Life-long protection from global cerebral ischemia and reperfusion in long-lived Mclk1+/− mutants

摘要

To achieve a long lifespan, animals must be resistant to various injuries as well as be able to avoid or delay lethality from age-dependent diseases. Here we show that long-lived Mclk1^+/− mutants have enhanced resistance to neurological damage following global cerebral ischemia/reperfusion (I/R) injury induced by transient bilateral common carotid artery occlusion (BCCAO). Both young (~100 days old) and relatively aged (~450 days old) mutants display increased resistance as indicated by a significant decrease in the amount of degenerating cells observed in forebrain cortex and in hippocampal areas after ischemia and reperfusion. Furthermore, less oxidative damage resulting from the procedure was measured in the brain of young Mclk1^+/− animals. The finding that both young and old mutants are protected indicates that this is a basic phenotype of these mutants and not a secondary consequence of their slow rate of aging. Thus, the partial resistance to I/R injury by enhancing recovery from age-dependent vascular accidents is likely part of what allows for the increased lifespan of Mclk1^+/− mutants. By relating this neuroprotective effect to previously reported characteristics of the Mclk1^+/− phenotype, including altered mitochondrial metabolism and increased HIF-1α expression, this study establishes these mutants as useful models to analyze the mechanisms underlying tolerance to ischemia, particularly those associated with ischemic preconditioning, as well as to clarify the relation between aging and age-dependent diseases.