TY - JOUR
T1 - microRNA-449a reduces growth hormone-stimulated senescent cell burden through PI3K-mTOR signaling
AU - Noureddine, Sarah
AU - Nie, Jia
AU - Schneider, Augusto
AU - Menon, Vinal
AU - Fliesen, Zoubeida
AU - Dhahbi, Joseph
AU - Victoria, Berta
AU - Oyer, Jeremiah
AU - Robles-Carrillo, Liza
AU - De Carvalho Nunes, Allancer Divino
AU - Ashiqueali, Sarah
AU - Janusz, Artur
AU - Copik, Alicja
AU - Robbins, Paul D.
AU - Musi, Nicolas
AU - Masternak, Michal M.
N1 - Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS.
PY - 2023/4/4
Y1 - 2023/4/4
N2 - 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 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.
AB - 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 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.
KW - adipose
KW - growth hormone
KW - longevity
KW - miR-449a
KW - senescence
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U2 - 10.1073/pnas.2213207120
DO - 10.1073/pnas.2213207120
M3 - Article
C2 - 36976763
AN - SCOPUS:85151167945
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 14
M1 - e2213207120
ER -