Fibroblast growth factor 23 null mice (Fgf-23−/−) have a short lifespan and show numerous biochemical and morphological features consistent with premature aging-like phenotypes, including kyphosis, severe muscle wasting, hypogonadism, osteopenia, emphysema, uncoordinated movement, T cell dysregulation, and atrophy of the intestinal villi, skin, thymus, and spleen. Furthermore, increased vitamin D activities in homozygous mutants are associated with severe atherosclerosis and widespread soft tissue calcifications; ablation of vitamin D activity from Fgf-23−/− mice, by genetically deleting the 1α (OH) ase gene, eliminates atherosclerosis and ectopic calcifications and significantly rescues premature aging-like features of Fgf-23−/− mice, resulting in prolonged survival of Fgf-23−/− 1α (OH) ase−/− double mutants. Our results indicate a novel role of Fgf-23 in developing premature aging-like features through regulating vitamin D homeostasis. Finally, our data support a new model of interactions among Fgf-23, vitamin D, and klotho, a gene described as being associated with premature aging process.