BUILD, Food for Your Muscles
September 26, 2021Hydrogen-Rich Water in Older Adults
October 31, 2021Metabolic Flexibility – a Cornerstone For Healthspan and Longevity
The main predictor of not only survival, but optimization of any species, is the capacity to efficiently adapt to its environment.
Some sections are written for more advanced readers, however, “layman” takeaways are below in italics
Energy homeostasis and adaptation to fluctuating environmental conditions is needed for survival of the organism. Human physiology evolved during times of inconsistent food availability, and various climate and seasonal changes, which forced the human species to develop highly coordinated metabolic programs to ensure energy equilibrium (a major survival advantage). This phenomenon is known as metabolic flexibility, which is the ability to smoothly alternate between the sensing, uptake, trafficking, storage, and utilization of different fuel substrates (whether that be carbohydrates, dietary fat, endogenous fat stores, amino acids, lactate etc) commensurate with physiological demand. Basically, being metabolically flexible means your body is equipped with the metabolic machinery to handle whatever nutritional/energetic state it’s in with ease. This relies on the appropriate configuration of metabolic pathways and coordination of key enzymes and transcription factors, collectively orchestrated by mitochondrial function, endocrine cues, and epigenetic modification. In a metabolically flexible system, nutrient and energetic signals are rapidly propagated and duly interpreted to elicit finely calibrated adjustments in fuel partitioning. It is not an “on-off” phenomenon, but involves tightly regulated subtle adjustments and exquisite inter-organ cross-talk (Smith at al., 2018; Goodpaster & Sparks, 2017).
You can think of this phenomenon like a symphony–where the liver, adipose tissue and skeletal muscle communicate with each other through hormonal and other molecular signaling cues. All of the different composers involved in the orchestra need to work together in a highly organized harmony to properly execute the music.
If you feel like a slave to food and that you need to frequently eat throughout the day in order to avoid symptoms of hypoglycemia (brain fog, lethargy, dizziness, and “hangriness”), you are probably metabolically inflexible and carb dependent. As such, your fatty acid oxidation machinery is downregulated (meaning your ability to use fat for fuel is decreased). This reduces one’s ability to use their stored body fat for fuel. When athletes are not fat-adapted, they are more prone to “hitting the wall” when their glycogen reserves run out (roughly 2000 kcal can be stored in the liver and muscle combined). Using your own body fat for fuel is glycogen-sparing and advantageous for an athlete. Conversely, people who consume ketogenic diets long term tend to become less adept at metabolizing carbohydrates for fuel, and less insulin sensitive.
Mitochondria Are Essential to Metabolic Flexibility
Let’s zoom into the mitochondria, which are pliable organelles within the cell that have their own genome (which is more vulnerable to insult than nuclear DNA). They are the final acceptors for metabolic substrates and are responsible for generating most of the chemical energy through cellular respiration. They play a fundamentally critical role in substrate flux and their morphology changes in response to nutrient exposure. Cells bombarded with excess nutrition have a fragmented mitochondrial network, whereas upon energy restriction, mitochondria appear more interconnected. When mitochondria are more interconnected and elongated, their bioenergetics are enhanced, and so have increased ATP synthesis capacity and efficiency. Conversely, fragmented mitochondria have a reduced bioenergetic efficiency, perhaps to protect itself from the deleterious effects of substrate overload (Smith et al., 2018; Muoio DM, 2014). Taken together, chronic overindulgence results in impaired fuel switching, mitochondrial metabolic indecision, and energy dysregulation. Mitochondrial indecision basically means the mitochondria become so overwhelmed with “noise” that its capacity to discern what metabolic path to take becomes muffled and things go awry.
