Western medicine’s reliance on drugs and intervention procedures to treat symptoms of disease. This dependence stems from an antiquated way of thinking about and applying medical advances, one that overlooks an enormous opportunity to avoid disease, preserve health, and extend a high quality of life. Indeed, most scientists and medical doctors still think of aging as a disease instead of what it is: a gradual slowing down of cellular processes. If we shift our thinking about aging to this more accurate way and seize the opportunity to re-energize our cellular systems by giving the cells what they need to stay efficient, then the so-called negative effects of aging—the digestive problems, the sleep problems, the loss of energy, the dwindling of mental focus, the memory loss, the loss of muscle and bone strength—are no longer inevitable. My approach to healthspan (i.e., healthy longevity) is about aging better. I don’t want to help my patients extend their lives for the sake of it; rather, I want to focus on how they can remain vital and productive and able to enjoy all of what they want to do in their so-called “second half.” This is a paradigm shift based on real science and one that will reshape your patient outcomes now and into the future.
Cellular Redox: A Key Contributor to Cell Efficiency
As practitioners committed to preventing and halting disease, producing better treatment outcomes when our patients do get sick, and redefining the expectations of so-called normal aging, it’s important for us to incorporate recent research that points to the importance of cellular redox and its impact on how the body continues to produce and utilize energy. This vast, interconnected metabolic system is made up of more than 8,700 reactions and 16,000 metabolites. As we age, the pathways and mechanisms of this system become more vulnerable to damage, which in turn leads to loss of function and/or illness or disease. But by using an array of supplemental interventions, we can support the body so that it resists damage and controls the excretion of toxins and the buildup of other harmful metabolites. Specifically, by supporting redox—the chemical reactions that occur within cells to maintain a balance between reducing and oxidizing agents—we have a targeted method of supporting overall homeostasis, cellular efficiency, microbiome integrity, and productive immunity.
Redox homeostasis is the most important way the body achieves this multifrontal offense to control inflammation, the single most powerful cause of all diseases and genetic mutations. Indeed, helping the body achieve redox balance can help us age better because it
- improves mitochondrial function,
- increases cell efficiency,
- tamps down inflammation,
- Mitigates and manages oxidative stress,
- helps transport nutrients to cells,
- supports microbiome integrity,
- restores immune adaptability, and
- protects nuclear and mitochondrial DNA from epigenetic damage.
As a quick reminder, in redox, molecules gain or lose electrons, leading to changes in their oxidation state. Oxidation is the process by which a molecule loses electrons, while reduction is the process by which a molecule gains electrons. Cellular oxidation is necessary for a number of processes, including cellular respiration, the process by which cells extract energy in the form of glucose from nutrients, as through both glycolysis and the citric acid cycle. Oxidation reactions also contribute to the breakdown of fatty acids and amino acids for energy production, two additional aspects of core cellular metabolism. These processes are crucial for providing cells with the necessary building blocks and energy to carry out various cellular and whole-organ functions.
Oxidation is also an integral part of supporting the immune system through detoxification of harmful substances within cells by converting such compounds into water-soluble forms that can be excreted by the body. Further, immune cells, such as macrophages and neutrophils, use reactive oxygen species (ROS)—the by-product of oxidation—as part of their defense mechanisms to destroy invading pathogens and protect against the development of disease. However, ROS are necessary in only moderate amounts, as they act as signaling molecules that modulate the activity of specific proteins important to cell metabolism, regulation, and immune functions such as apoptosis.
