{"doi":"10.1073/pnas.2213207120","title":"microRNA-449a reduces growth hormone-stimulated senescent cell burden through PI3K-mTOR signaling","abstract":"Cellular senescence, a hallmark of aging, has been implicated in the pathogenesis of many major age-related disorders, including neurodegeneration, atherosclerosis, and metabolic disease. Therefore, investigating novel methods to reduce or delay the accumulation of senescent cells during aging may attenuate age-related pathologies. microRNA-449a-5p (miR-449a) is a small, noncoding RNA down-regulated with age in normal mice but maintained in long-living growth hormone (GH)-deficient Ames Dwarf (df/df) mice. We found increased fibroadipogenic precursor cells, adipose-derived stem cells, and miR-449a levels in visceral adipose tissue of long-living df/df mice. Gene target analysis and our functional study with miR-449a-5p have revealed its potential as a serotherapeutic. Here, we test the hypothesis that miR-449a reduces cellular senescence by targeting senescence-associated genes induced in response to strong mitogenic signals and other damaging stimuli. We demonstrated that GH downregulates miR-449a expression and accelerates senescence while miR-449a upregulation using mimetics reduces senescence, primarily through targeted reduction of p16 Ink4a , p21 Cip1 , and the PI3K-mTOR signaling pathway. Our results demonstrate that miR-449a is important in modulating key signaling pathways that control cellular senescence and the progression of age-related pathologies.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":339504,"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":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9513,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":464307,"name":"Jia Nie","orcid":"0000-0001-9085-7224","position":1,"is_corresponding":false},{"id":297867,"name":"Augusto Schneider","orcid":"0000-0002-3410-2860","position":2,"is_corresponding":false},{"id":793906,"name":"Vinal Menon","orcid":"0000-0001-7121-3589","position":3,"is_corresponding":false},{"id":1073465,"name":"Zoubeida Fliesen","orcid":null,"position":4,"is_corresponding":false},{"id":781887,"name":"Joseph Dhahbi","orcid":"0000-0001-5832-3804","position":5,"is_corresponding":false},{"id":786925,"name":"Berta Victoria","orcid":"0000-0002-2267-4693","position":6,"is_corresponding":false},{"id":770718,"name":"Jeremiah L. Oyer","orcid":"0000-0002-9368-9323","position":7,"is_corresponding":false},{"id":1073466,"name":"Liza Robles‐Carrillo","orcid":null,"position":8,"is_corresponding":false},{"id":622485,"name":"Allancer Divino de Carvalho Nunes","orcid":null,"position":9,"is_corresponding":false},{"id":1030735,"name":"Sarah Ashiqueali","orcid":"0000-0003-1980-1054","position":10,"is_corresponding":false},{"id":1073467,"name":"Artur Janusz","orcid":null,"position":11,"is_corresponding":false},{"id":770719,"name":"Alicja J. Copik","orcid":"0000-0003-4109-5539","position":12,"is_corresponding":false},{"id":233167,"name":"Paul D. Robbins","orcid":"0000-0003-1068-7099","position":13,"is_corresponding":false},{"id":665069,"name":"Nicolas Musi","orcid":"0000-0003-4242-2888","position":14,"is_corresponding":false},{"id":297868,"name":"Michał M. Masternak","orcid":"0000-0002-8483-930X","position":15,"is_corresponding":false},{"id":690595,"name":"Sarah Noureddine","orcid":"0000-0002-7582-5985","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T01:10:45.048445Z","pmid":"36976763","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":[]}