Modern life has created a metabolic ‘energy crisis’. Many people seem to have dysfunctional energy metabolism resulting in persistent fatigue, high stress levels, weight gain and long-term metabolic dysfunction. ‘Unexplained’ fatigue is commonplace, comprising 5-7% of primary care appointments1 and is occurring in younger people too.2 Yet medical practitioners struggle to find solutions and are restricted to looking at a limited range of blood tests to identify obvious culprits such as anaemia. In fact, often the symptoms are sub-clinical and wrapped up in the complexities of energy homeostasis and the wider picture of stress and environmental demand.
The Energy Equation
Anxiety can occur for a variety of reasons and is influenced by your individual biology combined with environmental factors. The nervous system plays a fundamental role in our sleep-wake cycle, mood regulation, overall level of activity and ‘arousal’ (intensity of physiological activity), our response to stress, and reproductive behaviour.17 Neurotransmitters are chemical messengers that facilitate signalling between neurons, which are parts of the brain responsible for sending commands to different parts of the body.17 When working effectively, these neurotransmitters [e.g. serotonin, dopamine, noradrenaline and gamma-aminonutyric acid (GABA)] enable us to effectively adapt and respond to stressors, putting us into a sympathetic (activity mode) or parasympathetic (rest mode) state.
Fight or flight is an activity mode which is stimulated by a rise in cortisol and adrenaline that makes the body alert in response to stressors, which is normal in short bursts and is still essential when we face threats today. Those stressors used to be sporadic and consisted of animal predators or approaching tribes, but these days we rarely face serious threats. Instead, our body is constantly stimulated by alerts on devices, work, relationships and health issues. This results in chronically high circulating levels of cortisol, resulting in stress and anxiety.
The gut-brain axis refers to the bidirectional signaling between the gastrointestinal tract and the brain which is vital for maintaining homeostasis.18 The vagus nerve is the longest nerve in the body and connects the brain with the gut,19 enabling the brain to influence intestinal activities and vice versa.20 Research demonstrates that different strains of bacteria can alter the formation of neural pathways critical for the stress response, influencing symptoms of anxiety.20 There is often a high co-morbidity between anxiety and gastrointestinal disorders including irritable bowel syndrome (IBS) and irritable bowel disorder (IBD) highlighting that poor microbial diversity is associated with anxiety.21
Genetics can also influence the onset of anxiety disorders, with variations in genes know as SNPs (Single Nucleotide Polymorhisms) predisposing individuals.22 The COMT gene is involved in the breakdown of neurotransmitters, so variations that result in impaired metabolism can increase activity of dopamine and norephedrine, influencing feelings of overwhelm, worry, and anxiety.23
MAO-A is an enzyme that regulates the levels of serotonin, dopamine and noradrenaline (monamines) in the brain and variants known as warrior : worrier can influence anxiety.24 The ‘worrier’ gene breaks monamines down slowly and so individuals with this variant are overwhelmed easily as they cannot break down excess levels of neurotransmitters created under stress. Those with the ‘warrior’ gene however tend to thrive under stressful situations as they are able to effectively break down the excess levels of neurotransmitters.24
Methylation is a key process in the body and regulates a range of biochemical processes from growth and repair to DNA synthesis.25 It plays a key role in the nervous system from aiding neurotransmitter metabolism to synthesis of structural components, so individuals who have methylation issues can often experience mental health issues. COMT is methylation dependent, so the effective metabolism of neurotransmitters is dependent on methylation.26
‘FUELLING’ THE CELLS – ARE WE AT ODDS WITH OUR HUMAN NATURE?
We live in a unique period in human history, where most of us have easy access to a huge variety of food. From an evolutionary perspective, lack of regular access to food and seasonal scarcity of carbohydrates necessitated that we develop efficient pathways to readily store and access body fat for energy. Cells can adapt to different types of substrate that can be used as ‘fuel’ and different cells prefer different substrates. This adaptation is crucial and is achieved through the several regulatory mechanisms involved in controlling energy and its utilisation.3
But, we no longer ‘feast and famine’. Instead, we ‘graze and binge’. An over-abundance of calorie-dense, nutrient-scarce foods has led to a disconnection between hunger and true physiological needs.
