Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1

McCarty, Mark F.; DiNicolantonio, James J.; O’Keefe, James H.

doi:10.1016/j.mehy.2015.08.002

Cited by 61 publications

(48 citation statements)

References 179 publications

(185 reference statements)

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“…In neurones, the molecular mechanisms underpinning CR and SIRT regulated autophagy are not well understood. However, evidence from an alternative model supports the idea that a ketogenic style diet is likely to induce autophagy in a SIRT1‐dependent manner . Also, CR and AMPK are already known to increase up‐regulation and activity of SIRTs .…”

Section: Calorie Restriction Regulates Brain Functionmentioning

confidence: 95%

Less is more: Caloric regulation of neurogenesis and adult brain function

Morgan

Andrews

Davies

2017

J Neuroendocrinology

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Calorie intake is essential for regulating normal physiological processes and is fundamental to maintaining life. Indeed, both extremes of calorie intake result in increased morbidity and mortality. In this review, we discuss the effect of calorie intake on adult brain function, with an emphasis on the beneficial effects of mild calorie restriction.Recent findings relating to the regenerative and protective effects of the gastrointestinal hormone, ghrelin, suggest that it may underlie the beneficial effects of calorie restriction. We discuss the putative cellular mechanisms underlying the action of ghrelin and their possible role in supporting healthy brain ageing. K E Y W O R D Sacyl-ghrelin, adult hippocampal neurogenesis, calorie restriction, diet-induced obesity | INTRODUCTIONThe energy status of an organism is tightly controlled around a setpoint by hormonal and neural systems. These neuroendocrine checks and balances promote homeostasis, thereby ensuring an appropriate energy supply for the energetic demands of metabolism, physical activity, growth and repair.Disturbances to this homeostasis result in multiple physiological impairments, including age-related conditions such as type 2 dibetes mellitus and obesity. Perhaps less well recognised are the consequences of metabolic dysfunction on neuronal health and cognition.Diet-induced obesity (DIO) is a risk factor for neurodegenerative diseases such as Parkinson's disease (PD) and dementia. Conversely, calorie restriction (CR) (ie, an approximate 30% reduction in calorie intake) protects against neurodegeneration and promotes cognitive function (Figure 1). Indeed, there is a growing body of work supporting the CR paradigm as a tool for promoting lifespan and, perhaps more importantly, healthspan.1 However, the physiological mechanisms underlying these effects are not fully understood. Here, we review literature that identifies calorie intake as an important regulator of nerve cell function, with important implications for neurodegenerative disorders. Moreover, we describe recent research showing that CR promotes new neurone formation (neurogenesis) and neuroprotection in the adult brain and discuss the possible mechanisms that underpin this effect. | CALORIE RESTRICTION REGULATES BRAIN FUNCTIONCalorie restriction, in the absence of malnutrition, has beneficial effects on brain function, including reducing the incidence of age-related neurodegenerative disease, 2 eliciting anti-depressant behaviour 3 and improving memory function in rodents. 4 In nonhuman primates, prolonged CR in adulthood decreases the incidence of age-related disease, including measures of brain atrophy and glucose regulation. 5-7Translation of the carefully controlled CR experiments from preclinical models to humans is problematic. In particular, it is difficult to re-capitulate experimental controls such as genetic background and home environment (diet, temperature and lighting) that are standard in biomedical laboratory research. Nonetheless, in adult humans, a 3-month period of CR impr...

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Section: Calorie Restriction Regulates Brain Functionmentioning

confidence: 95%

Less is more: Caloric regulation of neurogenesis and adult brain function

Morgan

Andrews

Davies

2017

J Neuroendocrinology

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“…3OHB has also been reported to function as a ligand for one or more membrane receptors, and to inhibit some protein deacetylases [92]. Moreover, neurons treated with ketones exhibit increased SIRT1 activity, which may result from increased levels of NAD + (a cofactor for SIRT1 activation) and stimulation of autophagy [93]. The relative contributions of 3OHB as an energy supply for neurons and its signaling functions to beneficial effects of fasting on the brain remain to be determined.…”

