Prolonged expression of senescence markers in mice exposed to gamma-irradiation

Abstract

Although ionizing radiation is known to induce cellular senescence in vitro and in vivo, its long-term in vivo effects are not well defined. In this study, we examined the prolonged expression of senescence markers in mice irradiated with single or fractionated doses. C57BL/6 female mice were exposed to 5 Gy of γ-rays in single or 5, 10, 25 fractions. At 2, 4, and 6 months after irradiation, senescence markers including mitochondrial DNA (mtDNA) common deletion, p21, and senescence-associated β-galactosidase (SA β-gal) were monitored in the lung, liver, and kidney. Increases of mtDNA deletion were detected in the lung, liver, and kidney of irradiated groups. p21 expression and SA β-gal staining were also increased in the irradiated groups compared to the non-irradiated control group. Increases of senescence markers persisted up to 6 months after irradiation. Additionally, the extent of mtDNA deletion and the numbers of SA β-gal positive cells were greater as the number of radiation fractions increased. In conclusion, our results showed that ionizing radiation, especially that delivered in fractions, can cause the persistent upregulation of senescence marker expression in vivo. This should be considered when dealing with chronic normal tissue injuries caused by radiation therapy or radiation accidents.

The PI3K/Akt/mTOR Pathway Is Implicated in the Premature Senescence of Primary Human Endothelial Cells Exposed to Chronic Radiation

“…The higher dose rate (2.4 mGy/h) was able to induce premature senescence based on the appearance of classical hallmarks: the inhibition of growth, and increased number of cells stained by SA-ß-gal. as well as increased expression of the cell cycle inhibitory cyclin-dependent kinase inhibitor p21, a known senescence marker in cellular [43] and animal models [44]. Even at the lower dose rate (1.4 mGy/h), the level of p21 was significantly enhanced in irradiated cells at week 10.…”

Whole Brain Radiation-Induced Vascular Cognitive Impairment: Mechanisms and Implications

“…Senescent cells express markers such as p16 ink4a also known as CDKN2A [167-169], p38MAPK [170] and have high senescence associated beta galactosidase (SA β-gal) activity [171, 172]. Recent studies demonstrate that radiation induces premature senescence in vitro [173] and in vivo , senescent cells can persist at least to six months after radiation in mice [174]. Even though cellular senescence occurs following radiation, it remains unclear whether senescence per se is a contributing factor in impaired angiogenesis and it is not known whether specific cells are more susceptible to senescence than others.…”

Delayed effects of acute whole body lethal radiation exposure in mice pre-treated with BBT-059

“…Elevated expression of p21 has been previously reported following exposure to ionizing radiation 45 . An earlier report demonstrated increased expression of senescence-related markers in liver, brain, and lung tissues several weeks after exposure to ionizing radiation 20 . In contrast, the current study implies that the senescence markers examined reached increased expression levels after 30 days and remained relatively unchanged through the end of the 12 month study.…”

“…DEARE was studied in an early publication by Lawrence and Tennant 11 and since that time a number of studies to further our understanding have been published 10,[12][13][14][15][16][17][18][19][20] . Several of these studies have addressed DEARE in irradiated animals without the use of radiation countermeasures at set time points relative to TBI.…”