Project Summary – Project #1 The number and diversity of the physiological processes regulated by the bone-derived hormone osteocalcin raise the question of the regulation of osteocalcin secretion in vivo. Moreover, the fact that circulating levels of osteocalcin decrease so steeply in mice, horses, monkeys, and humans relatively early during life raises the question as to whether increasing circulating levels of this hormone in older animals could correct at least in part, manifestations of aging affecting the physiological process regulated by osteocalcin. In support of this hypothesis, we have already gathered evidence that osteocalcin can indeed rescue the age-related decrease in muscle functions and cognitive functions. To address in a more global manner the questions presented above we searched for a regulator of osteocalcin secretion whose biology could be harnessed to demonstrate that increasing osteocalcin secretion could correct some deleterious manifestations of aging. In performing this endeavor we have accumulated strong preliminary evidence that neuron-derived glutamate enters osteoblasts and, through competitive inhibition of the gamma-glutamyl carboxylase, allows the release of uncarboxylated osteocalcin from osteoblasts. We now want to 1) demonstrate the cell-specificity nature of this mechanism, 2) test whether this mechanism can be harnessed to rescue at least in past manifestations of aging caused by a decrease in the physiological functions that osteocalcin normally enhance. To achieve these overlapping goals the Specific Aims of this application are: Establish in vivo that it is through its expression in cells of the osteoblast lineage that Glast influences the release of the uncarboxylated form of osteocalcin in the general circulation. Test whether overexpressing Glast in osteoblasts or osteocytes would improve energy expenditure, glucose metabolism, adaptation to exercise, cognitive functions and fertility in aging mice by favoring OCN release.