CD44 in the Aging of the Vascular Endothelium
Comparing this paper with a recent examination of CD44 in species life span differences is a good illustration of the complexity of cellular biochemistry. CD44 expression seems arguably bad in the context of vascular aging, but arguably good in the context of central nervous system aging. It is quite common for genes to have very different positive or negative influences in different tissues, different circumstances, different levels of expression. Evolution tends to produce molecular machinery that is promiscuously reused in different ways in different circumstances. Nothing is simple! Thus CD44 can upregulate cell maintenance of one type in central nervous system cells, while impairing another form of cell maintenance in the vasculature, and this is just one example of many similar circumstances.
The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain unclear. Here, we identify a crucial role for CD44, a multifunctional adhesion molecule, in controlling autophagy and ageing in VECs. The CD44 intercellular domain (CD44ICD) negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes. CD44 and its homologue clec-31 are increased in ageing vascular endothelium and Caenorhabditis elegans, respectively, suggesting that an age-dependent increase in CD44 induces autophagy decline and ageing phenotypes.
Accordingly, CD44 knockdown ameliorates age-associated phenotypes in VECs. The endothelium-specific CD44ICD knock-in mouse is shorter-lived, with VECs exhibiting obvious premature ageing characteristics associated with decreased basal autophagy. Autophagy activation suppresses the premature ageing of human and mouse VECs overexpressing CD44ICD, function conserved in the CD44 homologue clec-31 in C. elegans. Our work describes a mechanism coordinated by CD44 function bridging autophagy decline and ageing.