The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions.

Certain metabolic interventions such as caloric restriction, fasting, exercise, and a ketogenic diet extend lifespan and/or health span. However, their benefits are limited and their connections to the underlying mechanisms of aging are not fully clear. Here, these connections are explored in terms of the tricarboxylic acid (TCA) cycle (Krebs cycle, citric acid cycle) to suggest reasons for the loss of effectiveness and ways of overcoming it. Specifically, the metabolic interventions deplete acetate and likely reduce the conversion of oxaloacetate to aspartate, thereby inhibiting the mammalian target of rapamycin (mTOR) and upregulating autophagy. Synthesis of glutathione may provide a high-capacity sink for amine groups, facilitating autophagy, and prevent buildup of alpha-ketoglutarate, supporting stem cell maintenance. Metabolic interventions also prevent the accumulation of succinate, thereby slowing DNA hypermethylation, facilitating the repair of DNA double-strand breaks, reducing inflammatory and hypoxic signaling, and lowering reliance on glycolysis. In part through these mechanisms, metabolic interventions may decelerate aging, extending lifespan. Conversely, with overnutrition or oxidative stress, these processes function in reverse, accelerating aging and impairing longevity. Progressive damage to aconitase, inhibition of succinate dehydrogenase, and downregulation of hypoxia-inducible factor-1α, and phosphoenolpyruvate carboxykinase (PEPCK) emerge as potentially modifiable reasons for the loss of effectiveness of metabolic interventions.

Brain Energy Deficit as a Source of Oxidative Stress in Migraine: A Molecular Basis for Migraine Susceptibility.

People with migraine are prone to a brain energy deficit between attacks, through increased energy demand (hyperexcitable brain) or decreased supply (mitochondrial impairment). However, it is uncertain how this precipitates an acute attack. Here, the central role of oxidative stress is adduced. Specifically, neurons' antioxidant defenses rest ultimately on internally generated NADPH (reduced nicotinamide adenine dinucleotide phosphate), whose levels are tightly coupled to energy production. Mitochondrial NADPH is produced primarily by enzymes involved in energy generation, including isocitrate dehydrogenase of the Krebs (tricarboxylic acid) cycle; and an enzyme, nicotinamide nucleotide transhydrogenase (NNT), that depends on the Krebs cycle and oxidative phosphorylation to function, and that works in reverse, consuming antioxidants, when energy generation fails. In migraine aura, cortical spreading depression (CSD) causes an initial severe drop in level of NADH (reduced nicotinamide adenine dinucleotide), causing NNT to impair antioxidant defense. This is followed by functional hypoxia and a rebound in NADH, in which the electron transport chain overproduces oxidants. In migraine without aura, a similar biphasic fluctuation in NADH very likely generates oxidants in cortical regions farthest from capillaries and penetrating arterioles. Thus, the perturbations in brain energy demand and/or production seen in migraine are likely sufficient to cause oxidative stress, triggering an attack through oxidant-sensing nociceptive ion channels. Implications are discussed for the development of new classes of migraine preventives, for the current use of C57BL/6J mice (which lack NNT) in preclinical studies of migraine, for how a microembolism initiates CSD, and for how CSD can trigger a migraine.

CGRP and Brain Functioning: Cautions for Migraine Treatment.

BACKGROUND: Calcitonin gene-related peptide has emerged as a therapeutic target in migraine. Monoclonal antibodies and small molecule receptor antagonists (gepants) directed against CGRP have been approved or are in Phase II or III clinical trials. For monitoring the long-term safety of these drugs, it is helpful to consider the role of CGRP in brain functioning. METHODS: Qualitative review of the preclinical literature on CGRP in brain physiology and pathophysiology. RESULTS: Within the brain, CGRP is upregulated by stresses such as ischemia, injury, hyperthermia, and seizure, and activates neuroprotective processes. Thus, CGRP buffers intracellular calcium, triggers antiapoptotic signaling, upregulates a number of neurotrophins (including insulin-like growth factor-1/IGF-1, basic fibroblast growth factor/bFGF, and nerve growth factor/NGF), reduces brain edema, and likely increases antioxidant defenses. When released outside the blood-brain barrier, CGRP likely protects the endothelium, upregulates growth factor signaling from the endothelium to the brain parenchyma, strengthens the blood-brain barrier, protects the immune privilege of the brain by inhibiting the movement of neutrophils and monocytes, and facilitates neurogenesis and angiogenesis at stem cell niches. CONCLUSIONS: CGRP participates in a wide range of neuroprotective processes. In theory, migraineurs with comorbid brain pathology might be at increased risk from CGRP inhibition. However, the extent of compensating processes is unknown and will determine whether these risks materialize in practice.

Harnessing migraines for neural regeneration.

