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Age related changes in mTOR-related gene expression in two primary human cell lines

Alexander D. Fellows, Alice C. Holly, Luke C. Pilling, David Melzer, Lorna W. Harries

Abstract

Background: Leukocyte transcriptomics studies suggest disrupted mTOR gene expression is a feature of human aging. We aimed to establish whether gene expression is also disrupted in other human tissues senesced in vitro.

Methods: We aged two primary cell types (fibroblasts and endothelial cells) in vitro, by repeated passage until growth arrest, and measured the expression of an mTOR-related transcript set by quantitative real-time PCR in low passage (‘young’) and high passage (‘old’) cells.

Results: We identified expression differences for 7/28 mTOR-related transcripts in senescent fibroblasts, which included up-regulation of mTORC1 inhibitory transcripts (DEPTOR, TSC1, TSC2; p=0.047, 0.007, and 0.024 respectively) with concurrent up-regulation of down-stream transcripts usually inhibited by mTOR activation (NFKB1, PRKCA, EIF4G3 and FOXO1; p=0.047, 0.007 0.005 and 0.038 respectively). Endothelial cells demonstrated 2 significant expression changes between senescent and non-senescent cells (PRCKA and SGK1; p<0.001 and p=0.0031 respectively), transcripts involved in mTORC2 signaling.

Conclusions: Our preliminary study suggests that age-related gene expression changes noted in human population studies also occur with senescence in some primary human tissue types. Age-related expression changes in primary human fibroblasts involve mainly mTORC1 transcripts, whilst in human endothelial cells, expression changes are less apparent and involve mTORC2-related transcripts.