Generation of a novel model of primary human cell senescence through Tenovin-6 mediated inhibition of sirtuins

Abstract

Cell senescence, a state of cell cycle arrest and altered metabolism with enhanced pro-inflammatory secretion, underlies at least some aspects of organismal ageing. The sirtuin family of deacetylases has been implicated in preventing premature ageing; sirtuin overexpression or resveratrol-mediated activation of sirtuins increase longevity. Here we show that sirtuin inhibition by short-term, low-dose treatment with the experimental anti-cancer agent Tenovin-6 (TnV6) induces cellular senescence in primary human fibroblasts. Treated cells cease proliferation and arrest in G1 of the cell cycle, with elevated p21 levels, DNA damage foci, high mitochondrial and lysosomal load and increased senescence-associated β galactosidase activity, together with actin stress fibres and secretion of IL-6 (indicative of SASP upregulation). Consistent with a histone deacetylation role of SIRT1, we find nuclear enlargement, possibly resulting from chromatin decompaction on sirtuin inhibition. These findings highlight TnV6 as a drug that may be useful in clinical settings where acute induction of cell senescence would be beneficial, but also provide the caveat that even supposedly non-genotoxic anticancer drugs can have unexpected and efficacy-limiting impacts on non-transformed cells.