Systemic factors as mediators of brain homeostasis, ageing and neurodegeneration

A rapidly ageing population and a limited therapeutic toolbox urgently necessitate new approaches to treat neurodegenerative diseases. Brain ageing, the key risk factor for neurodegeneration, involves complex cellular and molecular processes that eventually result in cognitive decline. Although cell-intrinsic defects in neurons and glia may partially explain this decline, cell-extrinsic changes in the systemic environment, mediated by blood, have recently been shown to contribute to brain dysfunction with age. Here, we review the current understanding of how systemic factors mediate brain ageing, how these factors are regulated and how we can translate these findings into therapies for neurodegenerative diseases. Cell-extrinsic changes in the systemic environment, transported to the site of action by the blood, have recently been shown to contribute to brain ageing. In this Review, Pluvinage and Wyss-Coray discuss how circulating molecules in the blood modulate brain function in health, ageing and disease.