PROGRAM SUMMARY Osteoporosis, obesity and Alzheimer's disease (AD) are public health hazards that affect millions of older adults. Despite crippling consequences, their therapeutic armamentarium pales when compared with diseases of similar magnitudes, such as diabetes and cancer. Our current U19 AG060917 and the ADRD supplement have allowed us to create a highly collaborative transdisciplinary translational research program that spans bone biology, metabolism and the neurosciences. The program builds on rigorous and transparent research, born from a longstanding collaboration between Drs. Mone Zaidi and Clifford Rosen, wherein data continues to be contemporaneously replicated in both labs. We have together identified the fertility hormone FSH as a unique target to prevent osteoporosis, obesity and AD. We have developed antibodies that block the action of FSH and, in doing so, prevent bone loss, obesity, and cognitive decline in mouse models1-4. We have now created a therapeutic antibody—MS-Hu6—which has undergone early stage testing, including safety studies in monkeys5,6—and, is therefore poised for efficacy testing in aging models of human disease. This is particularly relevant as elderly women in the AGES–Reykjavik cohort show a correlation between a high serum FSH, low bone mineral density (BMD) and fracture risk7. We have also unmasked a novel action of the second gonadotropin LH in reducing body fat—raising the question whether the leanness induced by a small molecule LH receptor agonist, ORG43553, can synergize with FSH blockade by MS-Hu6. Four projects will thus focus on both mechanism and translation. In Project 1, we will examine if FSH blockade by MS-Hu6 or genetic Fshr ablation in aged mice can reverse established osteoporosis, obesity and/or AD. Project 2 will use Cre lines to delete the Fshr in specific bone cells—osteoblasts, osteocytes and osteoclasts—as well as in adipocytes and examine the evolution of the respective phenotypes. This will be complemented by siRNA–mediated Fshr knockdown in hypothalamic neurons that might contribute to obesity. Project 3 will likewise probe the mechanism of action of LHCGR agonism on body fat, and specifically determine interactions between downstream signals by using chemical inhibitors and in vivo genetic epistasis. Project 4 remains as the program's epidemiological arm, which will utilize validated datasets from AGES–Reykjavik to probe relationships between brain health and bone health, and examine, using a case–cohort design, whether high serum FSH levels are associated with dementia or mild cognitive impairment. The Projects will be supported by three overarching Cores, namely a Skeletal, Metabolic and Neurobehavioral Core (Core A), an Antibody Production and Testing Core (Core B), and an Administrative, Biostatistics and Good Laboratory Practice (GLP) Management Core (Core C). In sum, our U19 renewal should allow us to break new ground in understanding the role of pituitary gonadotropins i...