Increased Stability of Tristetraprolin mRNA Supports Bone Health and Decreases Frailty During Aging

Age-related chronic low-grade inflammation contributes to both frailty and bone loss. One of the key regulators of inflammatory signaling that declines with age is tristetraprolin (TTP), an RNA-binding protein that promotes degradation of pro-inflammatory transcripts. In this study, we investigated whether stabilizing TTP during aging could reduce frailty and enhance bone health by mitigating inflammation and immune dysfunction. We utilized a knock-in mouse model (TTP∆ARE), in which an AU-rich region of the 3' untranslated region was deleted to stabilize TTP mRNA and increase protein expression. Aged TTP∆ARE mice had reduced physical frailty scores, a composite measure based on body weight and physical performance, than age-matched wild-type controls (WT). Since frailty is associated with fracture risk, we examined bone structure. Aged TTP∆ARE males exhibited significantly higher bone mineral density and improved bone microarchitecture relative to WT mice. Our prior work showed that aging elevates myeloid-derived suppressor cells (MDSCs), which possess osteoclastogenic potential. The monocytic MDSCs (M-MDSCs) from the bone marrow of aged TTP∆ARE formed fewer osteoclasts than those from WT mice. Further, transcriptomic analysis of M-MDSCs revealed downregulation of bone resorption and remodeling pathways, along with upregulation of immune activation genes. In addition, immunophenotyping revealed a healthier, youthful-like immune profile in aged TTP∆ARE mice, including increased T-cell reservoirs. These findings signify the critical role of TTP in bone health during aging by regulating osteoimmunological induction of M-MDSCs, which leads to a partial reversal of the age-associated immune senescent phenotype, resulting in increased bone mineral density and improved functional capacity during aging.