Part 2 The Impact of Advanced Glycation End Products on Collagen
Collagen is the most abundant structural protein in the body that makes up our skin, cartilage, bone, blood vessels, and connective tissue. Elastin is another protein in the extracellular matrix (ECM) that provides elasticity to our skin and connective tissues. Together, they play fundamental roles in the structure, resilience, elasticity, function, and biomechanical properties of an array of organs and tissues. The physiology of connective tissue is highly dependent on collagen and other ECM proteins that are hierarchically organized within the tissues. Collagen is one of the strongest proteins. In the skin, it not only serves as a supportive framework for cells and tissues, but also interacts with other cells and affects various cellular functions such as migration, differentiation and proliferation. There are 28 known types of collagen which vary in the type of structures they form. The most common types are I, II, II, IV, and V. Type I is the most abundant, accounting for over 90% in humans. Collagen is composed of the amino acids glycine, proline, and hydroxyproline. These amino acids form three strands, which make up the triple-helix structure characteristic of collagen. Since glycine is the smallest of all the amino acids, it allows the chain to form a tight configuration, providing some of its resilience. One of the hallmarks of aging is disruption to the integrity of collagen. This goes for both skin aging and global aging of the organism. What are Advanced Glycation End Products? Advanced glycation end products (AGEs) are a diverse group of heterogeneous compounds formed by a series of non-enzymatic reactions between reducing sugars (or their derivatives) and the free amino groups of proteins, nucleic acids, or aminophospholipids. There are three different modes of AGE formation: Maillard reaction, the polyol pathway, and lipid peroxidation. The Maillard reaction is the browning you see on cooked foods and baked goods. AGEs are ubiquitous and we can be exposed to them exogenously (diet, cigarette smoke, pollution, ultraviolet radiation, other environmental elements) or through endogenous production (produced within the body, hyperglycemic conditions, normal aging and metabolism, inflammatory conditions, metabolic diseases). They are one of the major drivers of aging. More than 20 different AGEs have been identified in human blood and tissues and in foods. The most prominent ones include carboxymethyl-lysine, carboxyethyl-lysine, pyrraline (nonfluorescent AGEs), pentosidine, and methylglyoxal-lysine dimer. Below is a schematic depicting different types of AGEs. What are Advanced Glycation End Products? Advanced glycation end products (AGEs) are a diverse group of heterogeneous compounds formed by a series of non-enzymatic reactions between reducing sugars (or their derivatives) and the free amino groups of proteins, nucleic acids, or aminophospholipids. There are three different modes of AGE formation: Maillard reaction, the polyol pathway, and lipid peroxidation. The Maillard reaction is the browning you see on cooked foods and baked goods. AGEs are ubiquitous and we can be exposed to them exogenously (diet, cigarette smoke, pollution, ultraviolet radiation, other environmental elements) or through endogenous production (produced within the body, hyperglycemic conditions, normal aging and metabolism, inflammatory conditions, metabolic diseases). They are one of the major drivers of aging. More than 20 different AGEs have been identified in human blood and tissues and in foods. The most prominent ones include carboxymethyl-lysine, carboxyethyl-lysine, pyrraline (nonfluorescent AGEs), pentosidine, and methylglyoxal-lysine dimer. Below is a schematic depicting different types of AGEs Photo credit: Kuzan, A., 2021 How AGEs Are Formed Dietary AGEs are mainly formed by high heat cooking and food processing techniques (especially dry-heat) such as frying, baking, grilling, carmelizing, searing, and barbecuing. While cooking is known to increase AGE formation in foods, even uncooked foods can contain large quantities of AGEs. This is probably due pasteurization, curing, or aging (as in aged cheeses). For example, many animal-derived foods contain high levels of AGEs, such as higher fat aged cheese. The generation of AGEs via the Maillard reaction occurs in three phases. First, a sugar molecule non-enzymatically attaches to a free amino acid from a protein, lipid, or nucleic acid forming a Schiff base. During the second