Restoring Lost Vascularization Capability via FDPS Inhibition

The ability of the body to build new blood vessels declines with age. One of the consequences is a loss of capillary density in tissues throughout the body, reducing the supply of nutrients and contributing to harmful changes in the fluid dynamics of the vasculature. Researchers have shown that increasing the ability to build and maintain capillaries via upregulation of VEGF can extend life in mice. Here, researchers report on another approach to increasing the capacity for vascularization in mice. The goal of increasing capillary density is an important one, but few research groups or companies are focused on this in any meaningful way.

The stem cell theory of aging dictates that a decline in the number and/or function of stem cells causes tissue degeneration and aging; however, it still lacks unequivocal experimental support. Here, using lineage tracing and single-cell transcriptomics, we identify a population of CD133+ bone marrow-derived endothelial-like cells (ELCs) as potential endothelial progenitor cells, which contribute to tubular structures in vitro and neovascularization in vivo. We demonstrate that supplementation with wild-type and young ELCs respectively restores neovascularization and extends lifespan in progeric and naturally aged mice.

Mechanistically, we identify an upregulation of farnesyl diphosphate synthase (FDPS) in aged CD133+ ELCs-a key enzyme in isoprenoid biosynthesis. Overexpression of FDPS compromises the neovascularization capacity of CD133+ ELCs, whereas FDPS inhibition by pamidronate enhances neovascularization, improves health measures and extends lifespan in aged mice. These findings highlight stem cell-based strategies for the treatment of progeria and age-related pathologies.