Autophagy inhibitor 3-methyladenine mitigates the severity of colitis in aged mice by inhibiting autophagy

• Published in: Experimental gerontology Vol. 201; p. 112697
• Main Authors: Liu, Ailing, Wang, Hongying, Lv, Hong, Yang, Hong, Li, Yue, Qian, Jiaming
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.03.2025; Elsevier
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Adenine - therapeutic use; Aged; Aging; Animals; Autophagy - drug effects; Cell autophagy; Colitis - chemically induced; Colitis - drug therapy; Colitis, Ulcerative - chemically induced; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - metabolism; Colitis, Ulcerative - pathology; Colon - drug effects; Colon - pathology; Dextran Sulfate; Disease Models, Animal; Female; Humans; Inflammation; Inflammatory bowel disease; Macrophagy; Male; Mice; Mice, Inbred C57BL; NF-kappa B - metabolism; Senescence; Severity of Illness Index; Inflammatory bowel disease; Senescence; Inflammation; Macrophagy; Cell autophagy
• ISSN: 0531-5565; 1873-6815; 1873-6815
• DOI: 10.1016/j.exger.2025.112697

The elderly ulcerative colitis (UC) patients pose unique challenges due to their comorbidities, diminished functional capacity, and heightened risk of treatment-related complications. Thus, finding a safe and effective treatment for this age group is crucial. This study investigates the role of autophagy in the pathogenesis of UC in young and elderly patients, and explores the therapeutic potential and mechanisms of autophagy modulators in aged mice with dextran sulfate sodium (DSS)-induced colitis. Colonic biopsies were collected from young and old UC patients as well as comparable healthy subjects. Young (6–8 weeks) and aged (56 weeks) C57BL/6 mice were treated with DSS to induce acute colitis model. The autophagy inhibitor 3-methyladenine was administered intraperitoneally to aged DSS-induced mice. The autophagy activity was detected by the protein expressions of LC3B-II, p62 and ATG5 by western blot and immunohistochemistry. The levels of TNF -α, IL-6, CCL4, CXCL12 and CD86 were measured by qRT-PCR. The transcriptional activity of NF-κB was measured by electrophoretic mobility shift assay (EMSA). Increased autophagy activity was observed in aged DSS-induced mice. Treatment with 3-methyladenine suppressed autophagy in intestinal epithelial cells (IECs) and alleviated colitis severity. Additionally, 3-methyladenine reduced macrophage recruitment, decreased IL-6 levels, and inhibited NF-κB signaling, thereby mitigating inflammation. Significant differences in autophagy activity were identified between young and aged DSS-induced mice. These findings underscore the potential therapeutic benefits of autophagy inhibition in elderly UC patients. •Elderly individuals with ulcerative colitis (UC) pose unique challenges due to their comorbidities, diminished functional capacity, and heightened risk of treatment-related complications. Thus, finding a safe and effective treatment for this age group is crucial.•This study found that autophagy was detected in intestinal epithelial cells (IECs) from both young and elderly UC patients and DSS-induced mice, with increased activity observed in elderly patients and aged mice.•The autophagy inhibitor 3-methyladenine reduced autophagy in IECs and lessened colitis severity in aged DSS-induced mice.•Furthermore, 3-methyladenine decreased macrophage recruitment, inhibited M1 macrophage polarization, reduced IL-6 levels, and suppressed the NF-κB signaling pathway, thereby reducing inflammation.•These results indicate that autophagy inhibition may be a viable therapeutic approach for elderly UC patients.