phase, the Schiff base undergoes a conformational change and forms early glycation products, known as Amadori products. The reaction is still reversible at this point. Further crosslinking and chemical rearrangement occurs with these molecules, ultimately becoming AGEs. Higher pH conditions can also increase the formation of AGEs, because the alkalinity promotes amino groups being in the basic deprotonated form, which increases reactivity. The polyol pathway is another well studied mechanism by which AGEs form. This is when glucose is converted to sorbitol via aldose reductase and then to fructose via another enzymatic reaction. Fructose metabolites transform into aldehydes and interact with monoacids to become AGEs. Finally, the oxidation of glucose or peroxidation of lipids are other pathways by which AGEs form. Given the different ways AGEs can form, this may partly explain their heterogeneity. Below is a simplified schematic illustrating how AGEs are formed. Photo credit: Uribari et al., 2015 The Deleterious Effects of AGEs AGEs induce pathology by two main mechanisms: 1) They directly crosslink with proteins, impairing their structure and function. 2) They activate intracellular signaling pathways through both receptor-mediated and non-receptor mediated mechanisms, leading to an increase in pro-inflammatory cytokines and oxidative stress. One such example is RAGE, which is one of the best studied receptors for AGEs. AGEs play a role in the pathophysiology of many different diseases, including type 2 diabetes mellitus (T2DM, Alzheimer’s disease (AD), kidney failure, atherosclerosis, etc. The microvascular and macrovascular damage seen in diseases such as diabetes is attributed to the accumulation of AGEs in tissues. AGEs cause stiffening and loss of elasticity of the arteries as well. How AGEs are Destructive to Collagen ECM proteins have been regarded as one of the major target structures for glycation. AGEs easily accumulate in the extracellular matrix of the dermis, which is where longevity proteins such as collagen, fibronectin, and elastin are. AGEs crosslink to these proteins and cause damage to their structure and biological properties. Collagen is particularly susceptible to destruction by AGEs due to the irreversibility of non-enzymatic cross-linking and the low turnover rate of collagen. Also, the levels of AGEs in collagen increase linearly with age.
Part 1 How Ultraviolet Radiation Damages the Skin and Causes Photoaging
(This is part 1 of a 3 part series of an article I wrote back in 2021 or 2022 for a supplement company I was helping to come up with the formulation of their product, which is why it’s tailored to those specific ingredients and the date of the references). The skin is the largest organ that serves as our primary protective barrier which interfaces with the external environment. It is constitutively exposed to various stimuli impacting its morphology and function, especially ultraviolet radiation (UVR). It has been reported that about 80% of skin aging can be attributed to UVR. Therefore, one of the best defenses against skin aging is diligent photoprotection. Anatomy Of The Skin The skin can be stratified into three major structural layers: the epidermis, the dermis and the hypodermis. Each of the cells within the skin have different proliferative capacities. The epidermis is the outermost layer of the skin comprised of 5 layers: Cells that the comprise the epidermis are: The dermis consists of two layers of connective tissue: the papillary and reticular layers, which merge together. The papillary layer is the upper part of the dermis composed of connective tissue. The reticular layer is the deeper portion that is less cellular and consists of dense connective tissue such as collagen. The hypodermis, also referred to as the subcutaneous fascia, is the deepest layer of skin and contains adipose lobules along with hair follicles, sensory neurons, and blood vessels. Photo credit: Yang et al., 2021 One of the most conspicuous ways that aging manifests itself is through the appearance of our skin. Skin aging is characterized by a cumulative loss of functionality and regenerative potential. It is a multi-factorial process that affects nearly every aspect of its biology and function. The skin is the most visible organ, where all changes, including aging, are very noticeable. The aging process of skin can be described as intrinsic (chronological) and extrinsic (elements in the environment). Unlike other organs of the human body, skin is not only impacted by