Section: Dietary Energy Restriction and Ketogenesismentioning

confidence: 99%

Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance

Raefsky

Mattson

2017

Free Radical Biology and Medicine

210

123

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An important concept in neurobiology is “neurons that fire together, wire together” which means that the formation and maintenance of synapses is promoted by activation of those synapses. Very similar to the effects of the stress of exercise on muscle cells, emerging findings suggest that neurons respond to activity by activating signaling pathways (e.g., Ca2+, CREB, PGC-1α, NF-κB) that stimulate mitochondrial biogenesis and cellular stress resistance. These pathways are also activated by aerobic exercise and food deprivation, two bioenergetic challenges of fundamental importance in the evolution of the brains of all mammals, including humans. The metabolic ‘switch’ in fuel source from liver glycogen store-derived glucose to adipose cell-derived fatty acids and their ketone metabolites during fasting and sustained exercise, appears to be a pivotal trigger of both brain-intrinsic and peripheral organ-derived signals that enhance learning and memory and underlying synaptic plasticity and neurogenesis. Brain-intrinsic extracellular signals include the excitatory neurotransmitter glutamate and the neurotrophic factor BDNF, and peripheral signals may include the liver-derived ketone 3-hydroxybutyrate and the muscle cell-derived protein irisin. Emerging findings suggest that fasting, exercise and an intellectually challenging lifestyle can protect neurons against the dysfunction and degeneration that they would otherwise suffer in acute brain injuries (stroke and head trauma) and neurodegenerative disorders including Alzheimer’s, Parkinson’s and Huntington’s disease. Among the prominent intracellular responses of neurons to these bioenergetic challenges are up-regulation of antioxidant defenses, autophagy/mitophagy and DNA repair. A better understanding of such fundamental hormesis-based adaptive neuronal response mechanisms is expected to result in the development and implementation of novel interventions to promote optimal brain function and healthy brain aging.

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“…However, metformin has diverse effects on brain cells. For example, metformin has been suggested to enhance the neuronal autophagy via AMPK [17], supports the recovery of Schwann cells from hypoxic conditions [18] and attenuates the disruption of the blood-brain barrier by ischemia [19].…”

Section: Introductionmentioning

confidence: 99%

The Antidiabetic Drug Metformin Stimulates Glycolytic Lactate Production in Cultured Primary Rat Astrocytes

2015

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Metformin is the most frequently used drug for the treatment of type 2 diabetes in humans. However, only little is known about effects of metformin on brain metabolism. To investigate potential metabolic consequences of an exposure of brain cells to metformin, we incubated rat astrocyte-rich primary cultures with this compound. Metformin in concentrations of up to 30 mM did not acutely compromise the viability of astrocytes, but caused a time- and concentration-dependent increase in cellular glucose consumption and lactate production. For acute incubations in the hour range, the presence of 10 mM metformin doubled the glycolytic flux, while already 1 mM metformin doubled glycolytic flux during incubation for 24 h. In addition to metformin, also other guanidino compounds increased astrocytic lactate production. After 4 h of incubation, half-maximal stimulation of glycolysis was observed for metformin, guanidine and phenformin at concentrations of around 3 mM, 3 mM and 30 µM, respectively. The acute stimulation of glycolytic lactate production by metformin was persistent after removal of extracellular metformin and was also observed, if glucose was absent from the incubation medium or replaced by other hexoses. The metformin-induced stimulation of glycolytic flux was not prevented by compound C, an inhibitor of AMP-dependent protein kinase, nor was it additive to the stimulation of glycolytic flux caused by respiratory chain inhibitors. These data demonstrate that the antidiabetic drug metformin has the potential to strongly activate glycolytic lactate production in brain astrocytes.

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Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1

Cited by 61 publications

References 179 publications

Less is more: Caloric regulation of neurogenesis and adult brain function

Less is more: Caloric regulation of neurogenesis and adult brain function

Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance

The Antidiabetic Drug Metformin Stimulates Glycolytic Lactate Production in Cultured Primary Rat Astrocytes

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