The absolute reliance of the mammalian brain on oxygen to generate ATP renders it acutely vulnerable to hypoxia, whether at high altitude or in clinical settings of anemia or pulmonary disease. Hypoxia is pivotal to the pathogeneses of myriad neurological disorders, including Alzheimer's, Parkinson's and other age-related neurodegenerative diseases. Conversely, reduced environmental oxygen, e.g. sojourns or residing at high altitudes, may impart favorable effects on aging and mortality. Moreover, controlled hypoxia exposure may represent a treatment strategy for age-related neurological disorders. This review discusses evidence of hypoxia's beneficial vs. detrimental impacts on the aging brain and the molecular mechanisms that mediate these divergent effects. It draws upon an extensive literature search on the effects of hypoxia/altitude on brain aging, and detailed analysis of all identified studies directly comparing brain responses to hypoxia in young vs. aged humans or rodents. Special attention is directed toward the risks vs. benefits of hypoxia exposure to the elderly, and potential therapeutic applications of hypoxia for neurodegenerative diseases. Finally, important questions for future research are discussed.

High-altitude illnesses (HAIs) result from acute exposure to high altitude/hypoxia. Numerous molecular mechanisms affect appropriate acclimatization to hypobaric and/or normobaric hypoxia and curtail the development of HAIs. The understanding of these mechanisms is essential to optimize hypoxic acclimatization for efficient prophylaxis and treatment of HAIs. This review aims to link outcomes of molecular mechanisms to either adverse effects of acute high-altitude/hypoxia exposure or the developing tolerance with acclimatization. After summarizing systemic physiological responses to acute high-altitude exposure, the associated acclimatization, and the epidemiology and pathophysiology of various HAIs, the article focuses on molecular adjustments and maladjustments during acute exposure and acclimatization to high altitude/hypoxia. Pivotal modifying mechanisms include molecular responses orchestrated by transcription factors, most notably hypoxia inducible factors, and reciprocal effects on mitochondrial functions and REDOX homeostasis. In addition, discussed are genetic factors and the resultant proteomic profiles determining these hypoxia-modifying mechanisms culminating in successful high-altitude acclimatization. Lastly, the article discusses practical considerations related to the molecular aspects of acclimatization and altitude training strategies.

Bioenergetic and hemodynamic consequences of cellular redox manipulations by 0.2–20 mM pyruvate were compared with those due to adrenergic stess (0.7–1.1 μM norepinephrine) using isolated working guinea‐pig hearts under the conditions of normoxia, low‐flow ischemia, and reperfusion. 5 mM glucose (+ 5 U/I insulin) + 5 μM lactate were the basal energy‐yielding substrates. To stabilize left ventricular enddiastolic pressure, ventricular filling pressure was held at 12 cmH₂O under all conditions; this preload control minimized Frank‐Starling effects on ventricular inotropism. Global low‐flow ischemia was induced by reducing aortic pressure to levels (20–10 cmH₂O) below the coronary autoregulatory reserve. Reactants of the creatine kinase, including H⁺ and other key metabolites, were measured by enzymatic, HPLC, and polarographic techniques.In normoxic hearts, norepinephrine stimulations of inotropism, heart rate × pressure product, and oxygen consumption (MVO₂) were associated with a fall in the cytosolic phosphorylation potential ([ATP]/([ADP] · [P_i])) as judged by the creatine kinase equilibrium. In contrast, infusion of excess pyruvate (5 mM) markedly increased [ATP]/([ADP] · [P_i]) and ventricular work output, while intracellular phosphate decreased; MVO₂ remained constant under the same conditions. During reperfusion following ischemia, pyruvate effected strking and concentration‐dependent increases in MVO₂, phosphorylation potential, and inotropism. Pyruvate dehydrogenase flux was augmented during reperfusion hyperemia followed by near‐complete recoveries of [ATP]/([ADP] · [P_i]), contractile force, heart rate × pressure product, and MVO₂ in the presence of 5–10 mM pyruvate. Pyruvate also attenuated ischemic adenylate degradation. Omission of glucose from the perfusion medium rendered pyruvate ineffective in postischemic hearts. Similarly, excess lactate (5–15 mM) or acetate (5 mM) failed to reenergize reperfused hearts and severe depressions of MVO₂ and inotropism developed despite the presence of glucose. Apparently, subcellular redox manipulations by pyruvate dissociated stimulated mitochondrial respiration and increased inotropism from low cytosolic phosphorylation potentials. This was evidence against the extramitochondrial [ADP] · [P_i]/[ATP] ratio being the primary factor in the control of mitochondrial respiration.The mechanism of pyruvate enhancement of inotropism during normoxia and reperfusion is probably multifactorial. Thermodynamic effects on subcellular [NADH]/[NAD⁺] ratios are coupled with a rise in the cytosolic [ATP]/([ADP] · [P_i]) ratio at constant (normoxia) or increased (reperfusion) MVO₂. In postischemic hearts the effect of pyruvate required the presence of glucose. It is proposed that pyruvate energization may improve ion pumping by the sarcoplasmic reticulum and hence Ca²⁺‐handling by the latter which, in turn, might increase the contractile state; decreased intracellular [P_i] due to improved phosphate fixation may also be contributory. In addition, augmented pyruvate dehydrogenase flux during reperfusion seemed to expedite cellular reenergization and functional recovery in the postischemic hearts.

During acute episodes of hypoxia, chemoreceptor-mediated sympathetic activity increases heart rate, cardiac output, peripheral resistance and systemic arterial pressure. However, different intermittent hypoxia paradigms produce remarkably divergent effects on systemic arterial pressure in the post-hypoxic steady state. The hypertensive effects of obstructive sleep apnea (OSA) vs. the depressor effects of therapeutic hypoxia exemplify this divergence. OSA, a condition afflicting 15–25% of American men and 5–10% of women, has been implicated in the pathogenesis of systemic hypertension and is a major risk factor for heart disease and stroke. OSA imposes a series of brief, intense episodes of hypoxia and hypercapnia, leading to persistent, maladaptive chemoreflex-mediated activation of the sympathetic nervous system which culminates in hypertension. Conversely, extensive evidence in animals and humans has shown controlled intermittent hypoxia conditioning programs to be safe, efficacious modalities for prevention and treatment of hypertension. This article reviews the pertinent literature in an attempt to reconcile the divergent effects of intermittent hypoxia therapy and obstructive sleep apnea on hypertension. Special emphasis is placed on research conducted in the nations of the former Soviet Union, where intermittent hypoxia conditioning programs are being applied therapeutically to treat hypertension in patients. Also reviewed is evidence regarding mechanisms of the pro- and anti-hypertensive effects of intermittent hypoxia.