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The ageing systemic milieu negatively regulates neurogenesis and cognitive function

Nature volume 477, pages 90–94 (2011)Cite this article

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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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Figure 1: Heterochronic parabiosis alters neurogenesis in an age-dependent fashion.
Figure 2: Factors from an old systemic environment decrease neurogenesis and impair learning and memory.
Figure 3: Systemic chemokine levels increase during ageing and heterochronic parabiosis, and correlate with decreased neurogenesis.
Figure 4: Systemic exposure to CCL11 inhibits neurogenesis and impairs learning and memory.

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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.).

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Author notes

  1. Markus Britschgi & Jeong-Soo Park

    Present address: 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.).,

Authors and Affiliations

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

    Saul A. Villeda, Kira I. Mosher & Tony Wyss-Coray

  3. AfaSci Research Laboratory, Redwood City, 94063, California, 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, 94305, California, 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, 98108-1597, Washington, USA

    Ge Li & Elaine R. Peskind

  8. Veterans Affairs Northwest Network Mental Illness Research, Education, and Clinical Center, Seattle, 98108-1597, Washington, 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,

    Jeffrey A. Kaye & Joseph F. Quinn

  10. and Portland VA Medical Center, Portland, 97207, Oregon, USA

    Jeffrey A. Kaye & Joseph F. Quinn

  11. Department of Neurosciences, University of California San Diego, 9500 Gilman Drive 0948, La Jolla, 92093-0948, California, USA

    Douglas R. Galasko

  12. Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System, Palo Alto, 94304, California, USA

    Thomas A. Rando & Tony Wyss-Coray

  13. The Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, 94305, California, 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.

Corresponding author

Correspondence to Tony Wyss-Coray.

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The authors declare no competing financial interests.

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Villeda, S., Luo, J., Mosher, K. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011). https://doi.org/10.1038/nature10357

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