Cellular Senescence in the Aging of Bone Tissue
Cells become senescent constantly, throughout life and throughout the body. Most such cells have reached the Hayflick limit on replication, but cells can also become senescent in response to damage, stress, or the signaling of other senescent cells. In youth, senescent cells are efficiently cleared by the immune system, but this clearance falters with age for reasons that are incompletely understood at the present time. The consequence of a mismatch between pace of creation and pace of clearance is a growing burden of lingering senescent cells. These cells secrete a mix of signals, the senescence-associated secretory phenotype (SASP), that is disruptive to tissue structure and function, and provokes continual, unresolved inflammation. This directly contributes to the onset and progression of many age-related conditions.
In today's open access paper, researchers discuss the presence of senescent cells and SASP in the context of bone tissue specifically. Bone loses density with age, leading to osteoporosis. This results from an imbalance between the activities of osteoblasts, creating bone, and osteoclasts, removing bone. Many contributing factors lead to a growing gap that favors the breakdown of bone tissue by osteoclasts, and the signaling produced by senescent cells is one such factor. Further, bone is a tissue of significant size, and the SASP produced by senescent cells spreads throughout the body. The larger the organ, the greater the impact as some proportion of cells becomes senescent. Cellular senescence in larger tissues such as skin, muscle, and bone may well have meaningful harmful effects elsewhere in the body.
Substantial evidence supports the causal role of cellular senescence in bone tissue during natural aging, premature aging syndromes, and many age-associated skeletal disorders, such as osteoporosis and osteoathritis. A central mechanism by which senescent cells expand the senescence program and impair the bone and bone marrow microenvironment is via senescent bone cell-associated SASP, namely "bone-SASP." It is now well recognized that the SASP is highly heterogeneous, varies depending on cell type and the senescence-inducing stimulus, and is very dynamic, changing over time after the stimulus. Thus, it is important to use a proteomic, unbiased approach to gain insights into highly complex SASP profiles.
However, in most studies of the detection of bone-SASP in pathological conditions such as the progeria-associated bone disorders, osteoarthritis, and osteoporosis, unbiased profiling of the SASP factors was not conducted. Only chosen panels of inflammatory factors and cytokines were detected. Given that the newly generated SenMayo dataset identifies bone-SASP across tissues and species with high fidelity, further detailed characterization and comprehensive identification of the bone-SASP in different age-associated skeletal conditions are warranted.
Recent studies suggest that the SASP, as a feature of cellular senescence, not only exerts a detrimental effect locally but may also cause systemic adverse effects. Although the SASP has an endocrine effect on regulating the activities of tissues and organs at remote sites, the endocrine role of the bone-SASP remains largely unexplored. Recent evidence revealed that PDGF-BB produced by senescent preosteoclasts serve as a systemic pro-aging factor that contributes to age-associated increase in arterial stiffness and cerebrovascular impairment. Further assessment is needed of the involvement of bone-derived PDGF-BB in the aging process of other organ systems to validate its endocrine function.
In summary, research into the endocrine role of senescent cells is still in the early stage. Given that some bone-SASP factors identified to date are important inflammatory factors and pro-aging factors, there is no doubt that the systemic effect of bone-SASP factors will become one of the main topics in the field of skeletal research.