{"doi":"10.14336/ad.2025.1243","title":"Increased Stability of Tristetraprolin mRNA Supports Bone Health and Decreases Frailty During Aging","abstract":"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.","journal":"Aging and Disease","year":2025,"id":587738,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":367409,"name":"Lixia Zhang","orcid":"0000-0002-2689-2452","position":1,"is_corresponding":false},{"id":1503859,"name":"Leticia Andrea Rojas Cortéz","orcid":null,"position":2,"is_corresponding":false},{"id":724827,"name":"Kyu Hwan Kwack","orcid":"0000-0002-7570-3734","position":3,"is_corresponding":false},{"id":1331846,"name":"Victoria Maglaras","orcid":"0009-0004-8821-4069","position":4,"is_corresponding":false},{"id":1019692,"name":"Nanda Kumar Yellapu","orcid":"0000-0002-3095-6375","position":5,"is_corresponding":false},{"id":516737,"name":"Yukitomo Arao","orcid":"0000-0003-1560-351X","position":6,"is_corresponding":false},{"id":484459,"name":"Kenneth L. Seldeen","orcid":"0000-0003-1989-6698","position":7,"is_corresponding":false},{"id":376177,"name":"Perry J. Blackshear","orcid":"0000-0002-9561-8529","position":8,"is_corresponding":false},{"id":484463,"name":"Bruce R. Troen","orcid":"0000-0002-3699-0021","position":9,"is_corresponding":false},{"id":314728,"name":"Keith L. Kirkwood","orcid":"0000-0003-4519-8973","position":10,"is_corresponding":false},{"id":484462,"name":"Ramkumar Thiyagarajan","orcid":"0000-0003-0188-7363","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:59:39.958043Z","pmid":"41619274","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}