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What Are Sirtuins and How Do They Affect Aging and Longevity?
Reproduced from original article:
https://articles.mercola.com/sites/articles/archive/2026/09/13/sirtuins-aging-longevity.aspx
Analysis by Dr. Joseph Mercola September 13, 2026
Story at-a-glance
- Sirtuins are proteins your body naturally produces that depend on NAD+ to regulate cellular energy production, DNA repair, metabolism, and healthy aging, making them central to how well your cells recover from everyday stress
- Your body contains seven different sirtuins, each with a specialized role in different parts of your cells, so healthy aging depends on multiple repair and energy systems working together instead of one “longevity gene”
- Mitochondrial sirtuins help keep your cellular power plants running efficiently by supporting ATP production, balancing metabolism, and helping your cells respond appropriately to normal oxidative stress
- Declining sirtuin activity and falling NAD+ levels are linked to reduced mitochondrial function, impaired DNA repair, and greater risk of age-related changes affecting your heart, brain, and muscles
- The most effective way to support healthy sirtuin activity is to strengthen your cellular energy system through consistent lifestyle habits, including adequate healthy carbohydrates, support for NAD+ recycling, regular movement, morning sunlight, and protection of mitochondrial health
Sirtuins (SIRTs) are a family of proteins that sit at the intersection of energy, repair, and aging — and understanding how they work may change the way you think about growing older. These enzymes rely on nicotinamide adenine dinucleotide (NAD+), and they spend a little of it every time they act, which is what links your body’s moment-to-moment energy status to DNA repair, mitochondrial function, inflammation, and metabolism.1
How well your sirtuins function helps determine how efficiently your cells adapt, recover, and maintain themselves over a lifetime, which is why researchers have placed them at the center of the science of healthy aging. Sirtuins are enzymes your body produces, not something you obtain directly from food. Different members of the sirtuin family work inside different parts of your cells, and each one performs a specialized job.
That division of labor matters enormously, because these proteins do not all behave the same way or produce the same effects. Together, they help coordinate how your body uses nutrients, responds to physical stress, and maintains healthy tissues over time. That distinction becomes much clearer once you look at how each member of the sirtuin family works inside the body and why researchers continue to study them so closely.
Different Sirtuins Perform Different Jobs
A News Medical article by science writer Chinta Sidharthan summarizes current research on all seven known human sirtuins and explains how each one performs a different job inside your cells rather than acting in the same way.2
It summarizes findings from multiple scientific studies to explain how these enzymes regulate metabolism, DNA repair, inflammation, mitochondrial function, and healthy aging. One of the most important messages is that researchers no longer see “activating sirtuins” as a simple solution because each sirtuin behaves differently depending on the tissue, organ, and biological process involved.
• Each member of the sirtuin family specializes in a different location inside your cells — Rather than working everywhere at once, SIRT1, SIRT6, and SIRT7 spend most of their time inside the cell nucleus, where they help regulate genes and preserve DNA stability. SIRT2 works mainly in the cell fluid but moves into the nucleus during certain stages of cell division.
Meanwhile, SIRT3, SIRT4, and SIRT5 operate inside mitochondria, where they oversee many of the chemical reactions that keep your cells supplied with energy.
This means healthy aging depends on many separate repair and energy systems working together instead of relying on one “longevity gene.” The review states that these enzymes respond to nutrient availability, environmental stress, metabolic regulation, and circadian rhythms, showing that your daily habits influence the very pathways scientists continue to investigate.
• Your body’s energy factories receive some of the greatest support from mitochondrial sirtuins — According to the review, SIRT3 serves as the major mitochondrial deacetylase, meaning it removes small chemical tags from proteins so those proteins work more efficiently.
This helps regulate enzymes involved in the electron transport chain and the tricarboxylic acid cycle, often called the TCA or Krebs cycle, the series of reactions that converts nutrients into adenosine triphosphate (ATP), the primary energy currency used by every cell.
The review also explains that SIRT5 regulates parts of the urea cycle, which helps remove excess nitrogen from your body, while also influencing glycolysis, the process that converts glucose into usable energy. SIRT4 works differently by slowing certain metabolic pathways, illustrating that healthy metabolism depends on balance rather than maximum activity.
• Healthy aging depends on constant maintenance instead of one-time repairs — The review highlights research showing that sirtuins preserve genomic integrity, meaning they help keep your DNA stable as cells divide throughout life. One example involves SIRT6, which helps repair dangerous double-strand DNA breaks and maintain telomeres, the protective caps at the ends of chromosomes that naturally shorten with age.
Animal research found that deficiency of SIRT6 produced features of premature aging, emphasizing how important continuous DNA maintenance becomes over a lifetime.3 The review also explains that SIRT1 and SIRT3 activate antioxidant defense pathways instead of simply eliminating every reactive oxygen species, or ROS.
These molecules often receive negative attention because excessive amounts damage cells, but moderate ROS also serve as important signals that tell your cells to strengthen their defenses. Researchers describe this as a hormetic response, meaning a small amount of biological stress helps build greater resilience over time.
• Researchers continue to uncover why declining mitochondrial function accelerates aging — The review explains what happens when SIRT3 slows down. Because its job is to strip those chemical tags off mitochondrial proteins, falling SIRT3 activity lets the tags accumulate, a state called hyperacetylation, and the tagged proteins gum up and lose efficiency.
As energy production falls, ROS rise, increasing the risk of cardiac fibrosis, neurodegeneration, and skeletal muscle loss during aging. Cardiac fibrosis refers to excessive scar tissue that stiffens the heart and reduces its ability to pump efficiently.
Neurodegeneration describes the gradual loss of nerve cells that contributes to disorders affecting memory and movement. These findings reinforce an important takeaway for your own health: protecting mitochondrial function supports far more than energy levels. It also helps preserve muscle, cardiovascular health, and healthy brain function as you grow older.
• Scientists remain optimistic, but they also urge caution about future therapies — One of the strongest themes throughout the review is that researchers have moved beyond the idea that simply increasing sirtuin activity solves every problem.
The article notes that compounds such as resveratrol, the molecule once made famous by red wine, have shown effects resembling calorie restriction, the long-studied practice of eating fewer calories without malnutrition that reliably extends lifespan in laboratory animals and remains the original discovery that launched sirtuin research.
In experimental models, resveratrol appeared to mimic some of those benefits, but its specificity and usefulness in people remain limited. Researchers are also studying NAD+ precursors because they help restore declining NAD+ levels, yet the evidence in humans remains disease-specific rather than universally consistent.
The review further explains that some sirtuins produce opposite effects depending on the tissue or disease stage, including certain cancers where SIRT1 acts either as a tumor suppressor or as a tumor promoter depending on the biological setting. That growing understanding encourages a practical mindset: supporting your overall cellular health through healthy lifestyle habits makes far more sense than expecting a single supplement or molecule to control the complex biology of aging.
Note: The research summarized here includes laboratory and animal studies as well as human research of varying scope. Findings from cell and animal models may not directly apply to human health.
Support Your Cellular Energy Every Day
Healthy sirtuin activity starts with healthy cellular energy. Sirtuins are one part of a much larger system rather than a single target to activate. Instead of chasing one supplement that promises longevity, build the daily habits that give your cells the fuel and raw materials they need to produce energy, repair damage, and adapt to stress. Those consistent habits also help maintain healthy NAD+ levels, the molecule sirtuins rely on to function.
1. Feed your cells enough quality carbohydrates — Most adults need about 250 grams of carbohydrates daily, adjusting upward if you’re very active. Focus on whole fruit, white rice, root vegetables, properly prepared starches, and other minimally processed carbohydrate sources that provide the glucose your cells need for efficient energy production. Your body relies on steady energy availability to support the same metabolic pathways that influence sirtuin activity.
You may have read that fasting or calorie restriction “activates” sirtuins, and in lab models it can. But chronic energy shortage is itself a stressor, and your cells need steady glucose to run the very repair and energy pathways sirtuins depend on. Keeping NAD+ recycling healthy matters more than starving your system.
2. Support your body’s natural NAD+ recycling system — Sirtuins depend on NAD+, but NAD+ levels naturally decline with age and fall more rapidly when your body spends large amounts repairing DNA or responding to chronic inflammation. One important reason is that your body’s NAD+ recycling process, called the salvage pathway, becomes less efficient over time. I recommend supporting that system with small, consistent amounts of niacinamide instead of large doses.
Niacinamide is a form of vitamin B3, not the same as flush-causing niacin. I recommend about 50 milligrams (mg) three times daily, which provides steady support for NAD+ production while avoiding the drawbacks associated with high-dose vitamin B3. Eating foods naturally rich in B vitamins, including grass fed beef, mushrooms, potatoes, bananas, and leafy green vegetables — if you tolerate them — also helps supply the nutrients your mitochondria need to produce energy efficiently.
