microRNA-449a reduces growth hormone-stimulated senescent cell burden through PI3K-mTOR signaling
| Autor: | Sarah Noureddine, Jia Nie, Augusto Schneider, Vinal Menon, Zoubeida Fliesen, Joseph Dhahbi, Berta Victoria, Jeremiah Oyer, Liza Robles-Carrillo, Allancer Divino De Carvalho Nunes, Sarah Ashiqueali, Artur Janusz, Alicja Copik, Paul D. Robbins, Nicolas Musi, Michal M. Masternak |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Proceedings of the National Academy of Sciences. 120 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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