Although cellular oxidation is necessary for these important physiological processes, the human body relies on the antioxidant system to control too-high production of ROS and avoid oxidative stress that can trigger a cascade of damaging cellular conditions that upset its ability to stay in homeostasis. This is where reduction processes come into play. Antioxidants are types of reducing agents that counteract oxidative stress and prevent the slippery slope related to loss of cell efficiency, lack of nutrition to cells, and poor cell signaling. (For the purposes of this book, I will be treating antioxidants as a general type of reducing agent.) They are on the front lines, protecting cells from damage caused by ROS and free radicals by donating electrons to neutralize ROS, thereby preventing the chain reactions that lead to cellular damage. Antioxidants also help preserve the structural and functional integrity of cellular components including proteins, lipids, and DNA. Further, since mitochondria, the primary site of cellular respiration, generate ROS as by-products, antioxidants mitigate the impact of ROS on mitochondrial function, ensuring efficient energy production and preventing damage to mitochondrial DNA. Some reducing agents, such as glutathione (GSH), serve as important regulators of cellular signaling pathways. Redox-sensitive signaling molecules and transcription factors are modulated by changes in the cellular redox state, influencing processes such as cell growth, differentiation, and apoptosis. In addition, antioxidants help maintain enzymatic activities important to cellular function. Many enzymes are sensitive to changes in redox status, and their activity is regulated by the availability of reducing agents. For example, enzymes such as superoxide dismutase (SOD) and catalase rely on antioxidants to function. Reducing agents help protect DNA from oxidative damage, which can lead to DNA strand breaks, mutations, and other forms of damage.
In this way, reducing agents are vital for maintaining redox balance within cells, protecting them from oxidative damage. An imbalance in redox status, with too many oxidizing agents and too few reducing agents, can not only undermine cell metabolism but also feed out-of-control inflammatory responses, leading to metabolic problems, disruption of microbiome integrity, mitochondrial damage, increased cellular senescence, and an overall decrease in functioning of the immune system—all of which can cause various diseases including cancer, neurodegenerative disorders, and cardiovascular disease. It’s crucial that we maintain a balance between oxidizing and reducing agents while supporting the antioxidant system and maintaining cell efficiency so that ROS do not propagate. Balance is crucial.
Antioxidants Necessary for Redox Balance
Reducing agents are substances that donate electrons or hydrogen atoms, facilitating reduction reactions in cells. At a cellular level, these agents play a crucial role in maintaining redox balance and supporting cellular efficiency. Here is a list of some common reducing agents in cells:
- Nicotinamide adenine dinucleotide (NADH): NADH is a key reducing agent involved in energy metabolism, particularly in glycolysis and the tricarboxylic acid (TCA) cycle. It donates electrons to the electron transport chain (ETC) in mitochondria during oxidative phosphorylation.
- Nicotinamide adenine dinucleotide phosphate (NADPH): NADPH is essential for anabolic processes such as fatty acid and cholesterol synthesis, as well as for antioxidant defense. It is generated primarily through the pentose phosphate pathway.
- Glutathione (GSH): Glutathione is a tripeptide composed of glutamate, cysteine, and glycine that acts as a major cellular antioxidant. It can donate electrons to neutralize reactive oxygen species (ROS) and protect cells from oxidative damage.
- Ascorbic acid (vitamin C): Ascorbic acid is a water-soluble antioxidant that can donate electrons, helping to scavenge free radicals. It also plays a role in regenerating other antioxidants, such as vitamin E.
- Tetrahydrobiopterin (BH4): BH4 is a cofactor involved in the synthesis of neurotransmitters and the regulation of nitric oxide synthesis. It acts as a reducing agent in various enzymatic reactions.
- Ubiquinol (coenzyme Q10): Ubiquinol is an electron carrier in the mitochondrial ETC. It accepts electrons from complex I and complex II and transfers them to complex III, contributing to adenosine triphosphate (ATP) production.
- Ferredoxin: Ferredoxins are iron-sulfur proteins that act as electron carriers in various cellular processes, including photosynthesis and certain redox reactions in the mitochondria.
- Dihydrolipoic acid (DHLA): DHLA is the reduced form of lipoic acid, and it acts as a cofactor for various enzymes involved in energy metabolism. It can also regenerate other antioxidants, such as vitamin C and vitamin E.
- N-acetylcysteine (NAC): NAC is a precursor to glutathione and can function as a reducing agent. It is sometimes used as a supplement to support cellular antioxidant defenses.
- Flavins (e.g., flavin mononucleotide [FMN] and flavin adenine dinucleotide [FAD]): Flavins are cofactors involved in various redox reactions, particularly in the ETC and in various enzymatic processes.
