Senescent cells accumulate with age in all tissues, an imbalance between the pace of creation, accelerated due to the damaged tissue environment, and the pace of clearance by the immune system, slowed for a range of reasons related to the age-related decline in immune function. This accumulation is harmful, as senescent cells generate an inflammatory mix of signals, the senescence-associated secretory phenotype (SASP). Sustained over the long term, the SASP contributes to chronic inflammation and many forms of tissue dysfunction, leading into age-related disease.
Osteoporosis, the loss of bone density and strength that takes place with age, is one of the many inflammation-linked conditions in which senescent cells are thought to play a meaningful role. The extracellular matrix of bone tissue, providing its structural properties, is constantly remodeled. At root osteoporosis is another form of imbalance, between the activities of osteoblast cells that create the matrix and osteoclast cells that break down the matrix. Beneath that simple summary lies a great deal of complexity and debate over the relevance of one mechanism over another, however. In today's open access paper, researchers tour a number of these debated mechanisms in the context of the presence of senescent cells and their inflammatory, disruptive signaling.
Bone is a complex organ serving roles in skeletal support and movement, and is a source of blood cells including adaptive and innate immune cells. Structural and functional integrity is maintained through a balance between bone synthesis and bone degradation, dependent in part on mechanical loading but also on signaling and influences of the tissue microenvironment. Bone structure and the extracellular bone milieu change with age, predisposing to osteoporosis and increased fracture risk, and this is exacerbated in patients with diabetes. Such changes can include loss of bone mineral density, deterioration in micro-architecture, as well as decreased bone flexibility, through alteration of proteinaceous bone support structures, and accumulation of senescent cells.
Senescence is a state of proliferation arrest accompanied by marked morphological and metabolic changes. It is driven by cellular stress and serves an important acute tumor suppressive mechanism when followed by immune-mediated senescent cell clearance. However, aging and pathological conditions including diabetes are associated with accumulation of senescent cells that generate a pro-inflammatory and tissue-destructive secretome (the SASP). The SASP impinges on the tissue microenvironment with detrimental local and systemic consequences; senescent cells are thought to contribute to the multimorbidity associated with advanced chronological age.
Here, we assess factors that promote bone fragility, in the context both of chronological aging and accelerated aging in progeroid syndromes and in diabetes, including senescence-dependent alterations in the bone tissue microenvironment, and glycation changes to the tissue microenvironment that stimulate RAGE signaling, a process that is accelerated in diabetic patients. Finally, we discuss therapeutic interventions targeting RAGE signaling and cell senescence that show promise in improving bone health in older people and those living with diabetes.