During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended ...exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease. Here, we consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. Such metabolic switching impacts multiple signalling pathways that promote neuroplasticity and resistance of the brain to injury and disease.
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.
Beyond its role in patterning the neural tube during embryogenesis, additional functions of Sonic hedgehog (Shh) in post-embryonic and mature brains have been coming into focus. However, the question ...of the abundance of endogenous Shh - the ligand of the signaling pathway - and its changes over time in post-embryonic and mature brains are less well understood. Here we find that while the amounts of Shh transcript and protein in rat brains are nearly undetectable at birth, they increase continuously during postnatal development and remain at readily detectable levels in young adults. This developmental age-associated increase in Shh levels is also seen in hippocampal neurons grown in culture, in which very young neurons produce minimal amounts of Shh protein but, as neurons grow and form synapses, the amounts of Shh increase significantly. Using immunolabeling with antibodies to different residues of Shh, we observed that the N-terminal fragment and the C-terminal fragment of Shh are present in hippocampal neurons, and that these two Shh forms co-exist in most compartments of the neuron. Our findings provide a better understanding of Shh expression in the brain, laying the groundwork for further comprehending the biogenesis of Shh protein in the young and mature brain and neurons.
•After undergoing carotid endarterectomy (CEA), 2.1% of patients experienced a postoperative transient ischemic attack (TIA).•The odds a patient will experience a TIA post-CEA are greater in patients ...with intraoperative electroencephalogram (EEG) and somatosensory evoked potential (SSEP) changes.•Our study found the odds of mortality post-CEA significantly doubled in patients who experienced postoperative TIA.
Transient ischemic attacks (TIA) after carotid endarterectomy (CEA) are not well-studied. We aimed to investigate the characteristics and the predictive role of intraoperative neurophysiological monitoring (IONM) in TIA post-CEA.
Patients who underwent CEA utilizing IONM from 2009-2020 were included. Analyses included TIA incidence, sensitivity, specificity, and predictive values of IONM, risk factor regression analyses, and mortality Kaplan Meier plots.
Out of 2232 patients, 46 experienced TIA, 14 of which were within 24 hours of CEA (p < 0.01). Nine of these patients displayed significant IONM changes during CEA. The odds of TIA increased with somatosensory evoked potential (SSEP) changes (Odds Ratio (OR): 2.48 95% Confidence Interval (CI): 1.14–5.4), electroencephalogram (EEG) changes (OR: 2.65 95% CI: 1.22–5.77), and combined SSEP/EEG changes (OR: 2.98 95% CI: 1.17–7.55). Patients with TIA were less likely to be alive after an average of 4.3 years (OR: 0.5 95% CI: 0.26–0.96).
The odds a patient will have TIA post-CEA are greater in patients with IONM changes. This risk is inversely related to the time post-CEA.
Changes in IONM during CEA predict postoperative TIA. Post-CEA TIA may increase long-term mortality, thus further research is needed to better elucidate clinical implications of postoperative TIA.
Evolutionary considerations suggest that the body has been optimized to perform at a high level in the food‐deprived state when fatty acids and their ketone metabolites are a major fuel source for ...muscle cells. Because controlled food deprivation in laboratory animals and intermittent energy restriction in humans is a potent physiologic stimulus for ketosis, we designed a study to determine the impact of intermittent food deprivation during endurance training on performance and to elucidate the underlying cellular and molecular mechanisms. Male mice were randomly assigned to either ad libitum feeding or alternate‐day food deprivation (ADF) groups, and half of the mice in each diet group were trained daily on a treadmill for 1 mo. A run to exhaustion endurance test performed at the end of the training period revealed superior performance in the mice maintained on ADF during training compared to mice fed ad libitum during training. Maximal O2 consumption was increased similarly by treadmill training in mice on ADF or ad libitum diets, whereas respiratory exchange ratio was reduced in ADF mice on food‐deprivation days and during running. Analyses of gene expression in liver and soleus tissues, and metabolomics analysis of blood suggest that the metabolic switch invoked by ADF and potentiated by exercise strongly modulates molecular pathways involved in mitochondrial biogenesis, metabolism, and cellular plasticity. Our findings demonstrate that ADF engages metabolic and cellular signaling pathways that result in increased metabolic efficiency and endurance capacity.—Marosi, K., Moehl, K., Navas‐Enamorado, I., Mitchell, S.J., Zhang, Y., Lehrmann, E., Aon, M.A., Cortassa, S., Becker, K.G., Mattson, M.P. Metabolic and molecular framework for the enhancement of endurance by intermittent food deprivation. FASEB J. 32, 3844–3858 (2018). www.fasebj.org
Abstract
Objective
Although decompressive laminectomy (DL) for lumbar spinal stenosis (LSS) is a common procedure among older adults, it is unclear whether surgical definitions of success translate ...into patient-defined success. Using goal attainment scaling (GAS) to compare goal achievement between individuals, we investigated the relationship between surgical-defined functional recovery and achievement of personalized goals in patients who underwent DL for LSS.
Participants
Twenty-eight community-dwelling veterans scheduled to undergo DL.
Methods
Participants were interviewed over the phone to set 1-year post-DL goals within 30 days before undergoing DL. Brigham Spinal Stenosis (BSS) score, comorbidities, cognitive function, and psychological factors also were assessed. GAS and BSS were repeated 1 year after DL. GAS scores were transformed into GAS-T scores (T-score transformation) to standardize achievement between patients and GAS-T change scores to compare study variables.
Results
Seventeen of 28 participants had successful DL outcomes by BSS standards, though none of the participants achieved all of their GAS goals, with follow-up GAS-T scores averaging 44.5 ± 16.8. All three BSS scales positively correlated with GAS-T change scores: severity change r = 0.52, P = 0.005; physical function change r = 0.51, P = 0.006; and satisfaction r = 0.70, P < 0.001. Covariate analysis revealed a negative correlation between GAS-T change score and fear-avoidance beliefs: r = -0.41, P = -0.029.
Conclusion
There was congruent validity between GAS and the BSS in older veterans undergoing DL for LSS. Given the need for patient-centered care in older adults, future investigations exploring GAS in larger studies that target additional pain conditions and include participants with greater demographic diversity are warranted.
Abstract
Objective
Pain management in persons with mild to moderate dementia poses unique challenges because of altered pain modulation and the tendency of some individuals to perseverate. We aimed ...to test the impact of an e-learning module about pain in communicative people with dementia on third-year medical students who had or had not completed an experiential geriatrics course.
Design
Analysis of pre- to postlearning changes and comparison of the same across the student group.
Setting
University of Pittsburgh School of Medicine and Saint Louis University School of Medicine.
Subjects
One hundred four University of Pittsburgh and 57 Saint Louis University medical students.
Methods
University of Pittsburgh students were randomized to view either the pain and dementia module or a control module on pain during a five-day geriatrics course. Saint Louis University students were asked to complete either of the two modules without the context of a geriatrics course. A 10-item multiple choice knowledge test and three-item attitudes and confidence questionnaires were administered before viewing the module and up to seven days later.
Results
Knowledge increase was significantly greater among students who viewed the dementia module while participating in the geriatrics course than among students who viewed the module without engaging in the course (P < 0.001). The modules did not improve attitudes in any group, while student confidence improved in all groups.
Conclusions
Medical students exposed to e-learning or experiential learning demonstrated improved confidence in evaluating and managing pain in patients with dementia. Those exposed to both educational methods also significantly improved their knowledge.
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