3. Protect your mitochondria every day — Your mitochondria produce the ATP that powers nearly every process inside your body. Help them work efficiently by avoiding seed oils, choosing traditional fats such as grass fed butter, ghee, or tallow instead, getting regular movement, and eating enough protein.
Aim for about 0.6 to 0.8 grams per pound (or 1.32 to 1.76 grams per kilogram) of ideal body weight, with one-third coming from collagen-rich sources like slow-cooked meats or bone broth. Those building blocks support the repair and maintenance processes that healthy cells perform continuously.
4. Support your natural daily rhythm — Your cells follow an internal clock, and sirtuins are wired directly into it. SIRT1 helps run the molecular machinery that keeps your circadian rhythm on time, and that rhythm in turn governs the daily rise and fall of NAD+. Spend time outdoors in morning sunlight to set that clock, then reduce bright artificial light after sunset.
If you still consume significant amounts of seed oils and other sources of linoleic acid (LA), avoid intense midday sun exposure (10 a.m. to 4 p.m.) until you have reduced those foods for at least six months. This is because LA is a polyunsaturated fat that oxidizes easily, builds up in your skin, and increases your risk of skin damage. Healthy light exposure supports cellular energy production and helps reinforce many of the biological pathways that interact with metabolism and healthy aging.
Just as important, protect your sleep itself: aim for high-quality sleep on a consistent schedule. Deep sleep is when much of your cellular repair and mitochondrial housekeeping happens, and it’s when your NAD+ recycling system does its most important work.
5. Build resilience through consistent movement instead of longevity shortcuts — If you’re mostly sedentary, begin with daily walking and gradually add resistance training twice a week that matches your fitness level. Exercise encourages your cells to become stronger and more efficient over time. Rather than depending on one “anti-aging” product, make consistency your goal.
Every healthy meal, every walk, every workout, and every good night’s sleep helps create the environment your sirtuins, mitochondria, and NAD+ recycling system need to support healthy aging.
FAQs About Sirtuins, Aging, and Longevity
Q: What are sirtuins, and why are they important?
A: Sirtuins are a family of proteins your body naturally produces that help regulate how your cells create energy, repair DNA, respond to stress, and maintain healthy tissues. Because they rely on NAD+ to function, they connect your body’s energy status with many of the biological processes that influence healthy aging.
Q: Do all sirtuins perform the same job?
A: No. Humans have seven different sirtuins, and each one has specialized responsibilities. Some help maintain your DNA, while others work inside your mitochondria to support energy production or regulate metabolism. Scientists now recognize that healthy aging depends on all of these systems working together rather than on one “longevity protein.”
Q: Why does NAD+ matter for healthy aging?
A: NAD+ serves as the fuel that allows sirtuins to work. As you grow older, NAD+ levels naturally decline and are depleted more quickly when your body repairs DNA or responds to chronic inflammation. Supporting your body’s ability to recycle NAD+ helps maintain the cellular processes that promote healthy aging.
Q: What daily habits help support healthy sirtuin activity?
A: The most effective approach focuses on strengthening your cellular energy system. Eating enough minimally processed carbohydrates, protecting your mitochondria, maintaining regular physical activity, getting morning sunlight, and supporting healthy NAD+ production all create an environment where sirtuins function more efficiently.
Q: Are longevity supplements enough to activate sirtuins?
A: No. Current research shows that healthy aging is far more complex than taking a single supplement. While scientists continue to study NAD+ precursors and other compounds, the strongest foundation remains healthy lifestyle habits that support cellular energy production, mitochondrial function, and your body’s natural repair systems.
This article is for informational purposes only and does not constitute medical advice. Sirtuins, NAD+ precursors, and related supplements are not a treatment for any disease. Consult a qualified health care provider before making changes to your health regimen.
The Surprising Role of Cortisol in Alzheimer’s
Reproduced from original article:
https://articles.mercola.com/sites/articles/archive/2026/03/18/role-of-cortisol-in-alzheimers.aspx
Analysis by Dr. Joseph Mercola March 18, 2026
Story at-a-glance
- New research shows that people with Alzheimer’s have higher cortisol levels and a skewed cortisol-to-DHEA-S ratio, revealing that chronic stress drives early brain degeneration long before memory loss appears
- Cortisol, your body’s main stress hormone, damages neurons and disrupts energy metabolism when it stays elevated, while DHEA-S acts as a protective neurosteroid that helps your brain resist inflammation and oxidative stress
- Bioenergetic researcher Georgi Dinkov connected these findings to thyroid and metabolic health, showing that when your cells don’t produce enough energy, cortisol rises and accelerates cognitive decline
- Tracking your cortisol-to-DHEA-S ratio offers a powerful early warning sign for chronic stress and neurodegeneration, allowing you to take preventive action years before symptoms develop
- You can rebalance these hormones naturally by fueling your metabolism with adequate healthy carbohydrates, improving sleep and light exposure, reducing overtraining, practicing calming breathwork, and using natural progesterone to help quiet cortisol
Alzheimer’s disease doesn’t begin with memory loss — it begins years earlier with a slow, silent shift in your body’s stress chemistry. Long before neurons die, your brain’s hormonal balance starts to erode under constant pressure from everyday stress. The same hormones that once kept you alert and focused start working against you, wearing down your brain’s repair systems and disrupting the flow of energy your cells depend on.
Cortisol, the body’s main stress hormone, plays a central role in this process. When it stays high for too long, it drains your metabolic reserves and interferes with memory formation. Meanwhile, a second hormone called DHEA-S acts as cortisol’s natural counterbalance, helping protect neurons and stabilize brain function.
When the ratio between these two hormones tilts toward cortisol, your brain loses its resilience and becomes more vulnerable to aging and degeneration. This hormonal tug-of-war — shaped by stress, diet, and metabolism — has drawn new attention from researchers exploring why some people develop Alzheimer’s while others do not. The latest findings suggest that long-term hormonal imbalance, not just genetics or plaque buildup, could be one of the earliest warning signs of decline.
Understanding this relationship changes how you think about prevention. By strengthening your metabolism, restoring hormonal balance, and reducing chronic stress, you can support your brain’s ability to heal and adapt — long before symptoms appear. The new research provides a roadmap for how to start.
Stress Hormones Tip the Balance Toward Alzheimer’s
A clinical study published in Cureus examined 85 adults in Serbia — 45 with diagnosed Alzheimer’s disease and 40 healthy peers of similar age and sex — to determine how two hormones, cortisol and DHEA-S, relate to brain health.1 Cortisol is your body’s main stress hormone, while DHEA-S (dehydroepiandrosterone sulfate) acts as its built-in counterbalance — a neurosteroid that supports brain resilience and energy metabolism.
Unlike DHEA, which is the fast-acting, active form, DHEA-S is its sulfated storage form that circulates in your blood far longer and provides a more stable picture of long-term stress balance. By focusing on DHEA-S, the researchers could better gauge chronic stress effects on the brain rather than short-term fluctuations. The scientists wanted to know whether Alzheimer’s patients showed measurable differences in these hormones or in their ratio, which indicates how well your body manages prolonged stress.
• People with Alzheimer’s had higher cortisol levels but not lower DHEA-S — Those with Alzheimer’s showed cortisol levels averaging nearly 399 nanomoles per liter (nmol/L) — about 20% higher than healthy adults — yet their DHEA-S concentrations stayed roughly the same.
This imbalance means the stress response remains chronically activated without the brain’s natural protection. When cortisol dominates, neurons experience more inflammation and less regeneration. The study also noted that this skewed balance was strongest among participants aged 65 to 75, suggesting that middle-to-late adulthood is when stress hormones begin exerting their most damaging effects.
• The cortisol-to-DHEA-S ratio proved to be the real warning sign — Although each hormone alone tells part of the story, the researchers emphasized that their ratio — how much cortisol outweighs DHEA-S — offers a clearer window into chronic stress and brain decline.
In Alzheimer’s patients, that ratio climbed steeply, implying that the body’s defense system against cortisol’s toxicity was failing. This finding helps explain why some people with normal cortisol readings still experience cognitive decline: it’s the imbalance, not just the level, that matters.
• Men and women responded differently, revealing hormonal sensitivity — In healthy adults, men had significantly higher DHEA-S levels than women, meaning their brains could have greater protection from chronic stress. But that sex difference disappeared in those with Alzheimer’s.
The disease seemed to override normal hormonal patterns, flattening DHEA-S levels in both sexes. This means that once neurodegeneration begins, your brain’s ability to maintain hormonal balance — one of its self-defense tools — breaks down.
• Age changed the picture again, suggesting a nonlinear hormonal response — When researchers divided participants by age, they noticed that younger Alzheimer’s patients (60 to 65) had higher DHEA-S levels, which dropped sharply in the 66 to 75 group before rising again after age 75.
This unexpected curve points to a possible window of hormonal collapse, where midlife stress overwhelms the body’s compensatory systems. If you’re in this age range and facing chronic stress, that’s when intervention — stress reduction, adequate rest, and metabolic support — could be most protective for your brain.
