Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland.
Department of Internal Medicine, First Clinic of Internal Medicine, University of Genoa, Genoa, Italy.
Eur J Clin Invest. 2021 Nov;51(11):e13600. doi: 10.1111/eci.13600. Epub 2021 Jun 2.
Epidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm-aging as a mediator and potential therapeutic target.
3 months- (young) and 18-20 months-old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 minutes followed by 48 hours of reperfusion. Old animals received weekly treatment with the TNF-α neutralizing antibody adalimumab over 4 weeks before tMCAO in a separate set of experiments. Plasma levels of TNF- α were assessed in patients with ischemic stroke and correlated with age and outcome.
Old mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood-brain barrier in old mice, i.e. increased post-stroke degradation of endothelial tight junctions and expression of tight junctions-digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF-α displayed the highest increase in old animals and its inhibition restored the volume of stroke, neuromotor performance, and survival rates of old mice to the levels observed in young ones. Patients with ischemic stroke showed increased TNF-α plasma levels which correlated with worsened short-term neurological outcome as well as with age.
This study identifies TNF-α as a causative contributor to the deleterious effect of aging on stroke and points to inflamm-aging as a mechanism of age-related worsening of stroke outcomes and potential therapeutic target in this context. Thus, this work provides a basis for tailoring novel stroke therapies for the particularly vulnerable elderly population.
流行病学证据将缺血性中风与年龄联系起来，但年龄对中风的具体和独立影响的机制仍难以捉摸，这阻碍了针对性治疗的发展。本研究检验了这样一个假设，即年龄直接加重中风的结果，并提出炎症衰老作为一个中介和潜在的治疗靶点。
3 个月大（年轻）和 18-20 个月大（年老）的小鼠进行短暂性大脑中动脉闭塞（tMCAO）30 分钟，然后再灌注 48 小时。在另一组实验中，年老的动物在 tMCAO 前 4 周每周接受 TNF-α 中和抗体阿达木单抗的治疗。评估了缺血性中风患者的血浆 TNF-α 水平，并与年龄和结果进行了相关性分析。
年老的小鼠比年轻的小鼠显示出更大的中风面积和更严重的神经运动缺陷。免疫组织化学分析显示，年老的小鼠血脑屏障受损，即中风后内皮紧密连接的降解和消化紧密连接和神经毒性基质金属蛋白酶的表达增加。在基线时，年老的动物表现出几种循环炎症介质的广泛调节。TNF-α在年老的动物中表现出最高的增加，其抑制作用使年老的小鼠的中风体积、神经运动性能和存活率恢复到年轻的小鼠的水平。缺血性中风患者的血浆 TNF-α 水平升高，与短期神经功能结局恶化以及与年龄相关。
本研究将 TNF-α 确定为衰老对中风有害影响的一个原因，并指出炎症衰老作为与年龄相关的中风结局恶化的机制和潜在的治疗靶点。因此，这项工作为为特别脆弱的老年人群量身定制新型中风治疗方法提供了基础。