Layman’s takeaway: Mitochondria have been gaining more publicity over the years as new research continuously emerges, uncovering the myriad of roles they are at the root of. They are most famously responsible for processing various fuels (amino acids, carbohydrates and fatty acids) to generate adenosine triphosphate (ATP). ATP is the energy currency of the cell that powers biological processes throughout the body. Beyond that, mitochondria play a critical role in a multitude of physiological processes, including many diseases, metabolic flexibility, aging, and apoptosis (programmed cell death—when a cell intentionally commits suicide). The human body is shaped through subtraction/tweaking; cells that are dysfunctional need to be removed via apoptosis to maintain proper functioning of the system. Aberrant cells can also divide and cause significant problems (like cancer). The more properly functioning mitochondria we have, the more energy we have to carry out our day-to-day activities. The number of mitochondria we have in any given cell is dictated by the energetic demand of that cell. When there is a mismatch in energy supply and energy demand, damage can occur to the mitochondria. Mitochondrial perturbations are associated with a whole host of pathological conditions. As I alluded to before, mitochondrial DNA is more susceptible to damage than nuclear DNA, and the inundation of fuel substrates (i.e., overconsumption of energy dense foods without matched energy expenditure) impairs redox status and triggers pernicious levels of oxidative stress (i.e., superoxide) which further damages the mitochondrial DNA.
The Metabolism and Aging Interface
Metabolic inflexibility is a hallmark of many diseases and is interwoven with immune metabolism, aging and cancer (Smith et al., 2018). The exquisitely regulated nutrient-sensing pathways insulin/IGF-1, mammalian target of rapamycin (mTOR), adenosine monophosphate-activated kinase (AMPK), and sirtuins (SIRTs) all converge on networks that modulate genes involved in aging and are evolutionarily conserved across a range of species (worms, flies, rodents, yeast, and mammals) (Smith et al., 2018; Bareja et al., 2019). They have different gene names depending on the species, but for our purposes I will refer to the mammalian gene designations. Upregulation of AMPK and SIRTs occur when low energy is sensed (high AMP/ATP ratio). Conversely, the insulin/IGF signal transduction network is upregulated in the fed state (particularly with detection of a higher glucose load). mTOR has a high affinity for certain amino acids, particularly leucine. Activation of AMPK and SIRTs upregulate the master transcription factor Forkhead box O (FOXO) which modulates an array of downstream effectors, ultimately promoting healthspan/longevity and bolstering cellular stress resistance. Insulin/IGF and mTOR both downregulate FOXO, which turns off those longevity programs. That’s not to say that it is optimal to aim to keep those pathways downregulated or upregulated all the time, it’s about calibrating the right “goldilocks” balance in pulses.
Like most things in biology, there’s a U/J-shaped curve. We obviously need anabolism (growth and building), too, and to not just be in a catabolic (breaking down) state all of the time. Furthermore, these pathways all converge on autophagy (SIRT and AMPK are positive regulators, TOR and IGF-1/Insulin are negative regulators), which is a catabolic process that recycles defective cellular material via lysosomes (an organelle in the cytoplasm where engulfed cargo is degraded by hydrolases) and promotes regeneration of healthy cells. FOXO-3 upregulates autophagy by promoting the expression of autophagy-related genes, including LC3, Bnip3, and Beclin1 (Yu et al., 2021; Bareja et al., 2019). Hydrogen has been shown regulate autophagy in a context-dependent, beneficial manner. For instance, hydrogen inhibited inappropriate levels of autophagy in hypertrophied cardiomyocytes in cell culture and a mouse model (Zhang et al., 2017) and activated autophagy in a manner that was favorable in rats (Jiang et al., 2019; Du et al., 2016).
A combination of hormetic stressors such as fasting, caloric restriction, exercise, dietary bioactives that are recognized as xenobiotic, and pharmacological agents (such as metformin) modulate all of these signal transduction networks (generally, they increase AMPK and SIRTs and decrease IGF-1/Insulin and TOR). In fact, one of the promulgated benefits of phytochemicals in certain food and beverages is the hormetic response they induce by upregulating your own endogenous defense and repair systems (as opposed to direct antioxidant signaling molecules). Their signaling cascade turns on transcription factors that bind to something called an antioxidant response element (ARE) in the promotor regions of genes. Hydrogen water also has been shown to induce hormesis (please see https://drinkhrw.com/blog/hormesis-molecular-hydrogen/ for more detail), which could explain the vast benefits observed in clinical research on the hydrogen tablets; including the anti-aging benefits just published, and the trials showing significant metabolic benefits. This is just a snippet of how metabolism is interwoven with aging and healthspan, but there is much more biological plausibility beyond what is mentioned here.