Cortisol Acts Like an Overzealous Cleanup Crew That Damages What It’s Meant to Protect
Elevated cortisol increases inflammation and oxidative stress — chemical reactions that corrode neurons and disrupt communication between brain cells. It also suppresses the growth of new neurons in your hippocampus, the brain’s memory center, making it harder to store new information.
In contrast, DHEA-S supports neuronal survival, enhances energy metabolism, and shields brain tissue from the harmful effects of excessive cortisol. When cortisol wins this hormonal tug-of-war, brain networks lose their flexibility and begin to deteriorate.
• Why stress and memory loss are so tightly linked — Chronic cortisol elevation interferes with glucose uptake in brain cells, depriving them of the fuel needed to form memories. It also increases amyloid-beta and tau accumulation — the same proteins that define Alzheimer’s pathology.
Meanwhile, DHEA-S helps counter these effects by enhancing insulin sensitivity and calming overactive immune responses in your brain. In simple terms, one hormone burns your mental circuits, the other repairs them.
• A new biological marker for early intervention — Instead of waiting for memory loss or imaging changes, tracking your cortisol-to-DHEA-S ratio could signal early stress damage years before cognitive symptoms arise.
If your cortisol stays high while DHEA-S falls or stagnates, that’s a red flag. Supporting your metabolic health, prioritizing quality sleep, and restoring hormonal balance could help keep your brain’s internal environment stable long before Alzheimer’s develops.
Lowering Cortisol and Raising Metabolic Energy Could Reverse Brain Decline
In a commentary, bioenergetic researcher Georgi Dinkov analyzed the Cureus study showing that people with Alzheimer’s disease had significantly higher cortisol levels and a skewed cortisol-to-DHEA-S ratio compared to healthy adults.2 He explained that these results validate decades of bioenergetic research linking chronic stress, low metabolism, and neurodegeneration.
Dinkov emphasized that it’s not just elevated cortisol that drives decline — it’s the imbalance between cortisol and protective steroids such as DHEA, testosterone, and progesterone. When this ratio tips toward cortisol dominance, your body remains in a chronic “fight-or-flight” state that accelerates tissue breakdown and cognitive loss.
• Dinkov connected the findings to thyroid-driven metabolic stress — Building on the Cureus data, Dinkov explained that hypothyroidism — a sluggish thyroid that slows metabolic energy production — creates the same hormonal pattern seen in Alzheimer’s patients: high cortisol and suppressed DHEA-S.
When your metabolism slows, your body compensates by ramping up stress hormones to stay alert and energized. But this backfires over time, leading to chronic brain inflammation, poor glucose uptake, and reduced adenosine triphosphate (ATP) production — the energy currency your brain depends on.
• Your cortisol-to-DHEA-S ratio predicts long-term health better than any single hormone — According to Dinkov, this ratio — spotlighted by the Cureus research — is among the strongest predictors of all-cause mortality and neurodegenerative risk. Even when cortisol fluctuates throughout the day, the ratio reveals whether your stress and repair systems are balanced.
Dinkov suggested measuring cortisol and DHEA-S in hair or nails rather than blood, since these tissues reflect long-term hormonal patterns. For anyone trying to gauge chronic stress or cognitive risk, this offers a simple, objective biomarker that’s far more reliable than a one-time blood test.
• Natural compounds help restore hormonal balance and metabolic strength — Dinkov referenced several well-known substances — aspirin, niacinamide (vitamin B3), progesterone, pregnenolone, thyroid support, glycine, and emodin — that help correct the same imbalance observed in the Cureus study. These compounds work by lowering excess cortisol, improving mitochondrial energy output, and supporting the production of protective hormones.
Niacinamide, for instance, increases NAD+, which fuels cellular repair, while aspirin dampens inflammation and cortisol overproduction. Used together, these tools shift your body back into a “rest-and-repair” mode rather than the constant stress chemistry that drives brain aging.
• DHEA acts as a built-in cortisol regulator — Dinkov explained one of the key ways DHEA helps keep cortisol in check: it blocks the enzyme that turns inactive cortisol back “on” and boosts the one that clears excess cortisol from your body. This dual action makes DHEA a natural cortisol buffer that prevents the overactivation of stress pathways.
In other words, DHEA gives your brain a biochemical “cooling system,” stopping cortisol from overheating your neurons. Supporting DHEA through thyroid health, nutrition, and targeted supplementation helps restore this essential balance.
• Stress is a symptom of low energy, not just emotional strain — Dinkov described how the elevated cortisol levels observed in the Cureus Alzheimer’s cohort represent a deeper issue: energy failure. When your cells don’t make enough ATP — whether from poor thyroid output, nutrient deficiencies, or aging — they turn to cortisol to compensate.
The hormone breaks down tissue to release fuel, but that process worsens energy depletion over time. This self-reinforcing loop explains why chronic stress feels endless: it’s a metabolic, not psychological, trap. Dinkov concluded that maintaining a low cortisol-to-DHEA-S ratio protects more than memory — it sustains whole-body resilience.
People who keep this ratio balanced experience better sleep, stable mood, and slower biological aging. His message is practical: by restoring thyroid function, eating enough to prevent energy deficits, and lowering chronic inflammation, you directly influence the biochemical environment that determines whether your brain decays or endures.
Rebuild Your Energy System to Lower Cortisol and Protect Your Brain
If you wake up tired, crash midafternoon, or feel wired when you should be asleep, your body’s stress chemistry has taken over. The Cureus study3 and Dinkov’s review4 both point to the same conclusion: your brain suffers when your cells can’t make enough energy.
To fix that, you have to restore steady fuel, retrain your stress response, and help your body recognize that it’s no longer in survival mode. Here’s how to bring your hormones — and your energy — back into balance:
1. Feed your metabolism the fuel it’s been missing — Cutting carbs keeps your body trapped in a constant stress loop because cortisol spikes whenever blood sugar drops too low. Break that pattern by eating enough healthy carbohydrates — around 250 grams daily — to give your mitochondria a steady energy supply.
Start with gentle foods like fruit and white rice. When your digestion feels stable (no bloating or irregularity), add cooked root vegetables, then more vegetables, legumes, and well-tolerated whole grains. Once your body trusts it’s being fed regularly, cortisol naturally declines, and your energy and focus stabilize.
2. Move in ways that restore instead of deplete — Overdoing endurance exercise or high-intensity intervals keeps your body in fight-or-flight mode long after the workout ends. Cortisol stays elevated, recovery slows, and sleep suffers.
Replace long, punishing sessions with physical activities that build energy rather than drain it — strength training, walking outdoors, dancing, or swimming at an easy pace. Use how you feel afterward as your guide: if you finish feeling grounded and calm, you’ve helped your hormones, not hurt them.
3. Train your nervous system to shift out of stress — Your breath is the fastest lever you have to quiet cortisol and activate your parasympathetic, or “rest and digest,” system. Try rhythmic breathing patterns like 4-7-8 or 4-8 breathing — inhaling for four seconds, holding briefly, and exhaling slowly for seven to eight seconds.
The extended exhale stimulates your vagus nerve, lowering heart rate and cortisol while signaling safety to every organ. Practice before bed, after meals, or whenever tension rises. Over time, your body learns that it no longer needs to live in emergency mode.
4. Rebuild your circadian rhythm through light and sleep — Cortisol follows your light exposure, not your alarm clock. Get outside within an hour of waking to anchor your body’s circadian rhythm, and dim screens and overhead lighting at night so melatonin can rise naturally.
Keep your bedtime and wake-up times consistent — even on weekends — to lock in hormonal balance. Deep, regular sleep clears stress hormones, strengthens memory, and repairs brain tissue. If you’re dragging through the day, fix your light and sleep first instead of relying on caffeine.
5. Use natural progesterone to quiet the cortisol surge — Bioidentical progesterone acts as your body’s built-in cortisol brake, restoring calm where chronic stress has hijacked balance. Unlike synthetic versions, natural progesterone fits perfectly into your body’s own receptor system, lowering cortisol’s overstimulation and supporting deep rest.
FAQs About Cortisol and Alzheimer’s Disease
Q: What did the new Alzheimer’s study reveal about cortisol and DHEA-S?
A: Researchers found that people with Alzheimer’s disease had cortisol levels roughly 20% higher than healthy adults, while their DHEA-S levels stayed about the same. This created a skewed cortisol-to-DHEA-S ratio — meaning stress hormones were overpowering the brain’s natural defenses. That imbalance, not just genetics or amyloid buildup, appears to drive the early stages of brain decline.
Q: How are DHEA and DHEA-S different?
A: DHEA is the fast-acting form of the hormone, while DHEA-S is the stable, long-lasting form stored in your blood. Because DHEA-S changes slowly, it’s a better measure of long-term stress and brain resilience. It also acts as a neurosteroid, helping neurons resist inflammation and oxidative damage while buffering cortisol’s harmful effects.
