Kalailingam Pazhanichamy, Ngan SoFong Cam, Iyappan Ranjith, Nehchiri Afra, Mohd-Kahliab Khalilatul-Hanisah, Lee Benjamin Sian Teck, Sharma Bhargy, Machan Radek, Bo Sint Thida, Chambers Emma S, Fajardo Val A, Macpherson Rebecca E K, Liu Jian, Klentrou Panagiota, Tsiani Evangelia Litsa, Lim Kah Leong, Su I Hsin, Gao Yong-Gui, Richar A Mark, Kalaria Raj N, Chen Christopher P, Balion Cynthia, de Kleijn Dominique, McCarthy Neil E, Sze Siu Kwan
Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
Aging Cell. 2025 Apr;24(4):e14425. doi: 10.1111/acel.14425. Epub 2025 Jan 5.
Accumulation of damaged biomolecules in body tissues is the primary cause of aging and age-related chronic diseases. Since this damage often occurs spontaneously, it has traditionally been regarded as untreatable, with typical therapeutic strategies targeting genes or enzymes being ineffective in this domain. In this report, we demonstrate that an antibody targeting the isoDGR damage motif in lung tissue can guide immune clearance of harmful damaged proteins in vivo, effectively reducing age-linked lung inflammation. We observed age-dependent accumulation of the isoDGR motif in human lung tissues, as well as an 8-fold increase in isoDGR-damaged proteins in lung fibrotic tissues compared with healthy tissue. This increase was accompanied by marked infiltration of CD68+/CD11b + macrophages, consistent with a role for isoDGR in promoting chronic inflammation. We therefore assessed isoDGR function in mice that were either naturally aged or lacked the isoDGR repair enzyme. IsoDGR-protein accumulation in mouse lung tissue was strongly correlated with chronic inflammation, pulmonary edema, and hypoxemia. This accumulation also induced mitochondrial and ribosomal dysfunction, in addition to features of cellular senescence, thereby contributing to progressive lung damage over time. Importantly, treatment with anti-isoDGR antibody was able to reduce these molecular features of disease and significantly reduced lung pathology in vivo.
体内组织中受损生物分子的积累是衰老和与年龄相关的慢性疾病的主要原因。由于这种损伤通常是自发发生的，传统上一直被认为是无法治疗的，针对基因或酶的典型治疗策略在这一领域无效。在本报告中，我们证明了一种靶向肺组织中异天冬酰胺-甘氨酸-精氨酸（isoDGR）损伤基序的抗体能够在体内引导对有害受损蛋白的免疫清除，有效减轻与年龄相关的肺部炎症。我们观察到isoDGR基序在人肺组织中随年龄增长而积累，并且与健康组织相比，肺纤维化组织中isoDGR损伤蛋白增加了8倍。这种增加伴随着CD68+/CD11b +巨噬细胞的显著浸润，这与isoDGR在促进慢性炎症中的作用一致。因此，我们评估了在自然衰老或缺乏isoDGR修复酶的小鼠中isoDGR的功能。小鼠肺组织中isoDGR蛋白的积累与慢性炎症、肺水肿和低氧血症密切相关。这种积累还会导致线粒体和核糖体功能障碍，以及细胞衰老特征，从而随着时间的推移导致肺部进行性损伤。重要的是，用抗isoDGR抗体治疗能够减轻这些疾病的分子特征，并显著减轻体内的肺部病理变化。
