Bone as a Sensor of and Responder to Stress During Aging

Project summary Aging is associated with a myriad of deleterious physical consequences. Among them, we as a group have recently focused our work on the decreased ability to respond to stress whether it is endogenous, e.g., sex steroid deprivation or exogenous through bacterial infections or various stressors. This is why the focus of this P01 application is to characterize the role of bone as an endocrine organ in sensing and responding to stress. This work is largely motivated by the fact that we have in the past 2 years accumulated in vivo and through the study of gain and loss of functions animal models, numerous experimental evidence that the two molecules that this group of investigators characterized as bone-derived hormones, osteocalcin, and lipocalin 2, are involved in allowing the body to respond to stressors of various kinds. In pursuing this line of investigation, we have also identified one molecule glutamate, as a regulator of both osteocalcin and lipocalin 2 release during a stress reaction. At the same time, this work was unfolding another member of the original group of investigators that worked together in this PO1 application has gathered numerous preliminary evidence that an endogenous stressor such as estrogen deprivation affects ? cell number and biology in an osteocalcin- dependent manner. Lastly, a new member of our group Dr. Lori Zeltser, an accomplished neuroscientist and an expert in the biology of appetite and thermogenesis, is revisiting at the most fundamental mechanistic level an observation two project leaders in the PO1 application, Drs. Ducy and Karsenty had made over 13 years ago. This observation is that osteocalcin favors energy expenditure and as a result the ability to protect from another stressor, diet-induced obesity. These broad arrays of preliminary results obtained over the course of 13 years converge on asking the following fundamental and novel question that we propose to address in this application. Is bone as a sensor and responder to stress throughout life? To address as many aspects as possible of this question, we intend to blend in this application the bone biology endocrinology and neuroscience expertise of its four PI?s. Therefore, to address the broad questions we are asking, we propose to test the following Specific Aims: To determine whether the regulation of the release of osteocalcin can be harnessed to prevent or rescue manifestations of aging (Project#1) To determine whether bone is an acute inflammation-sensing organ that mounts lifesaving anti-inflammatory responder through lipocalin 2 secretion by osteoblasts (Project#2). To determine whether estrogen deprivation at menopause enhances the production of osteocalcin and as a result may affect ? cell biology and glucose homeostasis (Project#3). To investigate mechanistically whether the decrease in circulating osteocalcin during aging is, a least in part, responsible for the dysregulation of thermogenesis seen during aging (Project#4).