Q: What did Georgi Dinkov’s analysis add to this research?
A: Dinkov explained that the Cureus study confirms a broader principle: high cortisol and low metabolic energy often go hand in hand. He connected these hormone shifts to thyroid sluggishness, nutrient depletion, and aging — all of which drain cellular energy and raise stress chemistry. He also noted that maintaining a low cortisol-to-DHEA-S ratio predicts not just better memory but longer life and greater overall resilience.
Q: What practical steps help lower cortisol and restore hormonal balance?
A: To calm your stress system, start by fueling your metabolism. Eat enough healthy carbohydrates — about 250 grams per day — to keep blood sugar stable. Cut back on overtraining, use rhythmic breathing to activate your vagus nerve, and rebuild your circadian rhythm by getting morning sunlight and sleeping on a consistent schedule. These changes lower cortisol naturally while improving energy and mental clarity.
Q: How does progesterone fit into this picture?
A: Natural progesterone acts as a built-in cortisol blocker. Your body recognizes it as a calming, balancing hormone that reduces overstimulation, helps you sleep deeply, and stabilizes mood. Natural progesterone effectively blocks cortisol by reducing blood concentrations, helping restore hormonal harmony, protecting your brain and body from the long-term effects of stress.
Chronic Fatigue Syndrome Linked to Energy Metabolism and Immune Dysfunction
Reproduced from original article:
https://articles.mercola.com/sites/articles/archive/2026/03/05/chronic-fatigue-syndrome-energy-metabolism-immune-dysfunction.aspx
Analysis by Dr. Joseph Mercola March 05, 2026
Story at-a-glance
- Myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS), affects 2 million Americans with debilitating fatigue, post-exertional malaise, and cognitive problems. New research links this condition to mitochondrial dysfunction and impaired cellular energy production
- Studies show ME/CFS patients struggle to produce adequate energy through normal pathways
- The condition compromises immune function by reducing natural killer (NK) cells and dendritic cells, leaving the body with diminished defense capabilities and increased vulnerability
- Blood vessel function suffers when cellular energy drops, causing circulatory problems like poor oxygen delivery, dizziness, and cold extremities that worsen overall fatigue
- Recommended strategies include reducing seed oil consumption, supporting gut health with whole foods, exercising to generate new mitochondria, and prioritizing restorative sleep
Americans report high rates of chronic fatigue, but myalgic encephalomyelitis (ME), also called chronic fatigue syndrome (CFS), represents a distinct, clinically defined disease that affects a small subset of the population rather than a diagnosis that explains widespread tiredness. Around 2 million people currently have ME/CFS, which is characterized by crushing fatigue that does not improve with rest, plus post-exertional malaise, unrefreshing sleep, pain, and cognitive problems, such as brain fog.1
The exact cause of ME/CFS remains unknown. Research suggests that the condition can follow certain triggers, including acute viral infections and severe physical or psychological stress, but no single cause has been identified. In recent years, several studies have reported abnormalities in mitochondrial function and energy metabolism in people with ME/CFS, suggesting a possible role for disrupted ATP production.
Immune Cells Show Clear Signs of Energy Overload
A study published in Cell Reports Medicine examined how ME/CFS is linked to a failure in cellular energy production. For the analysis, the researchers looked at an array of biomarkers, including immune cell metabolism, immune cell composition, and blood makeup.2
The study population included 61 individuals who met strict diagnostic criteria for ME/CFS, meaning they had long-standing fatigue, profound crashes following physical or mental effort, unrefreshing sleep, and cognitive problems.
• There is an ATP imbalance — The study found that adenosine monophosphate (AMP) and adenosine diphosphate (ADP) — two forms of energy molecules that rise when the cell exhausts adenosine triphosphate (ATP) — were elevated in ME/CFS patients. To put that into perspective, ATP is your body’s ideal energy format, whereas ADP and AMP are the substrates for ATP synthesis. If your body begins to use these, the energy you’re using is substandard.
• A theory on how cellular energy production is compromised — The researchers believe that those with ME/CFS have trouble producing enough energy due to an obstacle in the production chain. While their findings aren’t solid enough to propose a definite conclusion, here’s what they theorized:3
“The elevated NAD+ [nicotinamide adenine dinucleotide] levels observed in PBMCs [peripheral blood mononuclear cells], together with the increased AMP and ADP, suggest that NAD+ is not being efficiently reduced to NADH [nicotinamide adenine dinucleotide + hydrogen] to drive ATP synthesis through oxidative phosphorylation.
This impaired reduction of NAD+ to NADH may also help explain the observed inverse correlation between plasma AMP and PBMC ATP levels, although this finding requires further study.”
• Another major finding involved the natural killer (NK) cells — The researchers also discovered changes in the balance of immune cell types, including a reduction in certain mature dendritic cells and terminal NK cells. These normally help coordinate immune responses and act as a first line of defense.
When the population of NK cells drops, the immune system loses some of its agility and responsiveness. This means the fatigue you’re feeling is not only about energy loss — your immune system shifts into a pattern that reflects reduced readiness.
• Blood tests paint a more complete picture — The team reported higher levels of proteins associated with thrombus formation and altered vascular reactivity in the ME/CFS group. For context, thrombus means blood clot formation, and vascular reactivity reflects how blood vessels respond to signals that regulate tightening and relaxation.
When these protein levels rise, it suggests the lining of the blood vessels is under strain, which disrupts healthy circulation. For someone with ME/CFS, that could mean poor oxygen delivery, dizziness upon standing, and cold extremities.
• The study highlighted where the largest metabolic imbalances appeared — Individuals with the most altered ATP-to-ADP ratios tended to show larger distortions in immune cell composition. That suggests a link between energy depletion and immune exhaustion. If the immune system lacks energy, its cells lose the ability to mature properly or carry out normal defense tasks.
In addition, the vascular protein shifts closely aligned with the energy imbalance. When cellular energy drops, blood vessel function suffers. When this happens, the delivery of nutrients and oxygen is affected. This creates a loop that leaves the entire body underpowered.
• The biological mechanisms behind these findings trace back to disrupted ATP production — Normally, mitochondria generate ATP through oxidative phosphorylation, a process that depends on oxygen, nutrients, and intact cellular machinery.
When ATP falls and ADP or AMP rises, the cell enters a state of metabolic stress. Here, the cell may shift into emergency survival mode instead of normal function. That shift drains resilience, reduces cellular performance, and leaves tissues — especially the immune system and blood vessels — operating at a deficit.
• Another mechanism involves immune maturation — Dendritic cells and NK cells rely on ATP to fuel activation, communication, and response signaling. When ATP drops, these cells lose their functional sharpness. The study found this exact pattern: fewer mature cells and more signs of immune imbalance.
• Mechanistic hallmarks of ME/CFS — Although the paper did not measure symptom improvement over time, it did compare variables to determine which markers best distinguished ME/CFS participants from healthy controls.
A statistical model that incorporated metabolic markers, immune shifts, and vascular proteins reliably separated the two groups. This includes an abundance of AMP and ADP. In addition, the immune system is skewed towards less mature pathogenic fighters, alongside a lower population of NK cells.
Energy Deficits Push the Immune System Toward Burnout
In a related study published in Biomolecules, researchers showed how energy metabolism and immune function interact in ways that worsen symptoms of ME/CFS over time. Here, they used a broad body of evidence to map out how energy shortages inside cells feed directly into immune dysfunction, especially immune senescence and immune exhaustion.4
• Mitochondrial dysfunction stands at the center of this illness — However, the study adds something new to the conversation. In particular, the researchers noted that those with ME/CFS have compromised levels of carnitine, which is needed for fatty acid oxidation and energy metabolism.
Moreover, the researchers noted that this chemical helps maintain integrity of the mitochondria and reduce the production of reactive oxygen species (ROS). The image below provides an overview of their hypothesis:
Source: • The link to viruses — The paper identifies striking parallels between ME/CFS and chronic viral infections. In chronic viral states, the immune system fights for long periods without rest. Over time, some immune cells lose function and responsiveness through a process called cellular senescence, a state in which cells remain alive but no longer divide or respond effectively to threats. And when this reaches a chronic state, ME/CFS pathology occurs.
• Immune function breaks down — The immune system in people with ME/CFS shifts into a dysfunctional state. Similar to the previous study, they have altered NK cell function, changes in cytotoxic T cells, and persistent immune activation patterns that resemble those seen with unresolved infections.
• How energy metabolism and immune regulation are linked — The researchers argue that mitochondrial defects impair the immune system’s internal communication network. In addition, the same dysfunction creates a bottleneck for immune activity itself. In other words, your cells do not produce enough energy to meet the demands of immune signaling, repair, or defense.
• ME/CFS displays patterns of metabolic inflexibility — Cells struggle to switch between energy pathways or ramp up ATP production during stress. When your cells cannot adapt, even minor activity can produce a disproportionate crash. The featured study highlights published literature showing impaired energy production and utilization.
