Objective
Intermittent fasting (IF) is a term used to describe a variety of eating patterns in which no or few calories are consumed for time periods that can range from 12 hours to several days, on ...a recurring basis. This review is focused on the physiological responses of major organ systems, including the musculoskeletal system, to the onset of the metabolic switch: the point of negative energy balance at which liver glycogen stores are depleted and fatty acids are mobilized (typically beyond 12 hours after cessation of food intake).
Results and Conclusions
Emerging findings suggest that the metabolic switch from glucose to fatty acid‐derived ketones represents an evolutionarily conserved trigger point that shifts metabolism from lipid/cholesterol synthesis and fat storage to mobilization of fat through fatty acid oxidation and fatty acid‐derived ketones, which serve to preserve muscle mass and function. Thus, IF regimens that induce the metabolic switch have the potential to improve body composition in overweight individuals. Moreover, IF regimens also induce the coordinated activation of signaling pathways that optimize physiological function, enhance performance, and slow aging and disease processes. Future randomized controlled IF trials should use biomarkers of the metabolic switch (e.g., plasma ketone levels) as a measure of compliance and of the magnitude of negative energy balance during the fasting period.
During fasting and vigorous exercise, a shift of brain cell energy substrate utilization from glucose to the ketone 3‐hydroxybutyrate (3OHB) occurs. Studies have shown that 3OHB can protect neurons ...against excitotoxicity and oxidative stress, but the underlying mechanisms remain unclear. Neurons maintained in the presence of 3OHB exhibited increased oxygen consumption and ATP production, and an elevated NAD+/NADH ratio. We found that 3OHB metabolism increases mitochondrial respiration which drives changes in expression of brain‐derived neurotrophic factor (BDNF) in cultured cerebral cortical neurons. The mechanism by which 3OHB induces Bdnf gene expression involves generation of reactive oxygen species, activation of the transcription factor NF‐κB, and activity of the histone acetyltransferase p300/EP300. Because BDNF plays important roles in synaptic plasticity and neuronal stress resistance, our findings suggest cellular signaling mechanisms by which 3OHB may mediate adaptive responses of neurons to fasting, exercise, and ketogenic diets.
In response to fasting and vigorous exercise, the ketone 3‐hydroxybutyrate (3OHB) is generated in the liver from fatty acids released from adipocytes. Circulating 3OHB enters the brain where it is transported into neurons by monocarboxylic acid transporter 2 (MCT2) and then enters mitochondria. 3OHB stimulates mitochondrial respiration and reactive oxygen species production, resulting in the activation of the transcription factor NF‐kB which translocates into the nucleus and induces the expression of the Bdnf gene. BDNF is believed to mediate, in part, beneficial effects of exercise and fasting on brain function and resistance to stress and neurodegenerative disease.
Abstract Recent findings have elucidated roles for mitochondrial uncoupling proteins (UCPs) in neuronal plasticity and resistance to metabolic and oxidative stress. UCPs are induced by bioenergetic ...challenges such as caloric restriction and exercise and may protect neurons against dysfunction and degeneration. The pharmacological uncoupler 2,4-dinitrophenol (DNP), which was once prescribed to >100,000 people as a treatment for obesity, stimulates several adaptive cellular stress-response signaling pathways in neurons including those involving the brain-derived neurotrophic factor (BDNF), the transcription factor cyclic AMP response element-binding protein (CREB), and autophagy. Preclinical data show that low doses of DNP can protect neurons and improve functional outcome in animal models of Alzheimer's and Parkinson's diseases, epilepsy, and cerebral ischemic stroke. Repurposing of DNP and the development of novel uncoupling agents with hormetic mechanisms of action provide opportunities for new breakthrough therapeutic interventions in a range of acute and chronic insidious neurodegenerative/neuromuscular conditions, all paradoxically at body weight–preserving doses.
