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Significance Cognitive function decreases during aging, but the mechanisms involved remain unclear. Revolutionary recent studies revealed that introduction of blood from young mice into old mice increased cognitive abilities and synaptic connectivity, suggesting that young blood contains specific factors supporting cognitive function. Here, we asked whether young blood is enriched in factors that act directly on neurons to promote synapse formation. We show that serum from young but not old mice indeed directly boosts synapse formation in cultured neurons, and identify two factors, thrombospondin-4 and SPARCL1, that are enriched in young blood and mediate these effects. Thus, our experiments show that young blood is enriched in multiple factors that directly promote synaptic connectivity between neurons.

Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment