Figure 1
From: Lipid-derived reactive aldehydes link oxidative stress to cell senescence
The aldehyde end-product of lipid peroxidation 4-HNE synergizes with DNA damage to induce accelerated senescence. (a) Detection of accelerated senescence in live cells by dual parameter flow cytometry using the far-red fluorescent probe DDAOG to measure senescence-associated beta-galactosidase (SA-β-Gal) and green autofluorescence to detect the age-related pigment lipofuscin. Treating B16 murine melanoma cells with 5 Gy of gamma irradiation shifts only a small fraction into senescence compared with a higher dose of 25 Gy or the topoisomerase II poison etoposide. Combined treatment with 4-HNE and 5 Gy drives more cells into senescence, demonstrating a compound effect. (b) Inducing senescence in melanoma cells with etoposide results in high levels of lipid peroxidation, 4-HNE adducts, and chromosomal breaks compared with untreated controls. Upper micrographs show lipid peroxidation reporter C11-BODIPY (LPO, orange). Lower images display dual immunofluorescence staining for 4-HNE adducts (cyan) and the DNA double-strand break (DSB) marker pH2AX (magenta). Bar=5 μm. (c) Schematic of our findings. We observed onset of accelerated senescence with a flow cytometry assay for SA-β-Gal and lipofuscin when proliferating cancer cells were treated with a high dose of radiation or topoisomerase poisons. Along with DNA DSBs, radiation and topoisomerase inhibitors each induced lipid peroxidation, leading to accumulation of reactive aldehydes such as 4-HNE. Treating cells with the aldehyde scavenging compound hydralazine blocked the effects of radiation or topoisomerase inhibitors, establishing a key role for lipid peroxidation in accelerated senescence
