Bone as a Target and a Regulator of Aging

Project Summary – Overall It is customary to view bone as a target of the aging process. This clinical observation has been a pillar of bone biology and of the biology of aging for decades. The continuous exploration of this aspect of the biology of aging eventually led to the fundamental discovery that bone has many more functions than previously thought before the era of analysis of physiology in model organisms. These in vivo advances identifying bone as an endocrine organ and as regulator of hematopoiesis have been made possible by studies in mouse and, some instances, human genetics. Of particular interest for this application is the fact that the majority of the physiological processes regulated by bone in its endocrine capacity decline with age. Hence, when considering together the classical identity of bone as a target of the aging process and the novel functions recently shown for bone, we are formulating the hypothesis that bone is both a target and a regulator of aging. This application will explore this hypothesis. In exploring this two-pronged hypothesis and through shared expertise and reagents, we have accumulated as a group in the last 18 months, numerous preliminary data that all point to an even richer bone biology and an even tighter connection between biology and the biology of aging. These preliminary data include an unanticipated link between bone's endocrine functions and bone mass regulation. A link that may be of therapeutic relevance for treating age-related bone loss. The role of bone in triggering emergency myelopoiesis in the case, for instance, of infection. The uncharted territory of the impact of the various and now popular modalities of restricted feeding on bone health. The influence of bone-derived hormones on the cross-talk between bone and the sympathetic nervous system. Cognizant of conceptual and experimental difficulties we may encounter, we also have enrolled the help of co-investigators and/or of members of our internal advisory board of experts in specific aspects of our projects that are experts in areas we will explore. To address the broad, distinct, and overlapping questions we are pursuing, we will use state-of-the-art molecular, histological, and physiological assays along with cell-specific genetic approaches to pursue the following Specific Aims: To determine whether bone in its endocrine capacity regulates through a bone-gut axis, bone mass accrual (Project #1). To define physiologic and molecular consequences of various diet manipulations on bone remodeling and its endocrine function during aging (Project #2). To determine whether bone-derived lipocalin-2 is required to mount emergency myelopoiesis to stimulate the production and maturation of myeloid cells in the bone marrow following inflammatory stress during acute inflammatory challenge and in aging (Project #3). To determine how the cross-talk between bone and sympathetic pre-ganglionic neurons in the spinal cord regulates acute metabolic responses (in brown adipose tissue) to dietary fats and cold (Project#4).