Blood Glucose Dysregulation
Diets rich in refined carbohydrates, low in fat/protein and low in micronutrients often result in metabolic maladaptation, ranging from dysglycaemia to insulin resistance. Chronically elevated insulin often correlates with elevated glucose as cells become less sensitive to insulin signalling. Glucose ‘peaks and troughs’ may result in energy dips as a result of reactive hypoglycaemia. Maintenance of plasma glucose under a variety of nutritional conditions and energetic demands must be tightly controlled to ensure that cells are not degraded by high sugar levels and avoid consequent formation of inflammatory Advanced Glycation End products (AGEs).4 It can also lead to dyslipidaemia which increases cardiovascular risk,5 testosterone issues in men and an increased risk of polycystic ovary syndrome (PCOS) in women.6
Blood Glucose Metabolism
Glucagon and insulin exert opposite influences as part of a feedback system that keeps blood glucose levels stable. Glucose stimulates secretion of insulin from the pancreas, promoting uptake of glucose and amino acids from blood into cells. Transport proteins known as glucose transporters (GLUT) facilitate transport of glucose over the cell membrane:
GLUT 1 is responsible for the low level of basal glucose uptake required to sustain respiration in all cells and can do so without the need for insulin.7
GLUT4 is an insulin-regulated glucose transporter, found in adipose tissues and skeletal and cardiac muscle, and plays a role in delivering glucose to muscles for physical activity8
GLUT2 (also known as solute carrier family 2 encoded by the SLC2A2 gene) plays more of a role in glucose management and is present in renal, liver, pancreatic beta and epithelial cells. Polymorphisms in SLC2A2, are associated with increased habitual consumption of sugars9 and type 2 Diabetes.10
Glucose not used directly for energy is stored as glycogen in the liver and muscles. When glycogen stores are full, glucose can be converted to fatty acids and triglycerides. Insulin also inhibits glucagon secretion, blocking the conversion of non-carbohydrate energy sources into glucose. This is presumably a protective mechanism for periods of fasting. Our bodies seem to prioritise storage of fuel rather than the release of it. A decrease in blood glucose stimulates glucagon causing the release of glucose from glycogen, release of fatty acids from stored triglycerides and stimulation of gluconeogenesis.
Cellular Energy Regulation
Now that we are well fuelled, we need to deliver that fuel to our cells, namely our mitochondria, to turn it into energy. The ultimate goal of delivering fuel substrates, such as carbohydrate, protein or fat, is conversion to adenosine triphosphate (ATP) - often referred to as the ‘molecular currency unit’ of energy transfer. ATP is actually a proton (H+) storage system. Removal of the phosphate group from ATP forms ADP and releases energy. It is this key ‘phosphorylation’ reaction, the coupling and uncoupling of phosphate, which powers the demands of our body. ATP can be synthesised by three different energy systems:
- Phosphocreatine (PCr) system – PCr is stored in muscle and other tissues can donate a phosphate molecule to ADP in order to create ATP through a reversible reaction.
- Glycolysis - Metabolism of glucose to pyruvic acid through a series of reactions. It is a quick way to make small amounts of energy, but it’s not sustainable for longer periods.
- Oxidative phosphorylation – In the mitochondria, in the presence of oxygen, pyruvic acid is converted to ATP via a number of different mechanisms, and so is more flexible and sustainable for longer periods of activity.11
Oxidative Phosphorylation
1) The key substrate that kicks off the process is acetyl-coenzyme A (acetyl-CoA). Acetyl CoA can be produced through carbohydrate, fatty acid, or amino acid metabolism. A vitamin B3 derivative, NAD+, is required as a cofactor for this conversion. Furthermore, if fats are used, carnitine is required for their transport into the mitochondria.
2) The citric acid (Krebs) cycle – In a chain of reactions, acetyl-CoA is used to make citric acid. The intermediates of this process donate electrons to two other vital molecules, NAD+ and FAD+, (flavin adenine dinucleotide derived from vitamin B2) to form the electron carrying molecules NADH and FADH2.
3) Electron transport chain (ETC) - a series of protein complexes in the inner mitochondrial membrane, enzymatically release the energy gradually by transferring electrons from donors to acceptors via redox reactions, resulting in production of ATP. ETC, involves five enzyme complexes (Complex I - Complex V) which require a range of nutrient cofactors including FAD, NADH, iron, cysteine, and co-enzyme Q10 (ubiquinone).
Mitochondrial Inefficiency
A number of environmental and physiological factors can have a damaging effect on the mitochondria. This includes toxic load and oxidative stress. High or chronic low level exposure to xenobiotics, alcohol, and particulate air pollution can directly interfere with mitochondrial energy production.12This can be more of a problem in a state of low mitochondrial antioxidants; manganese superoxide dismutase (MnSOD) and mitochondrial glutathione (mGSH) which can be caused by nutrient deficiencies (manganese, selenium, cysteine), or genetic polymorphisms e.g. glutathione reductase (GSR).13 Methylation is also a crucial process as the mitochondrial enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase 2) is responsible for producing 20–40% of cellular NADPH.14 As mentioned, ATP production is most efficient in the presence of oxygen, so low oxygen states due to anaemia or poor circulation, can significantly compromise energy production. Lastly, thyroid hormones are a key regulator of mitochondrial biogenesis and function, therefore hypothyroidism can be a contributing factor to mitochondrial dysfunction.
