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The ageing systemic milieu negatively regulates neurogenesis and cognitive function

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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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.

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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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