• Immune exhaustion driven by chronic metabolic strain — The paper explains that persistent energy deficits interfere with immune cell communication and their ability to generate powerful responses. When immune cells lack ATP, they lose the ability to proliferate, secrete cytokines, or kill infected targets effectively.
Strategies to Reclaim Your Energy and Live Life to the Fullest
If you’re low on energy, the solution isn’t drinking more coffee or energy drinks. It lies in your mitochondria, which has been compromised to such a point that it can’t function properly anymore. That said, I’ll be releasing a new book soon, “Cancer Cure,” which explores what changes occurred in our society today that resulted in a dramatic rise in metabolic dysfunction among millions of Americans.
The book will also discuss several strategies that can help you regain your cellular energy and improve your quality of life. Here are some of my recommendations:
1. Reduce linoleic acid (LA) intake — One of the reasons why you’re feeling fatigued is excess intake of LA, one of the most prominent toxins in the Western food supply. In fact, I’d go so far as to rank it above refined sugar, although that plays a role, too.
The reason why I’m saying this is because excess LA generates reactive byproducts that eventually suppress immune behavior, as well as damaging your mitochondria. So, get rid of any foods you have that contain LA, which are mainly seed oils — soybean, corn, cottonseed, canola, sunflower, and grapeseed.
In a previous article, I mentioned that modern Western diets now contain 15 to 25 grams of LA daily, which is a far cry from the estimated 2 to 4 grams that pre-industrial populations consumed.
In light of this, I recommend you keep your LA intake below 5 grams a day; if you can keep it below 2 grams, that’s even better. To track the LA in your food, sign up for the upcoming Mercola Health Coach app. It contains a feature called the Seed Oil Sleuth, which calculates daily LA consumption to a tenth of a gram. Swap LA-rich seed oils for healthier saturated fats like grass fed butter, ghee, tallow, and coconut oil.
2. Familiarize yourself about sources of LA — You’ll find LA not just in cooking oil sold in grocery stores. They’re found in most ultraprocessed foods, so it’s important to read through the ingredient list of whatever you’re buying.
In addition, it would be wise to minimize the times you eat in restaurants or order takeout. Unless strictly stated otherwise, it’s safe to assume that all the food cooked in these establishments use seed oils.
LA also is found in conventionally raised chicken and pork due to the ultraprocessed nature of their feed. Prioritize beef, lamb, bison, and other ruminants, which are likely to have lower LA levels.
3. Support your immune cells at the mitochondrial level — When ATP runs low, immune cells can’t communicate, divide, or kill threats efficiently. Several natural compounds have shown promising effects in boosting mitochondrial resilience and NK cell performance:
• Beta-glucans from yeast and mushrooms wake up your immune system by activating macrophages and NK cells.
• PQQ, found in papaya and green tea, sparks the production of new mitochondria and protects them from oxidative wear and tear.
• Urolithin A, a gut-derived compound from pomegranates, recycles defective mitochondria to keep your cellular engines running clean.
• Polyphenols like quercetin, fisetin, curcumin, and resveratrol scavenge harmful free radicals and reduce inflammatory suppression of NK cells.
In preclinical studies, when NK cells were given a combination of these compounds — delivered via nanoliposomes that targeted mitochondria directly—their killing capacity jumped five to tenfold. Instead of exhausting after five to ten kills, these cells could eliminate 30 to 50 targets before tiring out.
4. Repair your gut — Aside from your mitochondria, LA also wrecks your gut microbiome, which plays an extensive role in your health, including energy metabolism.5
Gut repair requires adequate carbohydrate intake to support intestinal cells and microbial balance. Your gut lining relies on glucose as a primary fuel, and insufficient carbohydrate intake can slow repair and weaken barrier integrity. Most adults need at least 250 grams of carbohydrates per day, adjusted for activity level and metabolic status. This intake supports gut repair, thyroid signaling, and overall energy balance.
Begin with well-tolerated carbohydrate sources such as sweet potatoes, carrots, winter squash, ripe fruit, and cooked white rice. These foods supply glucose while being lower in fermentable substrates. Add high-fiber foods slowly if gut health remains poor. Large amounts of fiber can intensify bloating, cramping, and constipation when intestinal permeability or dysbiosis persists. In this phase, prioritize digestible carbohydrates first and increase fiber only in small, gradual steps as tolerance improves.
As epithelial integrity strengthens and immune signaling stabilizes, fiber tolerance will improve as well. At that point, a broader range of fiber-rich foods can support short-chain fatty acid production and long-term resilience.
5. Exercise with restraint and precision — Your immune system relies on cytotoxic T lymphocytes and NK cells to remove damaged or dysfunctional cells. In ME/CFS, immune signaling, mitochondrial output, and energy recovery all falter, which changes how your body responds to physical stress. So, conventional exercise advice does not apply here.
High-intensity or endurance exercise often worsens symptoms and can trigger post-exertional malaise, a hallmark feature of ME/CFS. Rather than restoring immune function, excessive exertion can deepen mitochondrial injury and prolong recovery.
The goal is not fitness training. The goal is cellular signaling without metabolic overload. Most ME/CFS researchers emphasize gentle, low-stress movement that respects your available energy. Appropriate options include slow walking, light stretching, yoga, tai chi, and short bouts of resistance exercise that use body weight or very light loads.
Time and intensity matter more than duration. Many patients tolerate exercise best in intervals lasting seconds to a few minutes, followed by full recovery. Heart-rate monitoring and pacing strategies help you stay below your anaerobic threshold, which lowers the risk of symptom relapse. As mitochondrial function and autonomic balance improve, capacity often expands gradually.
Progress depends on consistency, recovery, and restraint, not intensity. Any program should adapt to daily energy limits rather than fixed schedules or goals.
6. Get restorative sleep — This is another cornerstone of health that’s often overlooked. In the case of people diagnosed with ME/CFS, research shows that sleep habits are often compromised — longer sleep onset latency and reduced sleep efficiency are common occurrences.6
When you get proper sleep, your body undergoes crucial repair processes. In particular, sleep allows your immune system to rest, allowing optimal surveillance in the long run against wayward cells that contribute to fatigue.
If you’re having a hard time sleeping, there are many strategies to help you. Read “Sleep — Why You Need It and 50 Ways to Improve It.” There, I also go over the science on what happens to your body while you rest, as well as the consequences of insufficient sleep.
Frequently Asked Questions (FAQs) About Chronic Fatigue Syndrome and Mitochondrial Function
Q: What is ME/CFS, and how common is it?
A: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects approximately 2 million Americans. It’s characterized by crushing fatigue that doesn’t improve with rest, post-exertional malaise, unrefreshing sleep, pain, and cognitive problems like brain fog.
Q: What does new research reveal about the underlying cause of ME/CFS?
A: Research found that ME/CFS patients have elevated adenosine monophosphate (AMP) and adenosine diphosphate (ADP) — energy molecules that accumulate when cells exhaust their primary energy source, adenosine triphosphate (ATP) — suggesting the body struggles to produce adequate cellular energy.
Q: How does ME/CFS affect the immune system?
A: Patients have reduced populations of natural killer (NK) cells and dendritic cells, both critical for immune defense. Because immune cells depend on ATP to function, energy deficits cause immune exhaustion and reduced ability to fight infections.
Q: Why do ME/CFS patients often experience circulatory symptoms like dizziness and cold extremities?
A: Studies found elevated proteins associated with blood clot formation and altered vascular function. When cellular energy drops, blood vessel function suffers, impairing oxygen and nutrient delivery throughout the body.
Q: What lifestyle strategies may help improve cellular energy production?
A: Recommendations include reducing linoleic acid intake (found in seed oils) to below 5 grams daily, optimizing gut health with fiber-rich whole foods, exercising according to ability to stimulate new mitochondria production, prioritizing restorative sleep, and supporting your immune cells at the mitochondrial level with natural compounds such as beta-glucans, PQQ, urolithin A, and polyphenols.
This Small Molecule Reverses Alzheimer’s Disease Progression, Study Shows
Reproduced from original article:
https://articles.mercola.com/sites/articles/archive/2026/02/17/nad-reverses-alzheimers-progression.aspx
Analysis by Dr. Joseph Mercola February 17, 2026
Story at-a-glance
- Nicotinamide adenine dinucleotide (NAD+) is central to cellular energy and mitochondrial health, driving redox reactions that produce ATP. Declining levels are linked to metabolic disorders, sarcopenia, and diabetes
- Alzheimer’s disease has strongly associated with disrupted NAD+ balance, and research suggests restoring intake can reverse cognitive decline rather than merely slowing disease progression
- Animal studies show restoring NAD+ fully reversed advanced Alzheimer’s features, including memory loss, inflammation, tau pathology, oxidative stress, and DNA damage, even after severe disease was established
- NAD+ functions as an upstream regulator of brain resilience, coordinating energy production, DNA repair, inflammation control, and protein processing, reframing Alzheimer’s as a systems-level energy failure
- Practical strategies emphasize testing NAD+ status and supporting production safely via niacinamide alongside adequate intake of other B vitamins
Nicotinamide adenine dinucleotide (NAD+) may be one of the most overlooked factors when it comes to optimizing cellular health. It is a cellular coenzyme that plays a role in many metabolic and signaling reactions.
