BIOMARKERS OF AGING--CIRCULATING/DEPOSITED OSTEOCALCIN

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Osteocalcin (OC), a vitamin K-dependent protein is made specifically by osteoblasts. The major portion of newly synthesized OC is deposited in bone; however, a proportional amount is released into the circulation and finally degraded in the kidney. The circulating portion provides a measure of OC synthesis in bone and of the response of osteoblasts to hormones and other agents. OC is currently used clinically to monitor changes in osteoblast function and bone turnover and has been useful in evaluating the effect of experimental therapies in the treatment of osteoporosis and other bone disorders. Since osteocalcin provides a measure of bone metabolism and since serum levels appear to be aged related, it is likely that serum OCs reflect bone physiologic changes that are concomitants of aging. The aging rodent colonies maintained as a resource for aging research by the NIA will be tested for changes in serum osteocalcin as a function of age and diet restriction and in the presence or absence of acute and chronic administration of the calcitropic hormones, PTH, calcitonin and the vitamin D metabolite 1,25(OH)2D3. The RIA measurement for rat osteocalcin is already operative in our laboratory and an RIA for mouse osteocalcin is under development. Serum osteocalcin will be correlated with transcriptional levels of osteocalcin mRNA and osteocalcin synthesis in bone. The overall vitamin K status of the rats will be monitored by examining the urinary ouput of free 4- carboxyglutamic acid. Bone deposited osteocalcin is initially free of glycation (nonenzymatic glycosylation) but becomes glycated with time. We have already shown in humans that the glycatation of osteocalcin is low in children, fairly constant in adults, but rapidly increases in the elderly as new bone synthesis decreases and older bone accumulates. The measurement of glycated osteocalcin should also serve as a valuable biomarker of aging. Its content will be evaluated in relation to total bone osteocalcin and bone density (mineral) in male and female aging rats.