Dysregulated RNA processing and metabolism: a new hallmark of ageing and provocation for cellular senescence

Abstract

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Three‐dimensional chromatin re‐organization during muscle stem cell aging

“…Clusters enriched in young MuSCs were marked by genes that participate in signaling by receptor tyrosine kinases (fibroblast growth factors, VEGFA, EGFR), which are known to regulate MuSC homeostasis (Hindi & Kumar, 2016 ; Pawlikowski et al, 2017 ; Verma et al, 2018 ), as well as Notch signaling ( Notch1, Maml1/2/3, Dtx2 ) and ubiquitination‐proteosome activity ( Ubc , Uba52 , Rtf1 ), which are known to support MuSC quiescence (Fujimaki et al, 2018 ; Kitajima et al, 2018 ; Noguchi et al, 2019 ). Clustering also revealed differences in linkages regulating RNA homeostasis whereby mRNA splicing was uniquely enriched in young MuSCs (splicing factors, spliceosome components, ribonucleoproteins, DEAD box proteins), while mRNA decay was marked in aged MuSCs ( Zfp36l1 , exosome complex genes, U6 snRNA‐associated Sm‐like protein genes), which regulates myogenic gene expression (Hausburg et al, 2015 ; Relaix et al, 2021 ) and is associated with the aging phenotype (Deschênes & Chabot, 2017 ; Harries, 2022 ; Stegeman & Weake, 2017 ; Stoeger et al, 2022 ).…”

The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence

“…When the DNA damage response (DDR) is prolonged, it promotes senescence [4]. Further known mechanisms underlying senescence are: (1) persistent DDR activation at telomeres, the ends of chromosomes, which is sufficient to activate replicative cell senescence [8]; (2) oncogene activation partly via reactive oxygen species (ROS) production, determining hyperproliferation and altered DNA replication profiles [4,8]; (3) cell cycle arrest by upregulation of p21 and p16 [9]; (4) mitochondrial abnormalities with an increase in ROS synthesis and impairment in biogenesis and mitophagy [10]; (5) induction to resistance to apoptosis by upregulation of the antiapoptotic proteins [10]; (6) metabolic changes determined by senescence-associated-β-galactosidase (SA-β gal) accumulation along with the increase in cellular lysosomal content [10]; (7) large-scale chromatin reorganization occurring with the generation of senescence-associated heterochromatin foci, which suppress transcription of pro-proliferation genes [10]; (8) secretion of pro-inflammatory cytokines, chemokines, proteases, and growth factors that influence the neighbouring cells (SASP profile); (9) morphological alterations including cellular flattening and enlargement [10]; (10) post-transcriptional regulatory pathways taking place at different levels: through the action of mRNA-binding proteins (RBPs) and noncoding RNAs [11][12][13][14]; through a dysregulated splicing factor expression [12,15]; and through N6-methyladenosine (m6A) processes with specific m6A-binding proteins [14].…”

A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma

“…Albeit interferon signaling has earlier on been linked with senescence [48, 49], only later Katlinskaya and Yu et al showed a role of IFNAR1 in the induction of senescence [50, 51]. Recently the accumulation of double stranded RNA was proposed to also contribute to the onset of senescence [52, 53]. These findings suggest a link between senescence and viral mimicry, which can engage autocrine and paracrine secretion of interferons.…”