The Ageing Systemic Milieu Negatively Regulates Neurogenesis and Cognitive Function

Regenerative capacity and cognitive function decline during ageing. A study using heterochronic parabiosis, in which pairs of young and old mice are surgically joined by a shared blood supply, shows that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in ageing mice. A proteomic screen identified a subset of plasma signalling proteins that correlate with the decreased neurogenesis observed in both normal ageing and parabiosis. CCL11 (also known as eotoxin) and β2-microglobulin — factors classically involved in immune responses — were among the identified factors able to decrease progenitor frequency and neural differentiation. 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.