Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes SKN-1, IRE-1, and XBP-1

Vitamin D is a secosteroid that has multiple regulatory roles including the regulation of bone and calcium homeostasis. Deficiency of 25-hydroxyvitamin D, the major circulating form of vitamin D, is associated with an increased risk of age-related chronic diseases including Alzheimer’s disease, Parkinson’s disease, cognitive impairment, and cancer. In this study, we utilized Caenorhabditis elegans to examine the mechanism by which vitamin D influences aging. We found that Vitamin D3-induced lifespan extension requires the stress response pathway genes SKN-1, IRE-1, and XBP-1. Vitamin D3 induced expression of SKN-1 target genes, but not canonical targets of IRE-1/XBP-1. Vitamin D3 suppressed an important molecular pathology of aging, that of widespread protein insolubility, and prevented the toxicity caused by human β-amyloid. Our observation that vitamin D3 improves protein homeostasis and slows aging highlights the importance of maintaining appropriate vitamin D serum levels, and may explain why such a wide variety of human age-related diseases are associated with a vitamin D deficiency.