intrinsic aging factors, but is also affected by extrinsic environmental factors. UVR imposes one of the most significant causes of extrinsic aging. This is known as photoaging, which is characterized by morphological changes including loss of elasticity, wrinkles, volume loss and redistribution of facial fat, and changes to the underlying structures of the skin. Photoaging is also characterized by histological changes such as dryness and alterations to the extracellular matrix, including disrupted collagen in the dermis. Furthermore, Skin aging is associated with a compromised protective role; namely impaired wound healing and barrier function, increased inflammation, disrupted water and thermal homeostasis, and increased susceptibility to various skin disorders. The Different Types of Ultraviolet Radiation UVR can be broken down into various subtypes, each having a different deleterious impact on the skin. UVC is absorbed in the stratosphere, and therefore, only UVA and UVB reach the surface of the earth (∼95% UVA, ∼5% UVB). Owing to its shorter wavelength, UVB rays are mostly absorbed by the stratum corneum in the epidermis (outermost layer of the skin) and are responsible for sunburns. UVB radiation is primarily a DNA-damaging agent because it is directly absorbed by DNA and causes the formation of cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine pyrimidone dimers (6-4PP). Conversely, UVA rays. which are the most predominant, can penetrate into the deeper dermal layers of the skin and cause profound damage to DNA and other biomolecules. UVA has the strongest ability to generate reactive oxygen species (ROS) and lipid peroxidases, therefore causing destruction to collagen and elastin in the dermis. The major visible damaging effects of UVA radiation are cumulative and appear after years of exposure. UVA is principally responsible for photoaging. Some evidence suggests that visible light and shorter waves of infrared (IR) light may also play a role in photoaging. Several studies have shown that Exposure to IR resulted in the typical clinical signs of photoaging. How Ultraviolet Radiation Causes Damage To Skin UVR exposure can induce tremendous insult to the skin in many ways. Changes to Facial Fat The morphology, distribution, and volume of subcutaneous facial fat is one of the hallmarks of a youthful phenotype. The structure and volume of the facial subcutaneous white adipose tissue undergo significant changes during aging, and this is accelerated by UVR. The changes in facial fat are depot specific and connected to a perturbed collagen network. One of the mechanisms by which UVR does this may be by decreasing expression of the adipokines leptin and adiponectin in the subcutaneous fat. A study by Ju Kim et al showed that UVR-induced silencing of adiponectin and leptin led to an upregulation of MMP-1 and decrease in type 1 procollagen expression. Treatment with adiponectin and leptin reversed these effects. UVR can also affect facial fat through inflammation. Photoinduced aging of facial fat also manifests as reduction of thickness, change of the intercellular matrix, quantitative and qualitative differences in preadipocytes. Induction of Reactive Oxygen Species UV-mediated ROS production is upstream of many of the mechanisms that lead to photoaging. UVR causes generation of reactive oxygen species (ROS) and DNA damage, resulting in cellular senescence, mitochondrial dysfunction, and a cascade of damage in the skin cells. Excess ROS drives global aging of the skin. It destroys cellular macromolecules such as proteins, lipids, as well as both nuclear and mitochondrial DNA. Excess ROS production by UVR can inundate the endogenous antioxidant capacity of the skin. This warrants the judicious use of exogenous antioxidants and other compounds as photoprotectants to mitigate UV-mediated ROS production. UVA is known to be the oxidizing component of the sun, and its destruction to biomolecules occurs indirectly through the generation of ROS via its interaction with a variety of chromophores. It has been demonstrated that the proteome is one of the major targets of damage by UVA-induced ROS. Upregulation of Matrix Metalloproteinases UVR increases the expression of matrix metalloproteinases (MMPs) in human skin. MMPs are enzymes that are responsible for degrading the extracellular matrix (ECM) proteins such as collagen, fibronectin, elastin, and proteoglycans. Dermal fibroblasts are the most abundant cell
Insulin Resistance and Metabolic Dysfunction – The Ubiquitous Driver of Disease?