These reducing agents (aka antioxidants) work in concert with other cellular processes to maintain the redox balance in cells, ensuring the proper functioning of cellular processes and protecting cells from oxidative stress.
Enzymatic and Nonenzymatic Antioxidant Systems
Enzymatic and nonenzymatic antioxidant systems are components of the body’s defense mechanisms that protect against oxidative stress, which is caused by an imbalance between the production of reactive oxygen species (ROS) and the ability of the body to neutralize ROS. Both systems play crucial roles in maintaining cellular health and preventing damage caused by oxidative stress.
Enzymatic Antioxidant Systems:
Enzymatic antioxidants are proteins that catalyze the breakdown or removal of ROS. Following are some key enzymes in this system:
- Superoxide dismutase (SOD): Converts superoxide radicals into hydrogen peroxide and oxygen
- Catalase: Breaks down hydrogen peroxide into water and oxygen
- Glutathione peroxidase: Uses glutathione to reduce hydrogen peroxide and lipid peroxides
These are some of the important enzymes that work together to neutralize different types of ROS and maintain a balanced oxidative environment within cells.
Nonenzymatic Antioxidant Systems:
Nonenzymatic antioxidants are molecules that directly neutralize free radicals or enhance the activity of enzymatic antioxidants. Following are some important nonenzymatic antioxidants:
- Vitamins (e.g., vitamin C and vitamin E): Act as scavengers of free radicals and help regenerate other antioxidants
- Glutathione: A tripeptide that plays a central role in neutralizing ROS
- Melatonin: Exhibits antioxidant properties and helps protect against oxidative stress
- Coenzyme Q10 (CoQ10): Participates in electron transport and acts as a lipid-soluble antioxidant
- Polyphenols (e.g., flavonoids and resveratrol): Found in plant-based foods and have antioxidant properties
- Minerals: Examples include iron, zinc, copper, manganese, and selenium
Nonenzymatic antioxidants are essential for preventing oxidative damage in cellular structures, including lipids, proteins, and DNA. They complement the enzymatic antioxidant defenses to provide a comprehensive antioxidant network.
Both enzymatic and nonenzymatic antioxidant systems are crucial for maintaining cellular homeostasis and protecting the body from the harmful effects of oxidative stress, which is associated with various health conditions including aging, inflammation, and chronic diseases. A balanced intake of antioxidants through a diverse and nutritious diet is essential for supporting these defense mechanisms.
How Exercise Improves Redox Balance
A helpful way to understand redox in action is to consider the role it plays in physical exercise. During aerobic exercise, oxygen is used to break down glucose and fatty acids, releasing energy in the form of adenosine triphosphate (ATP). This process produces nicotinamide adenine dinucleotide (NADH), which is a reduced form of NAD+. During resistance exercise, ATP is used to contract muscles, a process that produces NAD+, which is an oxidized form of NADH. The overall effect of exercise increases the ratio of NAD+ to NADH, which not only helps to increase energy production but also improves redox balance.
The specific changes in NAD+ and NADH that occur during aerobic exercise are as follows: NAD+ is reduced to NADH, which is then used to produce energy. During resistance exercise, NAD+ is oxidized to produce energy. However, this association between resistance exercise and the production of ATP is both an oversimplification and a common and misleading interpretation of what’s really going on. Resistance exercise, such as weight lifting, leads to muscle contraction. The energy for this contraction is powered by ATP. As we exert our muscles, they require more energy, which leads to an increased demand for ATP. This ATP is primarily produced in mitochondria through a process called oxidative phosphorylation, but also via anaerobic glycolysis, especially during high-intensity workouts.
While ATP breakdown and NAD+ production both occur during resistance exercise, they are not directly linked. During resistance exercise, or any other physical activity, the demand for energy increases in the body, particularly in muscle cells. ATP is the main source of energy for most cellular processes, and it’s broken down into adenosine diphosphate (ADP) and inorganic phosphate to release energy that can be used by the cells. This breakdown of ATP doesn’t directly lead to the production of NAD+.