How to Achieve Metabolic Flexibility
The key to achieving metabolic flexibility is to train your body to be to acutely and robustly receptive to varying circumstances by exposing it to different conditions that build your metabolic machinery. Fasting is one of the most effective tools to do this. Fasted exercise, and in particular, training both anaerobic (fast-twitch explosive movements like sprinting) and aerobic (steady-state exercise that uses oxygen) systems in the fasted state is another potent tool. Exercise in general is a principle strategy for becoming more metabolically flexible and promoting healthspan (which go hand in hand) (Rynders et al., 2018), and requires metabolic flexibility in order to accommodate enormous increases in physiological demands. Exercise training induces changes in the epigenome, transcriptome and proteome to support increased storage of fuel and increased capacity for substrate utilization (Goodpaster & Sparks, 2018).
Hydrogen water, with its many pleiotropic effects, has been shown to potentiate the beneficial effects of exercise (Mikami et al., 2019; Yue-Peng & Liang, 2017; Nogueira et al., 2018). A sedentary lifestyle is an underlying cause of age-related metabolic diseases that tends to worsen with age. However, a study in middle-aged postmenopausal women showed that endurance training improved their ability to mobilize and oxidize free fatty acids, suggesting that metabolic flexibility can still be trained in the elderly (DiPietro L., 2010).
While there is evidence that ketones (especially beta hydroxybutryate) act as therapeutic signaling molecules, oscillating in and out of ketosis with a cyclical low carbohydrate diet–not perpetually being in ketosis, is better at promoting metabolic flexibility. Long-term exposure to ketogenic diets are associated with cardiac fibrosis and impaired mitochondrial biogenesis (Xu et al., 2021). Also, despite the popularity with high-fat ketogenic diets, there are people who do not do well on higher fat diets due to their microbiome, variations in their fatty acid metabolism genes, or other reasons. There are also populations for whom a ketogenic diet is medically necessary, such as those with epilepsy.
High carbohydrate diets have been shown to be major drivers of insulin resistance, metabolic dysfunction, cardiovascular disease, type 2 diabetes, and accelerated aging. However, carbohydrates are an umbrella macronutrient that encompass a variety of different sources. The quality and the quantity of the carbohydrate source (and overall dietary pattern) matters. Higher quality carbohydrates like properly prepared beans, legumes, vegetables and lower glycemic fruits in limited quantities are different than highly refined, nutrient-poor carbohydrate sources.
A randomized control trial that was just published in the American Journal of Clinical Nutrition found that that a low carbohydrate diet (20%) that was higher in saturated fats (21%) lowered insulin resistance score by 15%, whereas the high carbohydrate diet group (60% carbohydrates and 7% saturated fat) had a 10% increase in insulin resistance score. Carbohydrate restriction had favorable effects on insulin resistance in a dose-dependent manner and did not have adverse effects on LDL cholesterol, LDL particle size, total cholesterol, inflammatory biomarkers or blood pressure. The low carbohydrate diet also increased the fat cell hormone adiponectin, which promotes insulin sensitivity and anti-atherogenesis. Saturated fat paired with a low carbohydrate diet did not aggravate cardiometabolic risk factors in this study; however, saturated fat paired with a diet high in processed carbohydrates potentiated the insulin response (Ebbeling et al., 2021). We know this to be true in cell culture models as well – when you pair various fatty acids with glucose, the insulin secretion is higher than glucose alone in the same amounts.
In summary, acute metabolic flexibility is a universal feature of healthy cells and pillar of healthspan, whereas metabolic inflexibility governs an overall unhealthy state and is central to the pathophysiology of many diseases. The ability to efficiently switch between the metabolism of different substrates and mobilize your own fat stores is pivotal for optimal performance and health. These metabolic mechanisms ( i.e., lipolysis, lipogenesis, proteolysis, glycogenolysis, gluconeogenesis, glycogenesis, glycolysis) that humans have adapted were borne out of necessity and, given our drastically different contemporary environment, these mechanisms have atrophied and are not as sharply tuned in many people–hence the epidemic proportions of metabolic disorders. Metabolism is intertwined with virtually every aspect of physiology, so poor metabolic health (i.e., metabolic inflexibility) affects every other aspect of your health.
