Comprehensive map of age-associated splicing changes across human tissues and their contributions to age-associated diseases

Abstract

Alternative splicing contributes to phenotypic diversity at multiple biological scales, and its dysregulation is implicated in both ageing and age-associated diseases in human. Cross-tissue variability in splicing further complicates its links to age-associated phenotypes and elucidating these links requires a comprehensive map of age-associated splicing changes across multiple tissues. Here, we generate such a map by analyzing ~8500 RNA-seq samples across 48 tissues in 544 individuals. Employing a stringent model controlling for multiple confounders, we identify 49,869 tissue-specific age-associated splicing events of 7 distinct types. We find that genome-wide splicing profile is a better predictor of biological age than the gene and transcript expression profiles, and furthermore, age-associated splicing provides additional independent contribution to age-associated complex diseases. We show that the age-associated splicing changes may be explained, in part, by concomitant age-associated changes of the upstream splicing factors. Finally, we show that our splicing-based model of age can successfully predict the relative ages of cells in 8 of the 10 paired longitudinal data as well as in 2 sets of cell passage data. Our study presents the first systematic investigation of age-associated splicing changes across tissues, and further strengthening the links between age-associated splicing and age-associated diseases.

Reduced RNA turnover as a driver of cellular senescence

“…In parallel, transcripts from SINEs/Alus, a family of repetitive elements particularly abundant in euchromatin, have been reported to accumulate in senescent cells with an impact on genome integrity (12). Finally, several studies have reported that cellular senescence is associated with numerous changes in the outcome of alternative pre-mRNA splicing (13). This results in the production of senescent toxins including progerin, a variant of Lamin A associated with the Hutchinson-Gilford progeria syndrome (14), while also favoring the synthesis of S-Endoglin and p53beta that may have a similar prosenescence activity (15) (16).…”

A Landscape of Murine Long Non-Coding RNAs Reveals the Leading Transcriptome Alterations in Adipose Tissue during Aging

“…Transcriptome change is a significant molecular signature of aging and serves as an essential factor in the aging-associated functional decline across organs ( Benayoun et al, 2019 ; Braun et al, 2016 ; Schaum et al, 2019 ; Stoeger et al, 2019 ; Yu et al, 2014 ; Zahn et al, 2007 ). Several earlier studies have profiled and analyzed age-correlated gene expression in different organs in rodents ( Barns et al, 2014 ; Benayoun et al, 2019 ; Braun et al, 2016 ; de Magalhães et al, 2009 ; Ori et al, 2015 ; Schaum et al, 2019 ; Stoeger et al, 2019 ; Yu et al, 2014 ; Zahn et al, 2007 ; Zhuang et al, 2019 ) and humans ( Ahadi et al, 2020 ; Glass et al, 2013 ; Wang et al, 2018 ; Yang et al, 2015 ; Zhuang et al, 2019 ). The majority of the genes altered during aging are associated with inflammatory responses ( Benayoun et al, 2019 ; Schaum et al, 2019 ; Stegeman and Weake, 2017 ), highlighting chronic inflammation as a hallmark of aging.…”

Transcriptome complexity in intravascular NK/T-cell lymphoma

“…In addition, tumour-specific splice variants of genes that control cell proliferation and apoptosis have been reported in the last decade 23–29 32 33. These processes are influenced both by genetic factors and environmental factors, for example, immune responses,34 35 age,36 heat stress37 and DNA damage 38. CNAs have also been described as having a particular association with AS 16 19.…”