic mice. Nat. Protoc. 1, 1671–1679 (2006).

Download references

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.).

Author information

Author notes

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

    These authors contributed equally to this work.

Affiliations

  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

Authors

  1. Search for Saul A Villeda in:

  2. Search for Kristopher E Plambeck in:

  3. Search for Jinte Middeldorp in:

  4. Search for Joseph M Castellano in:

  5. Search for Kira I Mosher in:

  6. Search for Jian Luo in:

  7. Search for Lucas K Smith in:

  8. Search for Gregor Bieri in:

  9. Search for Karin Lin in:

  10. Search for Daniela Berdnik in:

  11. Search for Rafael Wabl in:

  12. Search for Joe Udeochu in:

  13. Search for Elizabeth G Wheatley in:

  14. Search for Bende Zou in:

  15. Search for Danielle A Simmons in:

  16. Search for Xinmin S Xie in:

  17. Search for Frank M Longo in:

  18. Search for Tony Wyss-Coray in:

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.

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.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–12 and Supplementary Table 1

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nm.3569