For example, it partakes in redox reactions — chemical exchanges that transfer energy between molecules — which lead to the production of adenosine triphosphate (ATP), your body’s energy currency.1 In fact, research shows that a deficiency is linked to an array of conditions, such as sarcopenia and diabetes.2
But that’s not all — Alzheimer’s disease, the most common form of dementia,3 has now been linked to declining NAD+ levels. Following this line of thought, emerging research shows that boosting NAD+ intake can reverse the progression of Alzheimer’s disease. This discovery could be one of the biggest breakthroughs in recent times, as most people believe that Alzheimer’s only worsens the longer it goes,4 and treatment focuses on slowing decline rather than reversing it.
Restoring Brain Energy Reversed Advanced Alzheimer’s in Animal Models
A study published in Cell Reports Medicine set out to discover how Alzheimer’s disease can be reversed by boosting NAD+ levels. For the experiment, the researchers used multiple mouse models of Alzheimer’s disease that already showed severe cognitive impairment, brain inflammation, tau pathology, and structural brain damage.5
Mice were administered P7C3-A20 at a dosage of 10 milligrams (mg) per kilogram (kg) of weight each day. Analysis involved observing changes across behavior, brain chemistry, and physical brain structure. For context, P7C3-A20 is a carbazole compound that can readily cross the blood-brain barrier. It works by binding to NAMPT (an enzyme that controls how much NAD+ is made from niacinamide) to enhance NAD+ production6 at safe levels.
• One striking finding is the rate of improvement — The authors reported that in treated mice, cognitive function recovered fully, meaning their memory performance returned to levels seen in healthy animals. These mice performed just as well as non-diseased controls on learning and memory tests.
• What changed inside the brain samples — Multiple hallmarks of Alzheimer’s disease improved at the same time. Tau pathology, which refers to tangled protein structures that disrupt neuron function, decreased after NAD+ restoration. Neuroinflammation markers dropped, indicating a calmer immune environment in the brain. Signals of oxidative stress and DNA damage — both signs of energy failure inside cells — also declined.
• Results were observed right away — The intervention occurred after the disease had fully developed in these animals. Again, this directly challenges the long-standing belief that Alzheimer’s damage becomes permanent once it crosses a certain threshold.
• Other disease models were used to solidify the findings — The researchers tested the same approach in two different forms of Alzheimer’s pathology. In amyloid-driven mice and in tau-driven PS19 mice, restoring NAD+ reversed advanced disease features. That distinction matters because amyloid and tau represent different biological drivers of Alzheimer’s. Seeing improvement in both strengthens the argument that NAD+ disruption sits upstream of these visible brain lesions.
• Blood biomarkers also benefited — Treated animals showed reduced levels of phosphorylated tau 217, a biomarker now used clinically to track Alzheimer’s severity. This helps bridge the gap between animal research and its implications for Alzheimer’s disease in humans.
• At the center of all the changes is NAD+ homeostasis — NAD+ is required for cells to convert nutrients into usable energy and to repair daily damage to proteins and DNA. That said, the study found that Alzheimer’s disease severity correlated with how disrupted NAD+ balance became in the brain. In other words, as energy systems failed, disease features worsened and restoring that balance reversed the cascade.
The researchers described this as a “resilience” model rather than a single-target approach. Instead of attacking amyloid alone or tau alone, restoring NAD+ stabilized multiple systems at once — energy production, inflammation control, blood-brain barrier integrity, and cellular repair. Thus, the findings reframe Alzheimer’s as a system-level energy failure rather than a mystery buildup of toxic debris in the brain.
• Human relevance strengthened the findings further — Using human brain samples and sophisticated molecular analysis techniques, the authors reported that NAD+ disruption also tracked with Alzheimer’s severity in people. They identified overlapping biological nodes between mice and humans that responded to restored NAD+ balance.
• Mechanistic explanation of the benefits — The paper explained that NAD+ acts as a central coordinator for enzymes involved in DNA repair, mitochondrial function, and stress resistance. When NAD+ levels fall, these systems stall. Neurons, which require constant energy, suffer first. Restoring NAD+ reactivated these pathways simultaneously.
The study also highlighted why focusing solely on plaques has delivered limited success. Amyloid and tau accumulation appeared downstream of NAD+ disruption rather than as isolated causes. Once energy systems failed, the brain lost its ability to manage protein turnover, immune balance, and structural integrity. Fixing the upstream energy deficit corrected multiple downstream failures at once.
From a practical standpoint, the findings support the idea that improving cellular energy changes the trajectory of Alzheimer’s disease rather than simply slowing damage. It shows that neurons under metabolic stress can recover when you address cellular energy production at its root.
NAD+ Restores Memory by Rewriting Neuronal Instructions
In a related study published in Science Advances, researchers examined how restoring NAD+ reverses Alzheimer’s features inside brain cells from a genetic perspective. Specifically, the researchers focused on gene regulation, which influences how neurons read and process instructions that control memory and brain resilience.7
• Core findings of the analysis — Increasing NAD+ corrected widespread errors in gene instruction processing and restored memory performance, but only when a specific control protein, EVA1C, remained intact. When this was suppressed, the memory benefit disappeared, even with NAD+ restoration.
Another important improvement that was observed is memory retention. Animals receiving NAD+ showed clear restoration of learning and recall ability, measured through standardized behavioral tests used in neuroscience research. When researchers interfered with EVA1C expression in the hippocampus, those gains vanished, even though NAD+ levels rose.
• A deeper look into the mechanism at play — The study showed that NAD+ corrected abnormal alternative splicing events across many genes. For context, alternative splicing refers to how cells assemble genetic instructions before building proteins.
Think of the process as editing a recipe. If the editing goes wrong, the cell produces dysfunctional proteins. In Alzheimer’s models, these editing errors appeared widespread. NAD+ restored normal editing patterns, but only through EVA1C.
• The largest benefits appeared in hippocampal neurons — This is especially observed within the CA1 region. For context, the hippocampus is the brain’s memory hub, and CA1 neurons act as a relay station for forming and retrieving memories. When EVA1C levels dropped in this region, NAD+ no longer improved memory performance.
• Comparisons between test variables — NAD+ alone improved memory only when EVA1C function remained intact. Meanwhile, EVA1C suppression alone worsened memory outcomes even when energy levels improved. This shows that NAD+ and EVA1C did not work independently — they functioned as a linked system, with EVA1C acting as the gatekeeper for the cognitive benefits of NAD+.
The study also included human data. Researchers reported that EVA1C expression was reduced in the hippocampus of participants with Alzheimer’s disease compared to cognitively normal controls.
• A closer analysis of the mechanisms involved — Ribonucleic acid (RNA) splicing determines which protein versions neurons produce. In Alzheimer’s disease, incorrect splicing led to dysfunctional proteins that weaken synapses and disrupt communication between brain cells. Now, NAD+ restored normal splicing patterns by regulating EVA1C activity, which stabilized protein production inside neurons.
Again, the researchers emphasized that this process represented a form of resilience. Neurons did not simply slow deterioration — they regained the ability to produce functional proteins required for learning and memory.
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Before Boosting Levels, It’s Important to Get a Baseline
Based on the findings, boosting NAD+ has enormous potential when it comes to managing Alzheimer’s disease. Hence, testing your current levels is important, as it would be wise not to take any supplement without proper direction or planning.
• A new test will be launched in the future — I’m excited to introduce the upcoming Mitochondrial Wellness Test Kit, which is designed to offer you a current snapshot of your mitochondrial function. While this provides an overview, additional targeted testing may still be needed to fully understand the more intricate nuances of your health.
• Existing NAD+ tests fall short — NAD+ is highly unstable once it’s outside the cells and degrades quickly, making reliable measurement difficult. To maintain accuracy, it requires immediate processing and advanced laboratory methods.
In practice, this means blood samples need to be collected and analyzed rapidly within the same research facility, which is not possible at most clinics. Moreover, transporting samples between labs further compromises integrity. Despite these obstacles, my team and I have remained committed to advancing practical health testing for everyone.
• A higher standard for NAD+ assessment — Mercola Labs is developing a novel solution that avoids the pitfalls of measuring NAD+. Instead, we assess NAD+ levels by analyzing redox balance among these essential biomarkers — acetoacetate and beta-hydroxybutyrate, lactate and pyruvate, and the oxidized and reduced forms of glutathione. Additional details will be shared closer to release.