(I wrote this article in 2021, so the scientific references reflect that) The emerging interest in low carbohydrate, ketogenic diets has created infamy for the hormone insulin, painting it as a villain. Herein will hopefully elucidate some of the misconceptions around insulin, and discuss the insidious biological phenomenon that appears to underlie a whole host of diseases. WHAT IS INSULIN? Insulin is a potent anabolic hormone that confers a variety of functions, most famously glucose homeostasis (lowering of blood glucose). It is secreted by the beta cells of the pancreas upon detection of insulinogenic substrates (i.e., elevated blood glucose) and subsequently binds to its receptor (IRS-1 or IRS-2) on the surface of the cell membrane of target tissues. The binding of insulin to its receptor triggers autophosphorylation and a signal transduction cascade. In the muscle and adipocyte (fat cell), glucose transporter-4 (GLUT 4) translocates to the cell membrane to foster uptake of glucose into the cell. Virtually every cell in the body has been shown to have insulin receptors. Proper functioning of insulin is essential for any cell to maintain homeostasis, and thus survival of the organism. Insulin tends to gets a bad rap in the low carbohydrate high fat (LCHF) community because it inhibits lipolysis and promotes fat storage, among many other downstream metabolic effects that are disadvantageous when chronically occurring. Metabolic dysfunction reportedly plagues at least one third of the United States population, [1] and is intricately linked to cross-communication with various organ systems. Insulin resistance is a fundamental component of metabolic dysfunction and a key player in the pathogenesis of a myriad of seemingly unrelated diseases. Typically, one might associate insulin resistance with Type 2 Diabetes Mellitus (T2DM), but its pathophysiological effects are far more systemic and vast. It is even linked to cardiovascular disease (CVD), dementia, erectile dysfunction, and polycystic ovarian syndrome (PCOS). Insulin resistance can be defined as the cell becoming resistant to insulin’s signal concomitant with hyperinsulinemia. The insulin becomes chronically elevated to compensate for the cell’s muffled ability to respond to insulin, in order to maintain blood glucose homeostasis. Eventually, the beta cell can experience “burn out” from being overtaxed, and this manifests itself through prediabetes and eventually T2DM. THE DOMINO EFFECT OF INSULIN RESISTANCE What happens when insulin signaling becomes aberrant? Since insulin is a master regulator of so many difference biological processes, its failure to function properly has extensive consequences. Insulin resistance usually follows an order of operations whereby the adipocyte becomes resistant first, logically, as a survival mechanism to avoid necrosis. Adipose tissue is a highly malleable organ with immune-like characteristics that houses a substantial milieu of cells that collectively play an integral role in metabolic regulation. It is exquisitely sensitive to environmental cues and alters its composition in response to homeostatic changes (i.e., energy flux) or disease.[2] When adipocytes in white adipose tissue (WAT) hypertrophy beyond a threshold whereby they can sustain themselves, they prevent insulin from partitioning more energy into the fat cell so it doesn’t grow even bigger in size and explode; so, the adipocyte is leaking fat inappropriately (because lipolysis is not being switched off) and secreting pro-inflammatory adipokines into the circulation. The profile of the adipocyte becomes altered. Also, the fat cell is more prone to hypoxia as it deviates from proximity to the capillaries where it gets perfused with nutrients and gas exchange. In the process of becoming hypoxic, it becomes infiltrated with and releases pro-inflammatory cytokines, some of which stimulate angiogenesis because it’s trying to increase blood flow. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a) inhibit lipoprotein lipase (LPL), which is an enzyme that is responsible for the degradation of triglycerides from circulating VLDL and chylomicrons. Fatty acids liberated from the triglycerides are then stored in adipose tissue or utilized by other target tissues (cardiac or skeletal muscle) for fuel, and the chylomicron vestiges are endocytosed at the liver. When this mechanism is disturbed, the ability to clear triglycerides from the blood is impaired. Furthermore, these inflammatory molecules directly antagonize the insulin signaling cascade and cause destruction to tissues throughout the body. For instance, TNF-α and IL-6 inhibit the transcription of IRS-1 (insulin receptor substrate-1), GLUT-4, and