The ageing systemic milieu negatively regulates neurogenesis and cognitive function

In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise. 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. Adult neurogenesis occurs in local microenvironments, or neurogenic niches, in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampus. Permissive cues within the neurogenic niche are thought to drive the production of new neurons and their subsequent integration into the neurocircuitry of the brain, directly contributing to cognitive processes including learning and memory. Importantly, the neurogenic niche is localized around blood vessels, allowing for potential communication with the systemic environment. Therefore, the possibility arises that diminished neurogenesis during ageing may be modulated by the balance of two independent forces: intrinsic central nervous system (CNS)-derived cues and cues extrinsic to the CNS delivered by blood. Thus we hypothesized that age-related systemic molecular changes could cause a decline in neurogenesis and impair cognitive function during ageing. We first characterized cellular, electrophysiological and behavioural changes associated with the neurogenic niche in the dentate gyrus of the hippocampus in an ageing cohort of mice. We observed cellular changes consistent with markedly decreased adult neurogenesis and increased neuroinflammation with age (Supplementary Fig. 2a–e). Additionally, we detected deficits in synaptic plasticity (Supplementary Fig. 3a–c), and behavioural deficits in contextual fear conditioning (Supplementary Fig. 4a–c) and radial arm water maze (RAWM; Supplementary Fig. 4d–f) paradigms in old animals, consistent with decreased cognitive function during ageing. Next we investigated the contribution of peripheral systemic factors to the age-related decline in neurogenesis in the dentate gyrus of the hippocampus in the setting of isochronic (young–young and old–old) and heterochronic (young–old) parabiosis (Fig. 1a). Remarkably, the number of doublecortin (Dcx)-positive newly born neurons (Fig. 1b, c), BrdU-positive cells (Fig. 1e, f) and Sox2-positive progenitors (Supplementary Fig. 5a, b) decreased in young heterochronic parabionts. In contrast, we observed an increase in the number of Dcx-positive (Fig. 1b, d), BrdU-positive (Fig. 1e, g) and Sox2-positive (Supplementary Fig. 5a, c) cells in the old heterochronic parabionts. The number of Dcx-positive neurons between unpaired age-matched animals and isochronic animals showed no difference (Supplementary Fig. 6a, b). As a control, flow cytometry analysis confirmed a shared vasculature in a subset of parabiotic pairs, in which one parabiont was transgenic for green fluorescent protein (GFP; Supplementary Fig. 7a–d). Together our findings suggest that global age-dependent systemic changes can modulate neurogenesis in both the young and aged neurogenic niche, potentially contributing to the decline in regenerative capacity observed in the normal ageing brain. As previously reported by others, we rarely detected peripherally derived GFP cells in the CNS of wild-type mice, and these numbers did not differ between isochronic and heterochronic pairings (Supplementary Fig. 7e), suggesting that the observed effects are mediated by soluble factors in plasma. To confirm that circulating factors within aged blood contribute to reduced neurogenesis with age, we intravenously injected plasma isolated from young or old mice into young adult mice (Fig. 2a). The number of Dcx-positive cells in the dentate gyrus decreased in animals receiving old plasma compared to animals receiving young plasma (Fig. 2b, c), indicating that soluble factors present in old blood inhibit adult neurogenesis. To investigate the functional effect of the ageing systemic milieu, extracellular electrophysiological recordings were done on hippocampal slices prepared from young isochronic and heterochronic parabionts (Fig. 1h, i and Supplementary Fig. 6c). A decrease in long-term potentiation (LTP) in the dentate gyrus of heterochronic parabionts was detected (Fig. 1h, i). These data indicate that age-related systemic changes can elicit deficits in synaptic plasticity. As LTP is considered to be a correlate of learning and memory, these finding suggest that age-related systemic changes may also affect cognitive functions during ageing.