NAD+, on the other hand, is a coenzyme that’s vital for redox reactions in the cell. It exists in two forms: an oxidized form (NAD+) and a reduced form (NADH). During cellular respiration (glycolysis, citric acid cycle, and oxidative phosphorylation), NAD+ accepts electrons (along with a proton), becoming NADH.
Resistance exercise can lead to an increase in the ratio of NAD+ to NADH, but not directly due to the breakdown of ATP. Instead, it’s due to processes such as oxidative phosphorylation, where NADH donates its electrons to the electron transport chain (ETC) and is thereby converted back to NAD+, and the lactate production pathway under anaerobic conditions. During oxidative phosphorylation, the electrons are transferred from NADH and FADH2 (another coenzyme) to oxygen via a series of protein complexes in the inner mitochondrial membrane (the ETC). The energy from these electron transfers is used to pump protons across the inner mitochondrial membrane, creating a proton gradient. The flow of these protons back across the membrane drives ATP synthesis. In the process, NADH is oxidized back to NAD+. In anaerobic glycolysis, glucose is converted to pyruvate, generating ATP and NADH in the process. However, under anaerobic conditions, the pyruvate is then converted to lactate, and in this step, the NADH is used to reduce pyruvate, regenerating NAD+.
So, in both energy-generating pathways, NADH is used and converted back to NAD+. This leads to a decrease in the NADH concentration and an increase in the NAD+ concentration, thereby increasing the ratio of NAD+ to NADH.
Moreover, resistance exercise stimulates the production of certain proteins and signaling molecules, such as AMP-activated protein kinase (AMPK) and sirtuins. These molecules can upregulate the expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage pathway of NAD+ synthesis, leading to an increased total pool of NAD+ and thereby contributing to an increased ratio of NAD+ to NADH.
However, it’s important to note that the actual effect on the ratio of NAD+ to NADH can depend on several factors, including the intensity and duration of the exercise and the individual’s fitness level and diet. It’s also worth mentioning that the redox state of a cell (including the ratio of NAD+ to NADH) is tightly regulated, as it’s critical for maintaining normal cellular function.
So, while both ATP breakdown and NAD+ production occur during resistance exercise, they are parts of different but interconnected metabolic processes. The interplay of various molecular pathways, including the ratio of NAD+ to NADH, SIRT1 activation, AMPK signaling, and the activation of antioxidant response elements (AREs), plays a role in the regulation of antioxidant gene expression.
An increased ratio of NAD+ to NADH favors the activation of enzymes that are dependent on NAD+, such as SIRT1 (a deacetylase enzyme that is a member of the sirtuin family). An enhanced ratio of NAD+ to NADH activates SIRT1, which has various functions, including the deacetylation of transcriptional coactivator PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator 1-alpha). Once deacetylated by SIRT1, PGC-1alpha becomes available for further regulation. AMPK, an energy-sensing enzyme, can phosphorylate PGC-1alpha. Phosphorylated PGC-1alpha and NRF-2, a transcription factor, bind to AREs located in the promoter regions of antioxidant genes. This binding activates the transcription of various antioxidant genes, including those encoding enzymes such as glutathione peroxidase, superoxide dismutase (SOD), catalase, heme oxygenase-1 (HO-1), and others. These antioxidants help neutralize reactive oxygen species (ROS) and reduce oxidative stress.
In this way, these pathways represent a coordinated regulation of multiple factors involved in antioxidant defense. This regulation demonstrates how an improved ratio of NAD+ to NADH, SIRT1 activation, AMPK signaling, and the activation of AREs can collectively promote the expression of antioxidant genes, leading to increased antioxidant production and protection against oxidative stress. It’s important to note that the specific details of these molecular interactions and their regulation may vary depending on cell type, context, and physiological conditions. This is the beginning of gaining a better understanding of the mechanisms involved in antioxidant gene transcription, the complicated but important way of understanding the effects of different types of exercise, and its importance in maintaining cellular redox.
**Adapted from The Redox Promise (2024) by William A. Seeds MD