Produção Nacional
Revisado por pares
microRNA-449a reduces growth hormone-stimulated senescent cell burden through PI3K-mTOR signaling
2023; National Academy of Sciences; Volume: 120; Issue: 14 Linguagem: Inglês
10.1073/pnas.2213207120
ISSN1091-6490
AutoresSarah Noureddine, Jia Nie, Augusto Schneider, Vinal Menon, Zoubeida Fliesen, Joseph Dhahbi, Berta Victoria, Jeremiah L. Oyer, Liza Robles‐Carrillo, Allancer Divino de Carvalho Nunes, Sarah Ashiqueali, Artur Janusz, Alicja J. Copik, Paul D. Robbins, Nicolas Musi, Michał M. Masternak,
Tópico(s)Circular RNAs in diseases
ResumoCellular 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 p16Ink4a, p21Cip1, 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.
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