PPAR- . Cross-talk between the adipose tissue and macrophages instigates a vicious inflammatory cycle. Necrotic cells from the adipose tissue recruit macrophages to clear the debris. The macrophages engulf the dead cells resulting in lipid-laden macrophages designated as “foam cells” due to their foamy-appearing cytosol. This process further recruits more inflammatory molecules and coagulation factors perpetuating a signaling cascade that contributes to the pathogenesis of atherosclerosis (through vascular insult, atheromatous change, etc.). [3][4][5] When the fat cell becomes resistant to insulin, it spreads its sickness to the other organs, depositing ectopic fat in places where you don’t want it — such as the liver, heart, and muscle. The increased fatty acid flux to the liver increases triglyceride-rich VLDL production and, consequently, blood triglycerides. A high triglyceride-to-HDL ratio is indicative that someone is insulin resistant. Contrary to the muscle and fat cell, the liver does not need insulin to pull glucose into the hepatocytes (liver cells), but glucose output is unable to be shut off when needed (insulin inhibits gluconeogenesis). Consequently, there is elevated glucose concurrent with elevated fatty acids in the blood. So, glucose and fatty acid metabolism become disrupted, and uptake by the insulin-dependent fat and muscle cells are impaired. The muscle serves as the biggest reservoir to lower blood glucose. The glucose transporter (GLUT-4) for the muscle has an insulin-dependent mechanism to uptake glucose into the myocyte (muscle cell); so, when the muscle becomes insulin resistant, the predominant blood glucose buffer is no longer available, except during exercise when the muscle is able to consume glucose without the presence of insulin. Chronic hyperglycemia occurs resulting in cross-linking of proteins, advanced glycation end products (aptly known as AGEs[6]), oxidative stress, inflammation, and cell damage. This also triggers endothelial dysfunction, which initiates the sequence of events leading up to cardiovascular disease. Aberrant lipid metabolism results in dyslipidemia: hypertriglyceridemia, lower
The Role of Phytochemicals in Health
I wrote this article back in 2021 which is why my references are dated the way they are. Beyond vitamins, minerals, and fiber there are bioactive compounds in foods called phytochemicals (or phytonutrients) that confer nutrigenomic (gene-nutrient interactions) effects and play an important role in human health. Tens of thousands of phytochemicals have been identified, and there are likely many more that have yet to be illuminated. They are classified according to their chemical structures and functional properties, which influence their metabolic fate. Some major classes of phytochemicals are polyphenols, phytosterols, terpenoids, alkaloids, glucosinolates, saponins, and many more. Each of these classes have potent biological activities and can modulate various molecular targets. Plants produce these bitter-tasting compounds as a protective mechanism to dissuade predators, pathogens and other environmental stressors. As such, they exhibit low levels of stressors that, when consumed by humans, can stimulate a hormetic response and bolster cellular resistance much in the same way that exercise and fasting does. Photo credit: Bellik et al., 2012. The Unique Metabolism of Phytonutrients Within the parent compounds are a number of subclasses and the multiplicity of metabolites they produce. Their metabolism is intrinsically linked to their mechanisms of action, which is characteristic of that of xenobiotics–they are essentially treated by the body as drugs. The bioavailability of the most abundant phytochemicals is low and their half-life has been shown to be transient at about 90 minutes. Bioavailability means the rate and extent to which something is able to exert its beneficial effects in target tissues. So then how are they conferring all of these chronic health benefits that we see in long-term, large prospective cohort studies and randomized control trials (RCTs)? Some phytonutrients may get taken up in the small intestine and subsequently undergo first pass metabolism in the liver. The phytonutrients that are not absorbed in the small intestine pass through the colon and undergo degradation by colonic bacteria into microbial metabolites which are then released back into the circulation and absorbed in quantities far greater than the parent compound itself. A multitude of metabolites are generated and exert numerous biological effects.These metabolites can continue to be recycled extensively – even up to 20 times, and they are up to 100-fold greater in concentration in the