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A Brain Anti-Senescence Transcriptional Program Triggered by Hypothalamic-Derived Exosomal microRNAs.
Krarup, Josefa; Araya, Lucas; Álvarez, Felipe; Bórquez, Daniel A; Urrutia, Pamela J.
Afiliação
  • Krarup J; Laboratory of Cell Signaling & Bioinformatics, Center for Biomedical Research, Faculty of Medicine, Universidad Diego Portales, Ejército Libertador 141, Santiago 8370007, Chile.
  • Araya L; Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago 7810000, Chile.
  • Álvarez F; Laboratory of Cell Signaling & Bioinformatics, Center for Biomedical Research, Faculty of Medicine, Universidad Diego Portales, Ejército Libertador 141, Santiago 8370007, Chile.
  • Bórquez DA; Laboratory of Cell Signaling & Bioinformatics, Center for Biomedical Research, Faculty of Medicine, Universidad Diego Portales, Ejército Libertador 141, Santiago 8370007, Chile.
  • Urrutia PJ; Laboratory of Resilient Aging, Institute for Nutrition & Food Technology (INTA), Universidad de Chile, El Líbano 5524, Santiago 7830490, Chile.
Int J Mol Sci ; 25(10)2024 May 17.
Article em En | MEDLINE | ID: mdl-38791505
ABSTRACT
In contrast to the hypothesis that aging results from cell-autonomous deterioration processes, the programmed longevity theory proposes that aging arises from a partial inactivation of a "longevity program" aimed at maintaining youthfulness in organisms. Supporting this hypothesis, age-related changes in organisms can be reversed by factors circulating in young blood. Concordantly, the endocrine secretion of exosomal microRNAs (miRNAs) by hypothalamic neural stem cells (htNSCs) regulates the aging rate by enhancing physiological fitness in young animals. However, the specific molecular mechanisms through which hypothalamic-derived miRNAs exert their anti-aging effects remain unexplored. Using experimentally validated miRNA-target gene interactions and single-cell transcriptomic data of brain cells during aging and heterochronic parabiosis, we identify the main pathways controlled by these miRNAs and the cell-type-specific gene networks that are altered due to age-related loss of htNSCs and the subsequent decline in specific miRNA levels in the cerebrospinal fluid (CSF). Our bioinformatics analysis suggests that these miRNAs modulate pathways associated with senescence and cellular stress response, targeting crucial genes such as Cdkn2a, Rps27, and Txnip. The oligodendrocyte lineage appears to be the most responsive to age-dependent loss of exosomal miRNA, leading to significant derepression of several miRNA target genes. Furthermore, heterochronic parabiosis can reverse age-related upregulation of specific miRNA-targeted genes, predominantly in brain endothelial cells, including senescence promoting genes such as Cdkn1a and Btg2. Our findings support the presence of an anti-senescence mechanism triggered by the endocrine secretion of htNSC-derived exosomal miRNAs, which is associated with a youthful transcriptional signature.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Envelhecimento / MicroRNAs / Exossomos / Células-Tronco Neurais / Hipotálamo Limite: Animals Idioma: En Revista: Int J Mol Sci Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Chile

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Envelhecimento / MicroRNAs / Exossomos / Células-Tronco Neurais / Hipotálamo Limite: Animals Idioma: En Revista: Int J Mol Sci Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Chile