Preoperative Low-Dose Aspirin Exposure and Outcomes After Emergency Neurosurgery for Traumatic Intracranial Hemorrhage in Elderly Patients.

BACKGROUND: Antiplatelet medications are usually discontinued before elective neurosurgery, but this is not an option for emergent neurosurgery. We performed a retrospective cohort study to examine whether preoperative aspirin use was associated with worse outcomes after emergency neurosurgery in elderly patients. METHODS: We analyzed all cases of emergency neurosurgical procedures for traumatic intracranial hemorrhage from 2008 to 2012 at a level 1 trauma center. Demographics, comorbidities, and outcomes were compared for patients ≥65 years by preoperative aspirin exposure. Exclusion criteria were: (1) polytrauma, (2) concomitant use of other preoperative anticoagulants or antiplatelet agents, (3) surgical indication other than subdural, extradural, or intraparenchymal hemorrhage, and (4) repeat neurosurgical procedures within a single admission. Estimated intraoperative blood loss, postprocedural intracranial bleeding requiring reoperation, death in hospital, intensive care unit, and hospital lengths of stay and perioperative blood product transfusion from 48 hours before 48 hours after surgery were the study outcomes. We also examined whether platelet transfusion had an impact on outcomes for patients on aspirin. RESULTS: The cohort included 171 patients. Patients receiving preoperative aspirin (n = 87, 95% taking 81 mg/day) were the same age as patients not receiving aspirin (n = 84; 78.3 ± 7.8 vs 75.9 ± 7.9 years, P > .05), had slightly higher admission Glasgow Coma Scale scores (12.8 ± 3.4 vs 11.4 ± 4, P = .02) and tended to have more coronary artery disease (P< .05). Adjusted for Glasgow Coma Scale and coronary artery disease, patients receiving preoperative aspirin had a higher odds of perioperative platelet transfusion (adjusted odds ratio 9.89, 95% confidence interval, 4.24-26.25). There were no other differences in outcomes between the 2 groups. Preoperative or intraoperative platelet transfusion was not associated with better outcomes among aspirin patients. CONCLUSIONS: In patients age ≥65 years undergoing emergency neurosurgery for traumatic intracranial hemorrhage, preoperative low-dose aspirin treatment was not associated with increased perioperative bleeding, hospital lengths of stay, or in-hospital mortality.

Mitochondrial-targeted catalase is good for the old mouse proteome, but not for the young: 'reverse' antagonistic pleiotropy?

Reactive oxygen species (ROS) are highly reactive oxygen-containing molecules associated with aging and a broad spectrum of pathologies. We have previously shown that transgenic expression of the antioxidant enzyme catalase targeted to the mitochondria (mCAT) in mice reduces ROS, attenuates age-related disease, and increases lifespan. However, it has been increasingly recognized that ROS also has beneficial roles in signaling, hormesis, stress response, and immunity. We therefore hypothesized that mCAT might be beneficial only when ROS approaches pathological levels in older age and might not be advantageous at a younger age when basal ROS is low. We analyzed abundance and turnover of the global proteome in hearts and livers of young (4 month) and old (20 month) mCAT and wild-type (WT) mice. In old hearts and livers of WT mice, protein half-lives were reduced compared to young, while in mCAT mice the reverse was observed; the longest half-lives were seen in old mCAT mice and the shortest in young mCAT. Protein abundance of old mCAT hearts recapitulated a more youthful proteomic expression profile (P-value < 0.01). However, young mCAT mice partially phenocopied the older wild-type proteome (P-value < 0.01). Age strongly interacts with mCAT, consistent with antagonistic pleiotropy in the reverse of the typical direction. These findings underscore the contrasting roles of ROS in young vs. old mice and indicate the need for better understanding of the interaction between dose and age in assessing the efficacy of therapeutic interventions in aging, including mitochondrial antioxidants.

Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts.

Rapamycin, an inhibitor of mTOR signaling, has been shown to reverse diastolic dysfunction in old mice in 10 weeks, highlighting its therapeutic potential for a poorly treatable condition. However, the mechanisms and temporal regulation of its cardiac benefits remain unclear. We show that improved diastolic function in old mice begins at 2-4 weeks, progressing over the course of 10-week treatment. While TORC1-mediated S6 phosphorylation and TORC2 mediated AKT and PKCα phosphorylation are inhibited throughout the course of treatment, rapamycin inhibits ULK phosphorylation and induces autophagy during just the first week of treatment, returning to baseline at two weeks and after. Concordantly, markers of mitochondrial biogenesis increase over the first two weeks of treatment and return to control levels thereafter. This transient induction of autophagy and mitochondrial biogenesis suggests that damaged mitochondria are replaced by newly synthesized ones to rejuvenate mitochondrial homeostasis. This remodeling is shown to rapidly reverse the age-related reduction in fatty acid oxidation to restore a more youthful substrate utilization and energetic profile in old isolated perfused hearts, and modulates the myocardial metabolomein vivo. This study demonstrates the differential and dynamic mechanisms following rapamycin treatment and highlights the importance of understanding the temporal regulation of rapamycin effects.

Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice.

Rapamycin extends lifespan and attenuates age-related pathologies in mice when administered through diet at 14 parts per million (PPM). Recently, we reported that daily intraperitoneal injection of rapamycin at 8 mg/kg attenuates mitochondrial disease symptoms and progression in the Ndufs4 knockout mouse model of Leigh Syndrome. Although rapamycin is a widely used pharmaceutical agent dosage has not been rigorously examined and no dose-response profile has been established. Given these observations we sought to determine if increased doses of oral rapamycin would result in more robust impact on mTOR driven parameters. To test this hypothesis, we compared the effects of dietary rapamycin at doses ranging from 14 to 378 PPM on developmental weight in control and Ndufs4 knockout mice and on health and survival in the Ndufs4 knockout model. High dose rapamycin was well tolerated, dramatically reduced weight gain during development, and overcame gender differences. The highest oral dose, approximately 27-times the dose shown to extend murine lifespan, increased survival in Ndufs4 knockout mice similarly to daily rapamycin injection without observable adverse effects. These findings have broad implications for the effective use of rapamycin in murine studies and for the translational potential of rapamycin in the treatment of mitochondrial disease. This data, further supported by a comparison of available literature, suggests that 14 PPM dietary rapamycin is a sub-optimal dose for targeting mTOR systemically in mice. Our findings suggest that the role of mTOR in mammalian biology may be broadly underestimated when determined through treatment with rapamycin at commonly used doses.

mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome.

Mitochondrial dysfunction contributes to numerous health problems, including neurological and muscular degeneration, cardiomyopathies, cancer, diabetes, and pathologies of aging. Severe mitochondrial defects can result in childhood disorders such as Leigh syndrome, for which there are no effective therapies. We found that rapamycin, a specific inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, robustly enhances survival and attenuates disease progression in a mouse model of Leigh syndrome. Administration of rapamycin to these mice, which are deficient in the mitochondrial respiratory chain subunit Ndufs4 [NADH dehydrogenase (ubiquinone) Fe-S protein 4], delays onset of neurological symptoms, reduces neuroinflammation, and prevents brain lesions. Although the precise mechanism of rescue remains to be determined, rapamycin induces a metabolic shift toward amino acid catabolism and away from glycolysis, alleviating the buildup of glycolytic intermediates. This therapeutic strategy may prove relevant for a broad range of mitochondrial diseases.