Aging results from the accumulation of molecular damage that impairs normal biochemical processes. We previously reported that age-linked damage to amino acid sequence NGR (Asn-Gly-Arg) results in “gain-of-function” conformational switching to isoDGR (isoAsp-Gly-Arg). This integrin-binding motif activates leukocytes and promotes chronic inflammation, which are characteristic features of age-linked cardiovascular disorders. We now report that anti-isoDGR immunotherapy mitigates lifespan reduction of Pcmt1^−/− mouse. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1^−/− and naturally aged WT animals, which could also be induced via injection of isoDGR-modified plasma proteins or synthetic peptides into young WT animals. However, weekly injection of anti-isoDGR mAb (1 mg/kg) was sufficient to significantly reduce isoDGR-protein levels in body tissues, decreased pro-inflammatory cytokine concentrations in blood plasma, improved cognition/coordination metrics, and extended the average lifespan of Pcmt1^−/− mice. Mechanistically, isoDGR-mAb mediated immune clearance of damaged isoDGR-proteins via antibody-dependent cellular phagocytosis (ADCP). These results indicate that immunotherapy targeting age-linked protein damage may represent an effective intervention strategy in a range of human degenerative disorders.

中文翻译：

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针对 isoDGR 蛋白损伤的免疫疗法可延长蛋白脱酰胺小鼠模型的寿命


衰老是由损害正常生化过程的分子损伤的积累造成的。我们之前报道过，氨基酸序列 NGR (Asn-Gly-Arg) 的年龄相关损伤会导致“功能获得”构象转换为 isoDGR (isoAsp-Gly-Arg)。这种整合素结合基序激活白细胞并促进慢性炎症，这是与年龄相关的心血管疾病的特征。我们现在报道抗 isoDGR 免疫疗法可以减轻 Pcmt1 ^−/−小鼠寿命的缩短。我们在 Pcmt1 ^−/−和自然衰老的 WT 动物的多个组织中观察到 isoDGR 和炎症细胞因子表达的广泛积累，这也可以通过向年轻 WT 动物注射 isoDGR 修饰的血浆蛋白或合成肽来诱导。然而，每周注射抗 isoDGR mAb（1 mg/kg）足以显着降低身体组织中的 isoDGR 蛋白水平，降低血浆中促炎细胞因子浓度，改善认知/协调指标，并延长患者的平均寿命。 Pcmt1 ^−/−小鼠。从机制上讲，isoDGR-mAb 通过抗体依赖性细胞吞噬作用 (ADCP) 介导受损 isoDGR 蛋白的免疫清除。这些结果表明，针对与年龄相关的蛋白质损伤的免疫疗法可能代表了一系列人类退行性疾病的有效干预策略。