Abdelkader Basma, Shi Xiang Qun, Zhou Wen Bo Sam, Castaño Jesus D, Grant Audrey V, Beaudry Francis, Zhang Ji
The Alan Edwards Centre for Research on Pain, McGill University, Montréal, QC, Canada.
Integrated Program in Neuroscience, McGill University, Montréal, QC, Canada.
Pain. 2025 Jun 24. doi: 10.1097/j.pain.0000000000003684.
As individuals age, they often experience persistent, unresolved pain, impacting their quality of life. Aging as a process is accompanied by "inflammaging," a state of chronic, low-grade systemic inflammation contributing to various diseases. Understanding the functional link between inflammaging and age-related development of pain is crucial for identifying novel therapeutic targets. We hypothesized that the circulatory milieu plays a role in regulating pain and that inflammaging contributes to changes in pain behavior with age. To test these hypotheses, we monitored nociception and postsurgical pain in male and female mice aged 3 and 24 months and analyzed their serum proteome, including cytokine/chemokine profiles. Our results demonstrated that compared with young mice, aging mice were hyposensitive to mechanical stimulation, yet their pain response to incision was aggravated and prolonged. Serum proteomic analysis revealed sex-specific inflammaging patterns. To explore the link between inflammaging and age-related alteration in pain behavior, we applied a rejuvenation strategy by transferring serum from 3-month-old mice to 19- to 21-month-old mice. Young serum normalized mechanical sensitivity in aged mice, alleviated postsurgical mechanical pain, and promoted recovery. Alongside the improvements in pain behavior phenotype, young serum recalibrated the aging serum profile. It reduced age-associated increases of cytokine/chemokine levels in male mice and rescued age-related, female-selective downregulation of inflammatory pathways such as liver X receptor/retinoid X receptor activation, D24-dehydrocholesterol reductase, and complement signaling. Our findings suggest that the circulatory environment, notably inflammaging, plays a significant role in altered pain behavior of aging mice. The sex-specific signature of age-dependent systemic inflammation highlights the importance of investigating inflammaging through the lens of sexual dimorphism.
随着个体年龄的增长，他们常常会经历持续且未得到解决的疼痛，这会影响他们的生活质量。衰老作为一个过程伴随着“炎症衰老”，即一种慢性、低度全身性炎症状态，会引发各种疾病。了解炎症衰老与年龄相关的疼痛发展之间的功能联系对于确定新的治疗靶点至关重要。我们假设循环环境在调节疼痛中起作用，并且炎症衰老会导致疼痛行为随年龄发生变化。为了验证这些假设，我们监测了3个月和24个月大的雄性和雌性小鼠的伤害感受和术后疼痛，并分析了它们的血清蛋白质组，包括细胞因子/趋化因子谱。我们的结果表明，与年轻小鼠相比，衰老小鼠对机械刺激反应迟钝，但它们对切口的疼痛反应却加剧且持续时间延长。血清蛋白质组分析揭示了性别特异性的炎症衰老模式。为了探索炎症衰老与疼痛行为的年龄相关变化之间的联系，我们采用了一种年轻化策略，即将3个月大小鼠的血清转移到19至21个月大小鼠体内。年轻血清使衰老小鼠的机械敏感性恢复正常，减轻了术后机械性疼痛，并促进了恢复。除了疼痛行为表型的改善外，年轻血清还重新校准了衰老血清谱。它降低了雄性小鼠中与年龄相关的细胞因子/趋化因子水平升高，并挽救了与年龄相关的、女性特异性的炎症途径下调，如肝X受体/视黄酸X受体激活、D24-脱氢胆固醇还原酶和补体信号传导。我们的研究结果表明，循环环境，尤其是炎症衰老，在衰老小鼠疼痛行为改变中起重要作用。年龄依赖性全身性炎症的性别特异性特征凸显了从性别差异角度研究炎症衰老的重要性。