Niacinamide Supports NAD+ Production
Taking niacinamide is a convenient way of boosting your NAD+ levels. However, this approach calls for precision and balance — the reason why I encourage proper testing. While high doses have shown benefits in clinical settings, smaller and consistent amounts are far more appropriate for everyday use. This approach supports mitochondrial and metabolic function without placing unnecessary stress on the body, since excessive intake can disrupt methylation pathways and raise the risk of adverse events over time.
• Take small, evenly distributed daily doses — For daily support, take 50 milligrams of niacinamide three times per day. This modest dose supports NAD+ production without the risks associated with high-dose vitamin B3 supplementation. You can even divide it into four servings per day. Take one dose upon waking, one before bed, and space the remaining doses evenly throughout the day.
• Excessive B3 intake can be counterproductive — Taking too much vitamin B3, whether as niacin or niacinamide, will lead to negative outcomes. Research cited by the Cleveland Clinic indicates that high doses can increase cardiovascular risk.8 Although both compounds are forms of vitamin B3, niacin does not activate NAMPT the way niacinamide does, making niacinamide the preferred option.
• Don’t forget the other B vitamins — Adequate intake of other B vitamins is essential for overall health and mitochondrial function, particularly niacin, riboflavin, and folate. Suboptimal mitochondrial health is often linked to B-vitamin deficiencies,9 which can typically be corrected with a low-dose, high-quality B-complex supplement.
When it comes to food sources, vitamin B3 is abundant in grass fed beef and mushrooms.10 Vitamin B6 is found in grass fed beef, potatoes, and bananas.11 Folate (vitamin B9) is plentiful in spinach, broccoli, and asparagus,12 while vitamin B12 is concentrated in foods such as grass fed beef liver, wild rainbow trout, and wild sockeye salmon.
Frequently Asked Questions (FAQs) About NAD+ and Its Link to Alzheimer’s Disease
Q: What is NAD+ and why is it essential for cellular and brain health?
A: NAD+ is a core cellular coenzyme required for energy production, mitochondrial function, DNA repair, and metabolic signaling. Low NAD+ levels impair cellular energy and are linked to aging, metabolic disease, and neurodegeneration.
Q: How is NAD+ connected to Alzheimer’s disease progression?
A: Research shows Alzheimer’s disease severity correlates with disrupted NAD+ balance. Declining NAD+ levels impairs neuronal energy, repair, and resilience, suggesting the condition is driven by upstream energy failure rather than plaque buildup alone.
Q: Can restoring NAD+ reverse Alzheimer’s-related damage?
A: In advanced animal models, restoring NAD+ led to full cognitive recovery, reduced inflammation, improved tau pathology, and lower blood biomarkers, even after severe disease was established, challenging the idea of irreversible damage.
Q: How does NAD+ improve memory at a genetic and cellular level?
A: NAD+ restores proper gene instruction processing through EVA1C-dependent RNA splicing, particularly in hippocampal neurons. This allows neurons to rebuild functional proteins required for learning and memory, promoting true neuronal recovery.
Q: What is the safest way to support NAD+ levels?
A: Modest, consistent niacinamide dosing, combined with adequate B vitamins, supports NAD+ production safely without disrupting methylation or increasing health risks.
- 1 Plast Reconstr Surg. 2021 Sep 28;150(4 Suppl):41S-48S
- 2 npj Metabolic Health and Disease volume 3, Article number: 26 (2025)
- 3 WHO, March 31, 2025
- 4 Mayo Clinic, Alzheimer’s Stages: How the Disease Progresses
- 5 Cell Reports Medicine, Volume 7, Issue 1, 102535
- 6 Oxid Med Cell Longev. 2023 Feb 8;2023:7857760
- 7 Sci. Adv.11,eady9811(2025)
- 8 Nature Medicine February 19, 2024; 30: 424-434
- 9 Perm J. 2022 Jun 17;26(2):89-97
- 10 My Food Data, Top 10 Foods Highest in Vitamin B3 (Niacin)
- 11 My Food Data, Top 10 Foods Highest in Vitamin B6
- 12 My Food Data, Top 10 Foods Highest in Vitamin B9 (Folate)
The Importance of Getting Regular Health Tests
Reproduced from original article:
https://articles.mercola.com/sites/articles/archive/2025/08/16/importance-of-getting-regular-health-tests.aspx
Analysis by Dr. Joseph Mercola August 16, 2025
Story at-a-glance
- Regular lab testing provides precise, actionable insights that enable early detection of possible diseases to improve long-term health outcomes
- Iron overload testing is crucial since excess iron is more common than deficiency; check serum ferritin levels and GGT enzyme levels for accuracy
- Hormone testing reveals metabolic health by measuring cortisol for stress levels, testosterone for mortality risk, and insulin resistance through HOMA-IR calculations
- Comprehensive biomarker monitoring includes vitamin D levels, complete thyroid panel beyond thyroid-stimulating hormone (TSH), and NAD+ testing for cellular function
- Biannual gut microbiome testing provides insights into bacterial balance, enabling smarter dietary decisions
When was the last time you had a thorough assessment of your health? Guessing about the current state of your health can lead to risky assumptions and dangerous oversights. Without concrete information, symptoms are likely to be misinterpreted or dismissed, allowing underlying issues to progress unnoticed. On the other hand, too much intake of a specific nutrient will also lead to health issues.
Lab testing removes uncertainty by providing precise, actionable insights into your health. By leveraging data-driven results, you gain clarity about your body’s true state, enabling you to select the optimal strategy to boost your health and proactively address concerns. The following are the tests I recommend that you take to keep you updated on what’s happening inside your body.
How to Test for Iron
One good reason why I recommend taking regular tests is to catch an unsuspecting health problem affecting many people — iron overload. In fact, it’s more widespread than iron deficiency. In addition, I’ve also written a paper about the duality of iron as a toxin and a nutrient, which will be published in the future. The recommendations I mention below stem from the findings of that specific research.
• How iron is normally tested — Checking for excess iron is straightforward and starts with a basic serum ferritin test, which shows how much iron your body has stored. This test reveals if your iron storage has reached higher-than-normal levels.
For context, transferrin refers to a protein produced in your liver that transports (hence the “transfer” in the name) iron molecules it binds to, transporting it to tissues. One example is your bone marrow, which requires iron to create new blood cells.1
• Transferrin saturation (TSAT) — While a serum ferritin test is a cornerstone test, it shows an incomplete picture. It works best alongside a TSAT test.
TSAT levels — calculated as serum iron divided by total iron-binding capacity (TIBC) then multiplied by 100 — shows the current amount of transferrin protein that’s bound to iron. Thus, it shows you the current iron levels you have available for erythropoiesis, commonly known as red blood cell production.
• Results to watch out for — When it comes to serum ferritin levels, I believe that the ideal range is between 30 and 100 ng/mL (nanograms per milliliter). This is sufficient for hemoglobin synthesis and avoids iron accumulation that can lead to oxidative stress in your body.
As for TSAT, my research indicates that the ideal range is between 25% and 35%. If regular tests show a range above 35%, you likely have iron overload. At 35% to 40%, iron that isn’t bound by transferrin protein — also known as toxic non-transferrin-bound iron (NTBI) — will damage your vital organs.2 In fact, TSAT ranges between 45% and 55% are linked to a 60% to 67% increase in all-cause mortality.
•Ideal ranges — To summarize, healthy results should show TSAT levels between 25% and 35%, alongside serum ferritin levels between 30 and 100 ng/mL.
Now, if your combined results show TSAT levels below 20% and serum ferritin levels below 15 micrograms per liter (µg/L), you likely have depleted iron reserves. Conversely, TSAT levels above 45% and ferritin levels above 100 ng/mL indicate excess iron. Taken altogether, serum ferritin not only serve as diagnostic markers — they also function as risk predictors.
• Other tests that detect iron — A comprehensive assessment usually includes an iron panel, complete blood count (CBC), gamma-glutamyl transferase (GGT), and a metabolic panel to fully understand your body’s iron status and overall health.
A healthy ferritin level is between 20 and 40 ng/mL. If results show that you’re below 20 ng/mL, you’re deficient in iron, which isn’t what you also want to happen. Conversely, you want your ferritin below 100 ng/mL, which is the maximum cut off.
• GGT test — This refers to the enzyme mainly produced by the liver, and is responsible for breaking down medications and toxins. When too much iron builds up in your body, it can harm your liver cells, causing GGT levels to rise significantly in your bloodstream.
What’s great about this test is that it also gives you insights on your excess free iron, as well as your risk for sudden death, insulin resistance, and cardiometabolic disease. Once you have your results, refer to the table below to know where you stand:
| Ideal GGT Level, units per liter (U/L) | Average level, above which your risk for chronic disease increases significantly | “Normal” GGT Level | |
|---|---|---|---|
| Men | Less than 16 U/L | 25 U/L | Up to 70 U/L |
| Women | Less than 9 U/L | 18 U/L | Up to 45 U/L |
Fine-Tuning Your Lifestyle for Longevity
Testing for possible nutrient deficiencies (or overload) is just one aspect of the big picture. You also need to test for other biomarkers, such as your hormones (testosterone, cortisol, and insulin) to detect your current stress levels. Doing so will lead to better metabolic health management.
