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A delayed window integrates nicotinamide adenine dinucleotide (NAD)\n                      <jats:sup>+<\/jats:sup>\n                      \/sirtuin pathways (PKC\u03b5 [protein kinase C epsilon]\u2192NAMPT [nicotinamide phosphoribosyltransferase]\u2192NAD\n                      <jats:sup>+<\/jats:sup>\n                      , SIRT1 [sirtuin 1] control of glycolysis, and SIRT5 [sirtuin 5] desuccinylation), maintenance of the malate-aspartate shuttle, and proteostasis\/innate-immune programs (HSP70 [heat shock protein 70]\/HSP27 [heat shock protein 27]\/HO-1 [heme oxygenase-1]; interferon-biased signaling). These mechanisms exhibit similarities with evolutionary adaptations while preserving the capacity for plasticity via homeostatic scaling. Both preconditioning and postconditioning mitigate ischemia-induced cognitive impairment by limiting pathology in the septal nuclei. Specifically, physical exercise restores septohippocampal oscillatory coherence, which is linked to cognitive improvement. Clinically, the best scenarios for treatment are predictable ischemia and well-phenotyped high-risk cohorts. Future priorities are further elucidation of mechanisms of conditioning mimetics, rational combinations (eg, exercise or remote conditioning layered with these mimetics), and preclinical designs incorporating aging and comorbidities to derisk translation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.125.051164","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T18:00:37Z","timestamp":1777312837000},"page":"1464-1475","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Thomas Willis Lecture Award: Nature\u2019s Blueprint for Ischemic Tolerance: Preconditioning and Postconditioning Strategies"],"prefix":"10.1161","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6555-8935","authenticated-orcid":true,"given":"Miguel A.","family":"Perez-Pinzon","sequence":"first","affiliation":[{"name":"Department of Neurology, Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, and Neuroscience Program, University of Miami Leonard M. 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