Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes skn-1, ire-1, and xbp-1

• Published in: Cell reports (Cambridge) Vol. 17; no. 5; pp. 1227 - 1237
• Main Authors: Mark, Karla A., Dumas, Kathleen J., Bhaumik, Dipa, Schilling, Birgit, Davis, Sonnet, Oron, Tal Ronnen, Sorensen, Dylan J., Lucanic, Mark, Brem, Rachel B., Melov, Simon, Ramanathan, Arvind, Gibson, Bradford W., Lithgow, Gordon J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.10.2016; Elsevier
• Subjects: Alzheimer’s disease; Animals; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - genetics; Caenorhabditis elegans - physiology; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Calcitriol - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Ceanorhabditis elegans; Cholecalciferol - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Homeostasis - drug effects; insoluble protein; IRE-1; lifespan. aging; Longevity - physiology; Protein Aggregates; protein aggregation; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; proteostasis; SKN-1; Solubility; Stress, Physiological - genetics; Transcription Factors - genetics; Transcription Factors - metabolism; Unfolded Protein Response - drug effects; vitamin D; Vitamin D - pharmacology; XBP-1; Alzheimer’s disease; lifespan. aging; vitamin D; protein aggregation; insoluble protein; IRE-1; proteostasis; Ceanorhabditis elegans; XBP-1; SKN-1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.09.086

Vitamin D has multiple 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 (D3) induced expression of SKN-1 target genes but not canonical targets of XBP-1. D3 suppressed an important molecular pathology of aging, that of widespread protein insolubility, and prevented toxicity caused by human β-amyloid. Our observation that 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 vitamin D deficiency. [Display omitted] •Vitamin D metabolism is conserved between nematodes and mammals•Vitamin D prevents the age-dependent accumulation of SDS-insoluble proteins•Vitamin D enhances lifespan and protein homeostasis via IRE-1, XBP-1, and SKN-1 Maintenance of protein homeostasis is crucial to cellular health and contributes significantly to the lifespan of organisms. Mark et al. demonstrate that vitamin D supplementation promotes protein homeostasis and slows aging in the nematode, C. elegans. These findings identify a mechanism by which vitamin D influences aging.