Shown are hypothetical dysregulated hematopoietic pathways in old bone marrow. In young mice, sufficient osteopontin fragment-D (OPN-D) is produced by thrombin cleavage of OPN from BM stromal cells to maintain tonic Wnt5a signaling such that Cdc42 levels are not raised. In old animals, however, lower availability of OPN-D allows higher expression of Wnt5a, which stimulates Cdc42 expression. This can be pharmacologically blocked by CASIN, resulting in normalization of epigenetic changes in HSCs otherwise associated with a skewing of immune cell output with fewer B-cell and T-cell progenitors, more myeloid cells, and poor vaccine responsiveness. The end result is that CASIN-treated old HSCs transferred to a young environment reconstitute an immune system with a distribution of B cells, T cells, and myeloid cells similar to that observed after transfer of young HSCs that is able to respond to de novo antigen challenge in the form of a DNA vaccine. Professional illustration by Patrick Lane, ScEYEnce Studios.