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

Sci Rep. 2018 Jul 19;8(1):10929. doi: 10.1038/s41598-018-29086-2.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / genetics*
  • Alternative Splicing
  • Female
  • Gene Expression Profiling / methods*
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Organ Specificity
  • RNA / metabolism*
  • RNA Splicing
  • Sequence Analysis, RNA

Substances

  • RNA