circulation than the parent compounds themselves, having significantly higher bioavailability (Luca et al., 2019; Rathaur & S R, 2019; Selby-Fam, et al., 2017). Mechanisms of Action of Phytonutrients Phytonutrients have pleiotropic effects on cellular physiology that extend far beyond direct antioxidant activity. They address numerous mechanisms simultaneously, ultimately resulting in a multitude of downstream health benefits. Let’s take flavonoids, for example, which are one of the most studied and varied subclass of polyphenols. Flavonoids are categorized in different subtypes including flavones, isoflavonoids, flavanones, flavanols, catechins or flavonols, anthocyanins and chalcones. Within each of those categories are numerous other subtypes (i.e., quercetin and kaempferol are types of catechins), each of which produce an array of metabolites. One of the mechanisms by which flavonoids exert their beneficial health effects are through nitric oxide (NO) production and activity. Flavonoids inhibit inducible nitric oxide synthase (iNOS) and activate endothelial nitric oxide synthase (eNOS). Excess iNOS activity can have deleterious effects onvascular function including inhibition of mitochondrial respiration, hypotension, and necrosis (premature death of cells). Conversely, increased eNOS promotes increased vasodilation, angiogenesis, and beneficial endothelial and vascular effects. NO has anti-atherogenic, anti-thrombotic, anti-inflammatory, and anti-proliferative properties that play a pivotal role in vascular homeostasis and integrity. Decreased bioavailability and or production of NO is associated with endothelial dysfunction and a vascular phenotype that is more susceptible to atherogenesis. NO suppresses platelet aggregation, cellular migration and adhesion to the endothelium and smooth muscle cell proliferation. This mechanism overlaps with the Nitrosiginein BOOST which stimulates NO production. What’s good for the heart is good for the brain. There is overlap between the mechanisms by which polyphenols exhibit positive effects on the brain and the cardiovascular system. Quercetin and apigenin are among the most studied flavonoids which have been known to exhibit antibacterial and antiviral activities by antagonizing the replication and infectivity of certain RNA and DNA viruses. Furthermore, flavonoids help in the production of enzymes such as gluthione-S-transferase, quinone reductase and uridine 5-diphospho-glucuronyl transferase by which carcinogens are detoxified and excreted from the body. Flavonoids have been shown to modify lipid and glucose metabolism in both the fasted state and post-prandial.Theirability to act on dysfunctional processes related to glucose and lipid metabolism impact a number of biological systems. The mechanisms are not fully elucidated, but they may inhibit fat absorption at the level of the gut or possibly influencecholesterol and triacylglycerol transport in lipoproteins. Similar to the ageless defense formula, phytochemicals can prevent the formation of advance glycation end products (AGEs)and other complications (i.e., diabetic) associated with high oxidative stress conditions (Bacanli et al., 2019). Factors That Influence the Bioavailability of Phytonutrients There is so much nuance and so many factors that influence the bioavailability of phytonutrients and subsequent biological effects they exert on the individual—both external and internal. This is very important to consider, because it’s not what we consume, but what we absorb and how it gets utilized by our bodies that matters. Let’s discuss what some of those factors are. Food processing related factors: Storage, cooking and culinary preparation methods, thermal treatments, homogenization, liophylization (freeze drying) (D’Archivio et al., 2010). For example, thermal treatment has been shown to significantly reduce total phenolic content in extra virgin olive oil, beans and legumes (D’Archivio et al., 2010). For red wine that was produced with Cabernet Sauvignon grapes in Napa Valley (California, USA) the 1989 vintage contained 0.09 mg/L resveratrol whereas the 1994 vintage contained as much as 8.9 mg/L (D’Archivio et al., 2010). Environmental factors: Sun exposure, the soil the food was grown in, degree of ripeness, and rainfall. Food matrix–the configuration of and presence of other constituents in the food, or combinations with other compounds:Bioactive compound mixtures may produce a biological effect higher or lower than the summative effects of
Metabolic Flexibility – a Cornerstone For Healthspan and Longevity
I wrote this article back in 2021 which is why the references are dated as they are. 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