Vitamin D₃ inhibits p38 MAPK and senescence-associated inflammatory mediator secretion by senescent fibroblasts that impacts immune responses during ageing

Vitamin D₃ replacement in older insufficient adults significantly improves their antigen-specific varicella zoster virus (VZV) cutaneous immunity. However, the mechanisms involved in this enhancement of cutaneous immunity are not known. Here, we show for the first time that vitamin D₃ blocks the senescence-associated secretory phenotype (SASP) production by senescent fibroblasts by partially inhibiting the p38 MAPK pathway. Furthermore, transcriptomic analysis of skin biopsies from older subjects after vitamin D₃ supplementation shows that vitamin D₃ inhibits the same inflammatory pathways in response to saline as the specific p38 inhibitor, losmapimod, which also enhances immunity in the skin of older subjects. Vitamin D₃ supplementation therefore may enhance immunity during ageing in part by blocking p38 MAPK signalling and in turn inhibit SASP production from senescent cells in vivo.