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.
Bibliographical noteFunding Information:
This work was supported by NIH P01 AG043376, U19 AG056278, R56 AG059676, and R01 AG063543 (LJN & PDR). AUG is supported by NIH K99 AG049126. CEB is supported by NIH R00 AG057032. MJY is supported by The Irene Diamond?Fund/American Federation on Aging Research?Postdoctoral Transition Award. We are grateful to Shannon Howard, Tokio Sano, Jamie Harris, Kylie Frohmader, Alexshiandria Ingle, and the Scripps Florida Animal Research Center for help with animal care. We thank Mariah Witt for helpful comments.
This work was supported by NIH P01 AG043376, U19 AG056278, R56 AG059676, and R01 AG063543 (LJN & PDR). AUG is supported by NIH K99 AG049126. CEB is supported by NIH R00 AG057032. MJY is supported by The Irene Diamond Fund/American Federation on Aging Research Postdoctoral Transition Award.
© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
- DNA repair
- cellular senescence
- endogenous DNA damage