Grant: $105,064 - National Institutes of Health - Sep. 4, 2009
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Award Description: Phosphate homeostasis is maintained primarily by a bone-kidney endocrine axis. When phosphate is in excess, fibroblast growth factor-23 (FGF23) is secreted from bone and acts on kidney to promote phosphate excretion into urine, thereby inducing negative phosphate balance. FGF23 requires Klotho, a single-pass transmembrane protein expressed specifically in kidney, as an obligatory co-receptor. Thus, Klotho and FGF23 are essential components in the endocrine regulation of phosphate metabolism. Disruption of this bone-kidney endocrine axis by ablating Klotho gene expression not only induces phosphate retention but also results in a premature aging syndrome associated with molecular signatures of aging, including increased oxidative stress, increased somatic DNA mutation, and attenuated somatotroph axis. Importantly, low phosphate diet rescues Klotho-/- mice from these hallmarks of aging, indicating that phosphate retention is responsible for the accelerated aging. These observations have led us to the hypothesis that phosphate accelerates aging. The purpose of this supplement is to support this hypothesis by demonstrating that the aging processes in Klotho-/- mice can be reversed or accelerated depending on the amount of phosphate in diet. Specific aims are to: Aim 1: Test whether low phosphate diet reverses aging processes in Klotho-/- mice Under regular diet, aging phenotypes in Klotho-/- mice appear around 3 weeks after birth and progress rapidly until they die around 10 weeks of age. Six-week-old Klotho-/- mice with advanced aging phenotypes will be put on a low phosphate diet to test if it would reverse the pre-existing phenotypes. Aim 2: Test whether high phosphate diet accelerates aging processes in Klotho-/- mice Klotho-/- mice rescued by a low phosphate diet (0.02% phosphate) will be put on a regular diet (0.54% phosphate) to test if aging processes would come back and progress rapidly.
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This award's data was last updated on Sep. 4, 2009. Help expand these official descriptions using the wiki below.