LSD1-mediated demethylation of the DNA damage response factor ATM promotes senescence and organ aging
Yingying Zhang, Chen Yu, Xiaoqin Zhang, Linda Xiaoyan Li, Alice Shasha Cheng, Xiaogang Li
Yingying Zhang, Chen Yu, Xiaoqin Zhang, Linda Xiaoyan Li, Alice Shasha Cheng, Xiaogang Li
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Research Article Aging Cell biology

LSD1-mediated demethylation of the DNA damage response factor ATM promotes senescence and organ aging

Abstract

Aging occurs heterogeneously across organs, leading to progressive tissue dysfunction. Cellular senescence is a stress response triggered by age-associated insults, yet the mechanisms regulating senescence and organ aging remain incompletely understood. Here, we defined a role for lysine-specific demethylase 1 (LSD1) in DNA damage–mediated senescence and organ aging. LSD1 was upregulated in aged organs and senescent cells. In response to natural aging or ionizing radiation–induced DNA damage, LSD1 interacted with and demethylated ATM at lysine 3,016, as confirmed using a newly generated ATM-K3016me antibody. This modification sustained ATM phosphorylation, amplified DNA damage signaling, and delayed checkpoint recovery, promoting senescence and organ aging. Inhibition of LSD1 accelerated ATM dephosphorylation via WIP1, enhanced DNA repair, reduced senescence and DNA damage, and prevented irradiation-induced hair graying. Elimination of senescent cells with senolytics reduced LSD1 protein in aged organs, indicating a feedback loop between LSD1 and senescence. Mechanistically, LSD1 underwent autophagosome-lysosome degradation through interaction with LC3 and Beclin1, and autophagy impairment during DNA damage contributed to LSD1 accumulation in senescent cells. This study revealed LSD1 as a key regulator of DNA damage–induced senescence and organ aging and suggested that targeting LSD1 may attenuate senescence, delay organ aging, and prevent hair graying.

Authors

Yingying Zhang, Chen Yu, Xiaoqin Zhang, Linda Xiaoyan Li, Alice Shasha Cheng, Xiaogang Li

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Figure 2

Targeting LSD1 decreases cellular senescence and elimination of senescent cells leads to a decline of LSD1 protein in aged organs.

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Targeting LSD1 decreases cellular senescence and elimination of senescen...
(A–C) Western blot analysis of the expression LSD1, p16, and p21 in organs, including kidneys (A), heart (B), and liver (C), collected from aged 20–22-month-old mice treated with senolytic drugs (Dasatinib 5 mg/Kg and Quercetin 50 mg/Kg, D + Q). (D) Western blot analysis of the expression of LSD1, p16 and p21 in mouse IMCD cells treated with Dasatinib (D) or Quercetin (Q), and cotreated with ETO (5 μM). Represent data from 3 independent experiments are shown. (E) qRT-PCR analysis of p16 and p21 mRNAs in mouse IMCD cells treated with Dasatinib (D) or Quercetin (Q) and cotreated with ETO (5 μM). All experiments were independently repeated at least 3 times; ns, no significant, **P < 0.01; 1-way ANOVA. (F) Representative images and quantification of and SA-β-gal staining (top), TUNEL assay (middle), and Ki67 staining (bottom) in mouse IMCD cells treated with LSD1 siRNA (siLSD1) and control siRNA (siNC) for 48 hours after ETO (5 μM) treatment. Scale bar: 50 μm. The percentage of positive cells was quantified using the same software in 10 randomly selected fields; ns, not significant, **P < 0.01; 1-way ANOVA. (G) Western blot analysis of the expression of LSD1, PCNA, cleaved caspase-3, p21, and p16 in mouse IMCD cells treated with ETO (5 μM) and cotreat with or without siLSD1 for 48 hours. n = 3. (H and I) qRT-PCR analysis of p16 and p21 (H), and SASP factors Il6, Il1b, Ccl2, Tgfb1, and Tnfa (I) mRNAs in mouse IMCD cells with or without LSD1 siRNA, 48 hours after ETO (5 μM) treatment. All experiments were repeated at least 3 times; ns, not significant, *P < 0.05, **P < 0.01; 1-way ANOVA.