AHPA Axis & Adrenal Function
We also have sophisticated endocrine mechanisms that can further modulate energy production in response to circumstances. If blood sugar falls, or if there is a stress demand, the adrenal glands are normally activated as an essential back-up system to maintain ongoing fuelling. Thus, continual metabolic demand and reduced adaptation with poorly regulated blood sugar may have consequences affecting many systems including the adrenals.
When the brain detects a threat or stressor, excitatory neurons in the amygdalae fire rapidly, increasing the glutamatergic response, leading to higher levels of the neurotransmitter glutamate in the brain and a feeling of panic and fear. This nervous system response then triggers the endocrine system via the AHPA axis and increases dopamine.15 The hypothalamus stimulates the adrenal medulla to secrete the more potent stress hormones adrenaline along with noradrenaline, triggering an immediate sympathetic nervous response. The impact of adrenaline release is characterised by greater blood flow to muscles, increased heart rate, pupil dilation and elevated blood glucose levels.16 The primary role of noradrenaline, like adrenaline, is arousal and increasing overall wakefulness and responsiveness. In a secondary, complementary pathway, the AHPA axis, the hypothalamus releases corticotropin-releasing hormone (CRH) which triggers the anterior pituitary to release adrenocorticotropic hormone (ACTH). This stimulates the adrenal cortex to produce the glucocorticoid cortisol. Cortisol influences, regulates or modulates many of the changes that occur in the body in response to stress. The effects of cortisol are felt over almost the entire body, impacting on homeostatic mechanisms. There is an interplay between these two systems to intelligently manage a range of stressors, with adrenaline exerting a rapid and powerful response and cortisol providing a lower intensity but longer-term response. Elevated levels of adrenaline and cortisol are associated with anxiety states.17Conversely, gamma-aminobutyric acid (GABA) balances the excitatory action of glutamate18 and attenuates excessive sympathetic responses and thus CRH and ACTH. As such, GABA has a calming effect on our emotions and prevents us from becoming overwhelmed in stressful situations,19 by modulating cortisol as well as adrenaline, noradrenaline, dopamine and serotonin levels, and effectively promoting parasympathetic mode.20
Support Energy Adaptation
- Feast and Famine – We need to spend less time eating and more time digesting. This might mean cutting out snacks and focusing on 2-3 main meals based on wholefoods, or for some it might mean intermittent fasting, or even a ketogenic diet.
- Optimise blood glucose regulation – If you’re struggling with dysglycaemia, or even insulin resistance, increase your intake of chromium,21 magnesium,22 myo-inositol,23 and alpha lipoic acid.24
- Prioritise sleep – Inadequate sleep is an independent risk factor for metabolic abnormalities such as insulin resistance and hyperglycaemia, and also reduces our resilience to stress.
- Optimise cellular energy – reduce mitochondrial insults such as toxin exposure, inflammation and oxidative stress and prioritise regular movement to increase the number of mitochondria within cells. Provide key mitochondrial cofactors and antioxidants such as CoQ10,25 N-acetyl carnitine,26 B2,27 B3,28D-ribose, 29 alpha lipoic acid,30 and N-acetyl cysteine.31
- Manage stress by practising mindfulness and meditation. Learn to be more present and appreciate the simple things in life. Check out these books for inspiration - ‘Kintsugi’ by Tomás Navarro and ‘Japonisme’ by Erin Niimi Longhurst
- Support steroid hormone production - Vitamin B5 is used to make acetyl CoA, essential to cellular energy generation.32 It is also a cofactor for cortisol production and so can support the stress response.33 Vitamin C works in symphony with the AHPA response to stress.34 It is needed for the production of steroid hormones and catecholamines and can improve adaptation to stress.35
- Adaptogen support – Rhodiola and Ginseng reduce stress, fatigue,36 and anxiety,37,38 and improve mental performance.39,40 Reishi mushrooms help to regulate cortisol in response to stress.41
To some extent, the energy equation is as a simple as energy in = energy out. But energy metabolism is complex and its delicate balance can be easily disrupted, leading to fatigue and chronic disease. If we fuel our body appropriately, without overfeeding, whilst optimising cellular energy metabolism and supporting a balanced AHPA response with adequate time to rest and recuperate, we can improve energy adaptation and overall resilience.
References
References
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September 8, 2021
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