Abstract

In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions1. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise1. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines—including CCL11 (also known as eotaxin)—the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors.

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Acknowledgements

We thank A. Brunet for critically reading the manuscript; M. Buckwalter for parabiosis instruction; T.-T. Huang for irradiation instruction; R. Corniola and C. Clelland for behavioural advice, S. Bauer Huang, H. Johns, J. Sun, H. Hefner, H. Alabsi and I. Villeda for technical assistance. This work was supported by grants from Anonymous (T.W.-C.), Department of Veterans Affairs (T.W.-C.), National Institutes of Health Institute on Aging (R01 AG027505, T.W.-C.), a California Initiative for Regenerative Medicine Award (T.W.-C.), National Institutes of Health (R01 MH078194, X.S.X.), National Institutes of Health Institute on Aging (P30 AG08017, J.A.K.), a National Institutes of Health Director’s Pioneer Award (T.A.R.), a Larry L. Hillblom Foundation postdoctoral fellowship (K.M.L.; 2008-A-023-FEL), a Feodor-Lynen postdoctoral fellowship (E.C.), a Swiss National Science Foundation postdoctoral fellowship (A.E.), a National Science Foundation predoctoral fellowship (S.A.V.; K.I.M.; T.M.S.), and Kirschstein NRSA predoctoral fellowships (1 F31 AG034045-01, S.A.V.; 1 F31 NS066676-01A1, Z.D.).

Author information

Author notes

    • Markus Britschgi
    •  & Jeong-Soo Park

    Present addresses: CNS Discovery, pRED, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland (M.B.); Department of Biochemistry, College of Medicien, Dankook University, Cheonan 330-714, South Korea (J.S.P.).

Affiliations

  1. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA

    • Saul A. Villeda
    • , Jian Luo
    • , Kira I. Mosher
    • , Markus Britschgi
    • , Gregor Bieri
    • , Trisha M. Stan
    • , Nina Fainberg
    • , Zhaoqing Ding
    • , Alexander Eggel
    • , Kurt M. Lucin
    • , Eva Czirr
    • , Jeong-Soo Park
    • , Thomas A. Rando
    •  & Tony Wyss-Coray
  2. Neuroscience IDP Program, Stanford University School of Medicine, Stanford, California 94305, USA

    • Saul A. Villeda
    • , Kira I. Mosher
    •  & Tony Wyss-Coray
  3. AfaSci Research Laboratory, Redwood City, California, 94063, USA

    • Bende Zou
    •  & Xinmin S. Xie
  4. School of Life Sciences, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland

    • Gregor Bieri
  5. Immunology IDP Program, Stanford University School of Medicine, Stanford, California 94305, USA

    • Trisha M. Stan
    • , Zhaoqing Ding
    •  & Tony Wyss-Coray
  6. Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Strubergasse 21, A-5020 Salzburg, Austria

    • Sebastien Couillard-Després
    •  & Ludwig Aigner
  7. Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington 98108-1597, USA

    • Ge Li
    •  & Elaine R. Peskind
  8. Veterans Affairs Northwest Network Mental Illness Research, Education, and Clinical Center, Seattle, Washington 98108-1597, USA

    • Elaine R. Peskind
  9. Layton Aging and Alzheimer's Disease Center, Oregon Health and Science University, CR131, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201-3098, USA; and Portland VA Medical Center, Portland, Oregon 97207, USA

    • Jeffrey A. Kaye
    •  & Joseph F. Quinn
  10. Department of Neurosciences, University of California San Diego, 9500 Gilman Drive 0948, La Jolla, California 92093-0948, USA

    • Douglas R. Galasko
  11. Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System, Palo Alto, California 94304, USA

    • Thomas A. Rando
    •  & Tony Wyss-Coray
  12. The Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, California 94305, USA

    • Thomas A. Rando

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Contributions

S.A.V. and T.W.-C. developed the concept and designed all experiments. S.A.V. and J.L. designed and performed in vivo experiments. S.A.V. performed behavioural experiments. K.I.M. assisted with surgery. B.Z. and X.S.X. performed electrophysiology. M.B. and A.E. analysed human data. G.B. assisted with fear conditioning and irradiation analysis. S.A.V., T.M.S. and J.-S.P. performed in vitro experiments. T.M.S. assisted with MCSF analysis. N.F. assisted with radial arm maze. Z.D. performed flow cytometry. K.M.L. performed irradiation. E.C. assisted with in vivo plasma experiments. D.R.G., G.L., E.R.P., J.A.K. and J.F.Q. identified aging subjects and provided human samples. S.C.-D. and L.A. provided reagents and mice. T.A.R. provided reagents, conceptual advice and edited the manuscript. S.A.V. collected data, performed data analysis and generated figures. S.A.V. and T.W.-C. wrote the manuscript. T.W.-C. supervised all aspects of this project. All authors had the opportunity to discuss results and comment on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tony Wyss-Coray.

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DOI

https://doi.org/10.1038/nature10357

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