Mechanical rejuvenation of senescent stem cells and aged bone via chromatin remodeling

Abstract

Bone aging compromises skeletal integrity and increases vulnerability to osteoporosis and other age-related disorders, underscoring the need for new therapeutic strategies. Although pharmacological and genetic approaches have been widely explored, how cellular mechanical remodeling contributes to bone aging remains unclear. Here, we find that senescent bone marrow stem cells show markedly reduced intracellular force and impaired mechanical behavior. Moderate mechanical stimulation in cell culture and in mice restores cellular force, increases chromatin accessibility at the FOXO1 locus, activates its expression, and reverses cellular senescence and bone aging. These mechanical interventions also improve physical performance in aged female mice and show a tendency to reduce systemic inflammation, whereas excessive force induces chromatin overextension and DNA damage, indicating the necessity of precise force control. In this work, we show that optimized mechanical stimulation provides a simple and effective strategy to counteract age-related bone deterioration and systemic inflammation, offering potential for clinical translation. Senescent bone marrow stem cells were revealed to exhibit reduced intracellular force, and optimized mechanical stimulation restores this force, enhances FOXO1 chromatin accessibility, and reverses cellular senescence and bone aging.