The success of naturalistic or therapeutic neuroregeneration likely depends on an internal milieu that facilitates the survival, proliferation, migration, and differentiation of stem cells and their assimilation into neural networks. Migraine attacks are an integrated sequence of physiological processes that may protect the brain from oxidative stress by releasing growth factors, suppressing apoptosis, stimulating neurogenesis, encouraging mitochondrial biogenesis, reducing the production of oxidants, and upregulating antioxidant defenses. Thus, the migraine attack may constitute a physiologic environment conducive to stem cells. In this paper, key components of migraine are reviewed - neurogenic inflammation with release of calcitonin gene-related peptide (CGRP) and substance P, plasma protein extravasation, platelet activation, release of serotonin by platelets and likely by the dorsal raphe nucleus, activation of endothelial nitric oxide synthase (eNOS), production of brain-derived neurotrophic factor (BDNF) and, in migraine aura, cortical spreading depression - along with their potential neurorestorative aspects. The possibility is considered of using these components to facilitate successful stem cell transplantation. Potential methods for doing so are discussed, including chemical stimulation of the TRPA1 ion channel, conjoint activation of a subset of migraine components, invasive and noninvasive deep brain stimulation of the dorsal raphe nucleus, transcranial focused ultrasound, and stimulation of the Zusanli (ST36) acupuncture point.

The Migraine Attack as a Homeostatic, Neuroprotective Response to Brain Oxidative Stress: Preliminary Evidence for a Theory.

BACKGROUND: Previous research has suggested that migraineurs show higher levels of oxidative stress (lipid peroxides) between migraine attacks and that migraine triggers may further increase brain oxidative stress. Oxidative stress is transduced into a neural signal by the TRPA1 ion channel on meningeal pain receptors, eliciting neurogenic inflammation, a key event in migraine. Thus, migraines may be a response to brain oxidative stress. RESULTS: In this article, a number of migraine components are considered: cortical spreading depression, platelet activation, plasma protein extravasation, endothelial nitric oxide synthesis, and the release of serotonin, substance P, calcitonin gene-related peptide, and brain-derived neurotrophic factor. Evidence is presented from in vitro research and animal and human studies of ischemia suggesting that each component has neuroprotective functions, decreasing oxidant production, upregulating antioxidant enzymes, stimulating neurogenesis, preventing apoptosis, facilitating mitochondrial biogenesis, and/or releasing growth factors in the brain. Feedback loops between these components are described. Limitations and challenges to the model are discussed. CONCLUSIONS: The theory is presented that migraines are an integrated defensive, neuroprotective response to brain oxidative stress.

Migraine Triggers and Oxidative Stress: A Narrative Review and Synthesis.

BACKGROUND: Blau theorized that migraine triggers are exposures that in higher amounts would damage the brain. The recent discovery that the TRPA1 ion channel transduces oxidative stress and triggers neurogenic inflammation suggests that oxidative stress may be the common denominator underlying migraine triggers. OBJECTIVE: The aim of this review is to present and discuss the available literature on the capacity of common migraine triggers to generate oxidative stress in the brain. METHODS: A Medline search was conducted crossing the terms "oxidative stress" and "brain" with "alcohol," "dehydration," "water deprivation," "monosodium glutamate," "aspartame," "tyramine," "phenylethylamine," "dietary nitrates," "nitrosamines," "noise," "weather," "air pollutants," "hypoglycemia," "hypoxia," "infection," "estrogen," "circadian," "sleep deprivation," "information processing," "psychosocial stress," or "nitroglycerin and tolerance." "Flavonoids" was crossed with "prooxidant." The reference lists of the resulting articles were examined for further relevant studies. The focus was on empirical studies, in vitro and of animals, of individual triggers, indicating whether and/or by what mechanism they can generate oxidative stress. RESULTS: In all cases except pericranial pain, common migraine triggers are capable of generating oxidative stress. Depending on the trigger, mechanisms include a high rate of energy production by the mitochondria, toxicity or altered membrane properties of the mitochondria, calcium overload and excitotoxicity, neuroinflammation and activation of microglia, and activation of neuronal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. For some triggers, oxidants also arise as a byproduct of monoamine oxidase or cytochrome P450 processing, or from uncoupling of nitric oxide synthase. CONCLUSIONS: Oxidative stress is a plausible unifying principle behind the types of migraine triggers encountered in clinical practice. The possible implications for prevention and for understanding the nature of the migraine attack are discussed.

Chronic headaches and the neurobiology of somatization.

Pain sensitivity is an adaptive process affected by expectation, mood, coping, operant conditioning, and the preconscious allocation of attention. Underlying mechanisms may include encoding of similar experiences (eg, depression, loss, pain-distress) in overlapping patterns of activation, failure of common regulatory mechanisms, direct top-down activation of the pain matrix, and changes in descending pain facilitatory and inhibitory tone. In theory, the combination of glial cell activation from psychological stress and neural firing from nociceptive input may be particularly likely to lead to pain sensitization and long-term structural changes in pain processing regions of the brain. In these ways, headaches in which chronicity, diffuseness, and distress seem better accounted for by psychological than by medical variables can be understood in neurobiological terms. This can allow psychological treatment of physical distress to be objective, nonthreatening, and relatively precise.