Aging is a major international concern that brings formidable socioeconomic and healthcare challenges. Small molecules capable of improving the health of older individuals are being explored. Small ...molecules that enhance cellular stress resistance are a promising avenue to alleviate declines seen in human aging. Tomatidine, a natural compound abundant in unripe tomatoes, inhibits age-related skeletal muscle atrophy in mice. Here we show that tomatidine extends lifespan and healthspan in C. elegans, an animal model of aging which shares many major longevity pathways with mammals. Tomatidine improves many C. elegans behaviors related to healthspan and muscle health, including increased pharyngeal pumping, swimming movement, and reduced percentage of severely damaged muscle cells. Microarray, imaging, and behavioral analyses reveal that tomatidine maintains mitochondrial homeostasis by modulating mitochondrial biogenesis and PINK-1/DCT-1-dependent mitophagy. Mechanistically, tomatidine induces mitochondrial hormesis by mildly inducing ROS production, which in turn activates the SKN-1/Nrf2 pathway and possibly other cellular antioxidant response pathways, followed by increased mitophagy. This mechanism occurs in C. elegans, primary rat neurons, and human cells. Our data suggest that tomatidine may delay some physiological aspects of aging, and points to new approaches for pharmacological interventions for diseases of aging.
Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work ...implicates mitochondrial dysfunction in the disease progression. Here, we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 (PARP1). Indeed, inhibition of ribosomal DNA transcription leads to mitochondrial dysfunction in a number of cell lines. Furthermore, machine-learning algorithms predict that diseases with defects in ribosomal DNA (rDNA) transcription have mitochondrial dysfunction, and, accordingly, this is found when factors involved in rDNA transcription are knocked down. Mechanistically, loss of CSA or CSB leads to polymerase stalling at non-B DNA in a neuroblastoma cell line, in particular at G-quadruplex structures, and recombinant CSB can melt G-quadruplex structures. Indeed, stabilization of G-quadruplex structures activates PARP1 and leads to accelerated aging in Caenorhabditis elegans. In conclusion, this work supports a role for impaired ribosomal DNA transcription in Cockayne syndrome and suggests that transcription-coupled resolution of secondary structures may be a mechanism to repress spurious activation of a DNA damage response.
Dopaminergic neuronal cell loss in the substantia nigra is responsible for the motor symptoms that are the clinical hallmark of Parkinson’s disease (PD). As of yet there are no treatments that slow ...or prevent the degeneration of dopaminergic neurons in PD patients. Here we tested the hypothesis that dopaminergic neurons can be protected by treatment with the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) and the novel DNP prodrug MP201. We found that mice treated with low doses of DNP and MP201 were protected against motor dysfunction and dopamine neuron loss in the 6-hydroxydopamine PD model, with MP201 being more efficacious than DNP. Amelioration of motor deficits and dopamine neuron loss by MP201 treatment was associated with reductions in microglial and astrocyte activation and neuroinflammation. These preclinical findings suggest the potential application of mitochondrial uncoupling agents such as MP201 as disease-modifying therapies for PD.
•Treatment with a novel mitochondrial uncoupling agent (MP201) ameliorates motor deficits in the 6-hydroxydopamine model of Parkinson's disease.•Substantia nigra dopaminergic neurons are preserved in mice treated with MP201.•These preclinical findings suggest that mild mitochondrial uncoupling agents have a potential therapeutic application for Parkinson's disease.
Left ventricular ejection fraction (LVEF) is the most frequently used parameter in the assessment of heart failure (HF). Cardiac index (CI) is considered a potential alternative to LVEF despite ...limited evidence. We aimed to assess and compare the predictive accuracy of LVEF and echocardiographically-assessed CI in HF patients.
A single-centre, retrospective cohort study was conducted in patients hospitalized for acute HF from 2010-2016. Cox proportional hazard models including either LVEF or CI were created to predict all cause death, cardiovascular (CV) death, or first HF-readmission. Of 334 patients included in the analysis, 58.7% exhibited HF with reduced LVEF (HFrEF). Left ventricular ejection fraction did not show correlation with any endpoint, while CI was predictive of HF-readmission in the entire cohort. Both the LVEF-based and CI-based models demonstrated moderate discriminative accuracy when predicting all-cause death, CV death, or HF-readmission. Left ventricular ejection fraction proved to be an independent predictor of CV mortality in HFrEF-patients, while CI was predictive of HF-readmission in the non-HFrEF group.
Left ventricular ejection fraction seemed to be associated more closely with disease severity in HFrEF, and CI in the non-HFrEF group, in this real-life cohort of elderly HF patients. The LVEF-based and CI-based predictive models have clinically similar predictive accuracy for mortality and HF-readmission, thus CI may be a potential alternative to LVEF in the assessment of left ventricular function. Cardiac index may be an important new tool in the assessment of HF patients with midrange or preserved LVEF.
