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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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.).
The file contains Supplementary Figures 1-15 with legends and Supplementary Table 1.