Further reading:
https://drinkhrw.com/blog/hormesis-molecular-hydrogen/
References:
Bareja, A., Lee, D. E., & White, J. P. (2019). Maximizing Longevity and Healthspan: Multiple Approaches All Converging on Autophagy. Frontiers in cell and developmental biology, 7, 183. https://doi.org/10.3389/fcell.2019.00183
Cara B Ebbeling, Amy Knapp, Ann Johnson, Julia M W Wong, Kimberly F Greco, Clement Ma, Samia Mora, David S Ludwig, Effects of a low-carbohydrate diet on insulin-resistant dyslipoproteinemia—a randomized controlled feeding trial, The American Journal of Clinical Nutrition, 2021;, nqab287, https://doi.org/10.1093/ajcn/nqab287
DiPietro L. Exercise training and fat metabolism after menopause: implications for improved metabolic flexibility in aging. J Appl Physiol (1985). 2010;109(6):1569–1570.
Du, H., Sheng, M., Wu, L., Zhang, Y., Shi, D., Weng, Y., Xu, R., & Yu, W. (2016). Hydrogen-Rich Saline Attenuates Acute Kidney Injury After Liver Transplantation via Activating p53-Mediated Autophagy. Transplantation, 100(3), 563–570. https://doi.org/10.1097/TP.0000000000001052
Goodpaster, B. H., & Sparks, L. M. (2017). Metabolic Flexibility in Health and Disease. Cell metabolism, 25(5), 1027–1036. https://doi.org/10.1016/j.cmet.2017.04.015
Jiang, X., Niu, X., Guo, Q., Dong, Y., Xu, J., Yin, N., Qi, Q., Jia, Y., Gao, L., He, Q., & Lv, P. (2019). FoxO1-mediated autophagy plays an important role in the neuroprotective effects of hydrogen in a rat model of vascular dementia. Behavioural brain research, 356, 98–106. https://doi.org/10.1016/j.bbr.2018.05.023
Mikami, T., Tano, K., Lee, H., Lee, H., Park, J., Ohta, F., LeBaron, T. W., & Ohta, S. (2019). Drinking hydrogen water enhances endurance and relieves psychometric fatigue: a randomized, double-blind, placebo-controlled study 1. Canadian journal of physiology and pharmacology, 97(9), 857–862. https://doi.org/10.1139/cjpp-2019-0059
Muoio D. M. (2014). Metabolic inflexibility: when mitochondrial indecision leads to metabolic gridlock. Cell, 159(6), 1253–1262. https://doi.org/10.1016/j.cell.2014.11.034
Nogueira, J. E., Passaglia, P., Mota, C., Santos, B. M., Batalhão, M. E., Carnio, E. C., & Branco, L. (2018). Molecular hydrogen reduces acute exercise-induced inflammatory and oxidative stress status. Free radical biology & medicine, 129, 186–193. https://doi.org/10.1016/j.freeradbiomed.2018.09.028
Rynders, C. A., Blanc, S., DeJong, N., Bessesen, D. H., & Bergouignan, A. (2018). Sedentary behaviour is a key determinant of metabolic inflexibility. The Journal of physiology, 596(8), 1319–1330. https://doi.org/10.1113/JP273282
Smith, R. L., Soeters, M. R., Wüst, R., & Houtkooper, R. H. (2018). Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease. Endocrine reviews, 39(4), 489–517. https://doi.org/10.1210/er.2017-00211
Xu, S., Tao, H., Cao, W. et al. Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis. Sig Transduct Target Ther 6, 54 (2021). https://doi.org/10.1038/s41392-020-00411-4
Yue-Peng Sun., & Liang Sun. (2017). Selective protective effect of hydrogen water on free radical injury of athletes. Biomedical Research, 28 (10): 4558-456.
Yu, M., Zhang, H., Wang, B., Zhang, Y., Zheng, X., Shao, B., Zhuge, Q., & Jin, K. (2021). Key Signaling Pathways in Aging and Potential Interventions for Healthy Aging. Cells, 10(3), 660. https://doi.org/10.3390/cells10030660
Zhang, Y., Long, Z., Xu, J., Tan, S., Zhang, N., Li, A. … Wang, T. (2017). Hydrogen inhibits isoproterenol‑induced autophagy in cardiomyocytes in vitro and in vivo. Molecular Medicine Reports, 16, 8253-8258. https://doi.org/10.3892/mmr.2017.7601