Cellular senescence is now recognized as one of the fundamental aging mechanisms contributing to multiple
age-related degenerative conditions, including osteoporosis. In previous studies, we have systematically
identified senescent cells in the bone microenvironment and demonstrated a causal role for senescent cells in
mediating age-related bone loss in mice. In recent studies, we used a novel transgenic mouse model, p16-
LOX-ATTAC, capable of temporal- and cell-specific senescent cell clearance, and found that in contrast to
global clearance of senescent cells using the (p16)-INK-ATTAC model, clearance specifically of senescent
osteocytes only partially replicated the beneficial skeletal effects of global senescent cell clearance, suggesting
an important role for other cells in the bone microenvironment (e.g., immune cells) in contributing to skeletal
aging. In addition, in our previous work, we demonstrated a dramatic upregulation of the senescence-
associated secretory phenotype (SASP) in bone marrow myeloid cells with aging, and more recent studies by
our investigative team have shown that with aging, activated neutrophils can induce senescence in multiple
tissues in a paracrine manner. Conversely, senescent cells are capable of attracting neutrophils, which then
further propagate senescence to other cells. Collectively, these studies point to previously unexplored cross-
talk between skeletal and immune cells, specifically in the context of cellular senescence. Thus, our central
hypothesis is that senescence of immune cells contributes to skeletal deterioration and conversely, senescent
skeletal cells attract and contribute to an inflammatory and/or senescent phenotype of immune cells. We will
test this hypothesis by examining the effects of senescent immune cells on bone and in the reverse
experiment, evaluating the effects of senescent skeletal cells on immune cells. Our proposed studies make use
of novel mouse models: p16-LOX-ATTAC mice, developed in the Khosla/Monroe laboratory, which are capable
of temporal- and cell-specific (when crossed with a Cre mouse) senescent cell clearance; and Ercc1-/fl mice,
developed by Drs. Niedernhofer and Robbins (Co-Is), where we can induce a tissue-specific DNA repair defect
leading to premature cellular senescence only in that tissue (e.g., immune or skeletal cells). Collectively, our
studies will address a number of fundamental questions relevant to osteoimmunology: (1) What are the specific
populations of bone marrow immune cells that undergo senescence with aging using strictly defined criteria for
cellular senescence (rather than the much broader umbrella of “immunosenescence” that includes
inflammatory, but not necessarily senescent cells); (2) Does chronological or premature aging of the immune
system cause skeletal deterioration?; (3) Conversely, do senescent skeletal cells lead to senescence, or at
least inflammation, in bone marrow immune cells and does this further propagate senescence to other skeletal
cells and perhaps systemically?; and (4) What are the potential mediators of the cross-talk between senescent
skeletal cells and senescent/inflammatory immune cells?