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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\u2013mediated senescence and organ aging. LSD1 was upregulated in aged organs and senescent cells. In response to natural aging or ionizing radiation\u2013induced 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\u2013induced senescence and organ aging and suggested that targeting LSD1 may attenuate senescence, delay organ aging, and prevent hair graying.<\/jats:p>","DOI":"10.1172\/jci199854","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T18:01:18Z","timestamp":1789408878000},"source":"Crossref","is-referenced-by-count":0,"title":["LSD1-mediated demethylation of the DNA damage response factor ATM promotes senescence and organ aging"],"prefix":"10.1172","volume":"136","author":[{"given":"Yingying","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA."},{"name":"Department of Nephrology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, 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