Highlights • Energetic challenges (e.g., exercise and energy restriction) induce BDNF signaling. • BDNF enhances neuronal bioenergetics and promotes optimal brain health. • BDNF signaling improves ...peripheral energy metabolism and cardiovascular function. • Deficits in BDNF may contribute to metabolic morbidity and associated diseases.
Introduction
Analyses of off‐label use of acetylcholinesterase inhibitors (AChEIs) in mild cognitive impairment (MCI) has produced mixed results. Post hoc analyses of observational cohorts, such as ...the Alzheimer's Disease Neuroimaging Initiative (ADNI), have reported deleterious effects in AChEI‐treated subjects (AChEI+). Here, we used neuroimaging biomarkers to determine whether AChEI+ subjects had a greater rate of neurodegeneration than untreated (AChEI–) subjects while accounting for baseline differences.
Methods
We selected 121 ADNI MCI AChEI+ subjects and 151 AChEI– subjects with a magnetic resonance imaging (MRI) scan; 82 AChEI+ and 110 AChEI– also had a fluorodeoxyglucose (FDG) scan. A subset (83 AChEI+ and 98 AChEI–) had cerebrospinal fluid (CSF) or amyloid positron emission tomography (PET) assessment for amyloid positivity. Linear regression models were used to compare the effect of treatment on changes in Mini‐Mental State Examination and Clinical Dementia Rating‐Sum of Boxes scores. We used standard regression in SPM (for baseline) and the SPM toolbox sandwich estimator, SwE (for longitudinal) for comparisons of AChEI+ and AChEI– FDG PET and MRI data.
Results
At baseline, the AChEI+ group had significantly reduced cortical gray matter density (GMD) and more hypometabolism than AChEI– subjects. The greater rate of atrophy and hypometabolic changes over time in AChEI+ compared to AChEI– subjects did not survive correction for baseline differences. AChEI+ participants were more likely to be amyloid‐positive and have lower GMD and FDG standardized uptake value ratio than AChEI– at baseline. AChEI+ subjects showed greater atrophy over time, which remained significant after controlling for amyloid status.
Discussion
Our data suggest that the observed differences in rates of cognitive decline, atrophy, and hypometabolism are likely the result of significant baseline differences between the groups. Furthermore, the data indicate no treatment effect of AChEI (positive of negative), rather that physicians prescribe AChEI to subjects who present with more severe clinical impairment. This alone may account for the negative effect seen previously in the ADNI population of AChEI use among MCI subjects.
The impact of mitochondrial protein acetylation status on neuronal function and vulnerability to neurological disorders is unknown. Here we show that the mitochondrial protein deacetylase SIRT3 ...mediates adaptive responses of neurons to bioenergetic, oxidative, and excitatory stress. Cortical neurons lacking SIRT3 exhibit heightened sensitivity to glutamate-induced calcium overload and excitotoxicity and oxidative and mitochondrial stress; AAV-mediated Sirt3 gene delivery restores neuronal stress resistance. In models relevant to Huntington’s disease and epilepsy, Sirt3−/− mice exhibit increased vulnerability of striatal and hippocampal neurons, respectively. SIRT3 deficiency results in hyperacetylation of several mitochondrial proteins, including superoxide dismutase 2 and cyclophilin D. Running wheel exercise increases the expression of Sirt3 in hippocampal neurons, which is mediated by excitatory glutamatergic neurotransmission and is essential for mitochondrial protein acetylation homeostasis and the neuroprotective effects of running. Our findings suggest that SIRT3 plays pivotal roles in adaptive responses of neurons to physiological challenges and resistance to degeneration.
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•Exercise and glutamatergic signaling induce SIRT3 expression in cortical neurons•SIRT3 deacetylates SOD2 and cyclophilin D in neuronal mitochondria•SIRT3 prevents neuronal death in mouse models of epilepsy and Huntington’s disease•SIRT3 mediates adaptive responses of neurons to excitotoxic and metabolic stress
Cheng et al. find that neurons lacking the mitochondrial deacetylase SIRT3 are more vulnerable to dysfunction and degeneration in mouse models of epilepsy and Huntington’s disease. Exercise and synaptic activity induce hippocampal SIRT3 expression to modulate mitochondrial protein acetylation and bolster neuronal resistance to oxidative stress and apoptosis.
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