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Neurogenesis occurs in the brain during embryonic development and throughout adulthood. Neurogenesis occurs in the hippocampus and under normal conditions and persists in two regions of the brain—the subgranular zone (SGZ) in the dentate gyrus of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles. As the critical role in neurogenesis, the neural stem cells have the capacity to differentiate into various cells and to self-renew. This process is controlled through different methods. The mammalian target of rapamycin (mTOR) controls cellular growth, cell proliferation, apoptosis, and autophagy. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a major regulator of metabolism, protein quality control, and antioxidative defense, and is linked to neurogenesis. However, dysregulation in neurogenesis, mTOR, and Nrf2 activity have all been associated with neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s. Understanding the role of these complexes in both neurogenesis and neurodegenerative disease could be necessary to develop future therapies. Here, we review both mTOR and Nrf2 complexes, their crosstalk and role in neurogenesis, and their implication in neurodegenerative diseases.

Elderly patients (age > 75) sustain larger infarcts with greater mortality from ST elevation myocardial infarcts (STEMI) despite successful reperfusion treatment. Elderly age remains an independent risk despite correction for clinical and angiographic variables. The elderly represent a high-risk population and may benefit from treatment in addition to reperfusion alone. We hypothesized that modulation of cardiac signaling and metabolism with acute, high dose metformin given at reperfusion would exhibit additional cardioprotection. Using a translational aging murine model (22-24-month C57BL/6J mice) of in vivo STEMI (45 min artery occlusion with reperfusion for 24 hours); treatment acutely at reperfusion by high dose metformin decreased infarct size and enhanced contractile recovery, demonstrating cardioprotection in the high-risk aging heart.

Introduction: Metformin activates AMP-activated protein kinase (AMPK) to improve cardiac function during ischemia and reperfusion (I/R). We reported that Sestrin2 (Sesn2) is associated with AMPK and maintains oxidative phosphorylation (OXPHOS) under I/R stress. The role of age-related Sesn2-AMPK signaling in the beneficial actions of metformin on ischemic insults remains unknown. Hypothesis: Metformin maintains mitochondrial integrity and limits cardiac damage caused by ischemic insults through the Sesn2-AMPK signaling pathway. Methods: Young (3-6 months) and aged (22-24 months) C57BL/6J wild type mice, and 3 months of Sesn2 f/f and cardiomyocyte-specific Sesn2 knockout (cSesn2 -/- ) C57BL/6J mice were subjected to 45 minutes of ischemia followed by 2 mM metformin injection 5 minutes before 24-hour of reperfusion. Cardiac function and myocardial infarction were determined with echocardiography and 2,3,5-triphenyl tetrazolium chloride staining. Immunoblotting determines the mechanism of metformin in modulating Sesn2 to preserve mitochondrial OXPHOS components. The Seahorse XF Analyzer examined the mitochondrial respiratory functions. Results: Metformin administration can significantly improve cardiac function and reduce myocardial infarction size during I/R conditions in both young and aged wild-type C57BL/6J mice. Intriguingly, the beneficial effects of metformin administration on cardiac function and myocardial infarction were significantly blunted in the cSesn2 -/- versus Sesn2 f/f C57BL/6J mice. The immunoblotting showed metformin treatment augmented mitochondrial OXPHOS Complex II levels in young/aged wild type, and Sesn2 f/f but not cSesn2 -/- heart during I/R stress. Moreover, the mitochondrial respiration data displayed that metformin treatment improved the respiration rate of mitochondrial states 2 and 3μ in the isolated cardiomyocytes from Sens2 f/f but not from cSesn2 -/- mouse hearts under I/R stress conditions. Conclusions: Metformin can stabilize age-related Sesn2 levels in cardiomyocytes and improve cardiac function under I/R stress through maintaining mitochondrial integrity. Metformin is a potential therapeutic drug for ischemic heart disease in the elderly.

Introduction: Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent histone deacetylase. We revealed that the pressure-overload-induced SIRT1 can exacerbate cardiac systolic dysfunction. But the mechanisms by which SIRT1 undermines cardiac function under pathological conditions remain unclear. Hypothesis: SIRT1 induced by pathological hypotrophy disturbs mitochondrial dynamics homeostasis resulting in an exacerbated cardiac dysfunction. Methods: Wild-type littermates SIRT1 f/f (3-5 months) and inducible cardiomyocyte-specific SIRT1 knockout (icSIRT1 -/- ) (3-5 months) C57BL/6J mice were subjected to transverse aortic constriction (TAC) surgery for six weeks. Echocardiography assessed cardiac functions and CODA tail-cuff system measured blood pressure. The mitochondrial dynamics were examined by immunoblotting and transmission electron microscopy (TEM). Results: The echocardiography showed that there were significant reductions in ejection fraction (EF) and fractional shortening (FS) of the SIRT1 f/f mice after 6-weeks of TAC-induced pressure overload. The diastolic and systolic blood pressure were increased in SIRT1 f/f mice during TAC surgery. Intriguingly, icSIRT1 -/- versus SIRT1 f/f demonstrated significant resistance to pathological hypertrophy caused by TAC-induced pressure overload as determined with echocardiography and blood pressure measurements. The immunoblotting revealed that the six weeks of TAC surgery caused significantly higher levels of the mitochondrial fusion protein, mitofusin 2 (MFN2), in SIRT1 f/f versus icSIRT1 -/- hearts. In addition, TEM data showed more elongated mitochondria in SIRT1 f/f versus icSIRT1 -/- hearts, indicating a critical role of SIRT1 in maintaining mitochondrial dynamic homeostasis under pathological stress conditions. Metabolomics and proteomics showed that SIRT1 regulates carnitine palmitoyltransferase-1 and long-chain acyl CoA dehydrogenase to modulate fatty acid metabolism in response to TAC-induced stress. Conclusions: Cardiomyocyte SIRT1 plays a key role in cardiac mitochondrial dynamics during pathological stress conditions. Inhibition of SIRT1 activity could be a good strategy to ameliorate pressure overload-induced hypertrophy.