Bone Aging, Cellular Senescence, and Osteoporosis

The accumulation of senescent cells throughout the body with age contributes to the chronic inflammation of aging, as well as to many age-related conditions. Clearance of these cells produces a sizable and beneficial reversal of aspects of aging and the progression of age-related disease in mice. We will soon enough know whether this is also true in humans. Given the number of biotech companies presently working on senolytic therapies capable of targeted destruction of senescent cells, many clinical trials for senolytics will be undertaken in the years ahead. As noted below, osteoporosis is one of the age-related conditions in which growing numbers of senescent cells are implicated as a contributing cause.

Substantial alterations in bone architecture occur with aging, including decreases in trabecular thickness and number, cortical bone loss and porosity, and increase in marrow adiposity. These changes reflect imbalances in bone remodeling, favoring a net loss of bone caused predominately by increased osteoclast activity in postmenopausal women, as well as both poor bone formation and increased osteoclast activity in older men and women. Cellular senescence and apoptosis of osteoblasts and osteocytes account for much of the aging phenotype in bone, although appear to be independent of estrogen-mediated effects.

There is growing evidence to suggest that cellular senescence in bone can be triggered by reactive oxygen species, DNA damage, telomere dysfunction, and heterochromatin changes, depending on the cell type. miRNAs serve to modulate critical switching points, such as those between osteogenesis and adipogenesis, and aspects of the senescence program. The senescence-associated secretory phenotype (SASP) likely mediates local and even distant deleterious effects of senescent cells, especially by myeloid cells and osteocytes. Radiation-induced bone loss provides an accelerated aging bone model that recapitulates many aspects of age-related bone loss. With both physiological and premature bone aging, genetic and pharmacologic approaches to clearing senescent cells prevent, delay, or ameliorate osteoporosis in mouse models. Senolytic compounds are currently being evaluated in interventional clinical trials.



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