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This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm\u2010aging as a mediator and potential therapeutic target.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>3\u00a0months\u2010 (young) and 18\u201020\u00a0months\u2010old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30\u00a0minutes followed by 48\u00a0hours of reperfusion. Old animals received weekly treatment with the TNF\u2010\u03b1 neutralizing antibody adalimumab over 4\u00a0weeks before tMCAO in a separate set of experiments. Plasma levels of TNF\u2010 \u03b1 were assessed in patients with ischemic stroke and correlated with age and outcome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Old mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood\u2010brain barrier in old mice, i.e. increased post\u2010stroke degradation of endothelial tight junctions and expression of tight junctions\u2010digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF\u2010\u03b1 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\u2010\u03b1 plasma levels which correlated with worsened short\u2010term neurological outcome as well as with age.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study identifies TNF\u2010\u03b1 as a causative contributor to the deleterious effect of aging on stroke and points to inflamm\u2010aging as a mechanism of age\u2010related 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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/eci.13600","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T14:12:43Z","timestamp":1622643163000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["TNF\u2010\u03b1 antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm\u2010ageing"],"prefix":"10.1111","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1472-7975","authenticated-orcid":false,"given":"Luca","family":"Liberale","sequence":"first","affiliation":[{"name":"Center for Molecular Cardiology University of Z\u00fcrich Schlieren Switzerland"},{"name":"Department of Internal Medicine First Clinic of Internal Medicine University of Genoa Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole 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