Abstract
Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence‐associated secretory phenotype (SASP). Many types of stress induce senescence, including genotoxic stress. ERCC1‐XPF is a DNA repair endonuclease required for multiple DNA repair mechanisms that protect the nuclear genome. Humans or mice with reduced expression of this enzyme age rapidly due to increased levels of spontaneous, genotoxic stress. Here, we asked whether this corresponds to an increased level of senescent cells. p16Ink4a and p21Cip1 mRNA were increased ~15‐fold in peripheral lymphocytes from 4‐ to 5‐month‐old Ercc1 −/∆ and 2.5‐year‐old wild‐type (WT) mice, suggesting that these animals exhibit a similar biological age. p16Ink4a and p21Cip1 mRNA were elevated in 10 of 13 tissues analyzed from 4‐ to 5‐month‐old Ercc1 −/∆ mice, indicating where endogenous DNA damage drives senescence in vivo. Aged WT mice had similar increases of p16Ink4a and p21Cip1 mRNA in the same 10 tissues as the mutant mice. Senescence‐associated β–galactosidase activity and p21Cip1 protein also were increased in tissues of the progeroid and aged mice, while Lamin B1 mRNA and protein levels were diminished. In Ercc1 −/Δ mice with a p16Ink4a luciferase reporter, bioluminescence rose steadily with age, particularly in lung, thymus, and pancreas. These data illustrate where senescence occurs with natural and accelerated aging in mice and the relative extent of senescence among tissues. Interestingly, senescence was greater in male mice until the end of life. The similarities between Ercc1 −/∆ and aged WT mice support the conclusion that the DNA repair‐deficient mice accurately model the age‐related accumulation of senescent cells, albeit six‐times faster.
Highlights
Cellular senescence is a programmed, largely irreversible arrest of cellular proliferation, sustained even in the presence of mitogenic stimuli (Campisi, 2013)
We provide a comprehensive measure of senescence in aged WT mice
As measured by qRT-PCR and p16LUC signal, levels of p16Ink4a were significantly increased in aged WT mice compared with younger adult mice, as expected (Figures 1 and 5), p16Ink4a and p21Cip1 expression are found in peripheral T cells and numerous tissues (10 of 14 total tested) with the exception of heart and skeletal muscles
Summary
Cellular senescence is a programmed, largely irreversible arrest of cellular proliferation, sustained even in the presence of mitogenic stimuli (Campisi, 2013). Levels of p16Ink4a and p21Cip mRNA in T cells from 4- to 5-month-old Ercc1−/∆ mice were increased relative to age-matched WT controls (Figure 1a; 15-fold; p < .0001 and 13-fold; p < .01, respectively). The expression of these senescence markers was indistinguishable between the progeroid and aged WT mice. While the expression of p16Ink4a and p21Cip mRNA was significantly increased in both sexes of Ercc1−/∆ mice, it was significantly greater in males at 4 to 5 months of age than age-matched females in the liver, kidney, and spleen (Figure S1). The data demonstrate that senescent cells accumulate over time in Ercc1−/∆ mice, as occurs with aging in WT mice (Burd et al, 2013)
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