• How cortisol is measured — Cortisol is produced by your adrenal glands, and it can be detected via your blood, urine, or saliva. Once samples are provided, be sure to follow your doctor’s instructions to generate the most accurate results possible.3
According to the Cleveland Clinic, cortisol in the blood, urine, or saliva are at their highest during the early morning and then decline afterward — midnight is the lowest point.4
• What your cortisol levels tell you about your health — In addition to measuring your stress levels, cortisol tests help rule out other conditions. For example, Addison’s disease occurs when your body isn’t producing enough cortisol. Conversely, Cushing’s syndrome is marked by high cortisol levels. Tumors are also marked by elevated cortisol.5
Finding out your current cortisol levels is important for overall health. It drastically accelerates aging and even contributes to muscle degradation over time. Lastly, it contributes to inflammation and a weakened immune system.
• The importance of testosterone — In a previous article, I cited research showing the link between sex hormones and mortality risk in men. Basically, if your testosterone levels drop by 213 ng/dL (nanograms per deciliter), you have a higher risk of all-cause mortality. In addition, testosterone levels below 153 ng/dL were associated with increased cardiovascular mortality risk.
• Ideal testosterone range — To find out your current levels, you’ll need to have your blood tested. That said, what’s a healthy range? In this article, I mentioned 300 to 1,000 ng/dL as a baseline.
• Testing for insulin resistance — In addition to cortisol, another crucial test that I recommend you take is measuring your insulin resistance. This is essential because results will serve as warning signs for your metabolic health. That said, insulin resistance is measured via the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) test. It calculates how your fasting glucose and insulin levels interact, and finds out how your body uses insulin.
• Interpreting HOMA-IR results — Below is a breakdown on how the HOMA-IR test is calculated. A score below 1 means you are currently insulin-sensitive and functioning well. Anything above that means that you currently have insulin resistance.
HOMA-IR = (Fasting Glucose x Fasting Insulin) / 405, where
◦ Fasting glucose is measured in mg/dL
◦ Fasting insulin is measured in μIU/mL (microinternational units per milliliter)
◦ 405 is a constant that normalizes the values
If you’re using mmol/L for glucose instead of mg/dL, the formula changes slightly:
HOMA-IR = (Fasting Glucose x Fasting Insulin) / 22.5, where
◦ Fasting glucose is measured in mmol/L (millimoles per liter)
◦ Fasting insulin is measured in μIU/mL, and
◦ 22.5 is the normalizing factor for this unit of measurement
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Testing for Other Important Biomarkers
So far, I’ve covered the importance of having your iron, cortisol, insulin resistance, and testosterone levels tested. While they may seem like a lot, there’s still a few more tests that need to be done.
• Monitor your vitamin D — This nutrient is a crucial contributor to optimal health, and I’ve espoused its importance for many years now. Considering this, a simple blood test is all you need to know your current levels.
My recommended range is between 60 ng/mL and 80 ng/mL, and the cutoff for sufficiency is around 40 ng/mL. Once you’ve confirmed your level, you’ll know how much sun exposure or supplementation (if needed) is necessary for you to reach the ideal range. Then, retest in the next three to four months to make sure you’ve hit your goals.
• Don’t forget your thyroid hormones — Your endocrine system is a complex network of glands and organs that regulate hormone production. Among the many hormones produced in your body, the ones produced in the thyroid are perhaps the most important because they help regulate metabolism and are found in nearly every physiological process within you.
• Understanding thyroid antibodies — Examples include thyroglobulin antibodies (TgAb) and thyroid peroxidase antibodies (TPOAb). Results will give you deeper insight into whether autoimmune processes are attacking your thyroid gland. Pairing these antibody results with symptoms helps you make meaningful connections and clarifies what’s really going on with your body, particularly if you’re dealing with an autoimmune condition.
• Traditional thyroid assessments aren’t effective anymore — Testing for thyroid-stimulating hormone (TSH) alone often misses underlying issues. That’s because TSH levels fluctuate significantly and you’ll even appear relatively normal even when you’re actually experiencing severe symptoms.
For instance, individuals with Hashimoto’s thyroiditis might have completely normal hormone levels yet feel persistently unwell. Similarly, basal body temperature is also an unreliable indicator of thyroid health, as it can be influenced by multiple factors unrelated to thyroid function.
• How to test thyroid function — A full thyroid assessment should show the following results:
◦Low TSH
◦T3 levels in the upper range
◦rT3 levels in the lower range
◦Moderate T4 levels
However, note that even “normal” results will not guarantee that your thyroid is functioning properly. For deeper insight, test for rT3 and cholesterol. Small amounts of rT3 are normal and act as a buffer against thyroid overactivity. On the other end, elevated rT3 is problematic because it competes with T3, reducing your metabolic rate. Elevated cholesterol levels also usually signal suboptimal thyroid function.
Importance of NAD+ Testing
Nicotinamide adenine dinucleotide (NAD+) is an important molecule in your body. It plays a role in converting food to energy, as well as maintaining DNA integrity and proper cell function.
• A new test will come out soon — I’m excited to announce the upcoming Mitochondrial Wellness Test Kit, which will provide a snapshot of your latest mitochondrial function. While helpful, certain specialized tests will be needed to understand the nuances of your health.
• Current NAD+ testing is unsatisfactory — NAD+ rapidly deteriorates once it’s outside your cells, making accurate measurement tricky. Because of this fragility, samples require immediate handling and specialized techniques to avoid losing accuracy.
Typically, precise NAD+ measurement demands blood samples to be drawn and analyzed swiftly within the same specialized research facility — something not possible at most regular clinics. Transporting samples between labs also compromises results significantly due to degradation. However, these challenges haven’t stopped our mission to deliver valuable health insights.
• NAD+ testing standards will rise — My team and I have developed an innovative approach that bypasses the complexity of direct NAD+ measurement. Instead, our method evaluates your NAD+ status indirectly by examining the redox balance among these essential markers — acetoacetate and betahydroxybutyrate, lactate and pyruvate, and the oxidized and reduced forms of glutathione.
• The test will be affordable — I’m proud to share that this cutting-edge NAD+ test is inexpensive, giving more people access to their current cellular health. More announcements will be made once this product is available.
Assessing Your Gut Health
Another crucial aspect of your health that needs to be tested regularly is your gut function. As you know, certain gut strains are beneficial, while others aren’t. Thus, figuring out which bacteria are dominating your gut will give you an insight to what’s happening.
• Gut Microbiome Wellness Test Kit — Just like the Mitochondrial Wellness Test Kit, my team and I will be releasing the Gut Microbiome Wellness Test Kit. It’s uniquely crafted to help you gain insights into your gut bacteria’s profile. It will seamlessly pair with the upcoming Mercola Health Coach app, providing you with a seamless end-to-end journey — from collecting your sample to interpreting your results.
To paint a picture of this process, you’ll need to send over a fecal sample. Afterward, you’ll be provided with a detailed breakdown of key bacterial species, allowing you to make smarter dietary and lifestyle decisions. To encourage broad access among the public, we’re also giving it an affordable price tag.
• Frequency of gut microbiome testing — One major reason why we’ve made this test affordable is to encourage repeat testing, ideally twice a year. This is needed to see whether your situation has improved or worsened, and you cannot know what your status is if a single test already requires a significant amount of cash.
Tips on Addressing Nutritional and Hormonal Deficiencies
The reason why I recommend you get yourself screened is to help save you time and money. For example, if one vitamin is already at an optimal range, you can focus your effort on others that need more attention. That said, I recommend going through the following articles. They contain helpful strategies to help you maintain optimal health after you’ve completed your tests:
- Everything You Need to Know About Vitamin D for Your Health
- High Iron Levels Threaten Bone Health and Increase Fracture Risk
- How Low Testosterone Affects Men’s Health
- Blocking Cortisol Extends Lifespan by Improving Mitochondrial Function
- Key Nutrients to Support Optimal Thyroid Health
- The Crucial Role of NAD+ in Optimal Health
- Unlocking the Secrets of Gut Health
Frequently Asked Questions (FAQs) About Regular Health Screenings
Q: Why is guessing about your health risky?
A: Guessing or relying on symptoms alone can result in serious health issues going undetected, delaying necessary treatments and reducing your chances of successful recovery. Accurate lab testing removes uncertainty, providing clear insights into your health status.
Q: What tests are essential for assessing iron overload?
A: Begin with a serum ferritin test, which reveals how much iron your body stores. For a comprehensive view, consider an iron panel, Complete Blood Count (CBC), gamma-glutamyl transferase (GGT), and a metabolic panel to fully evaluate your iron levels and overall health risks.
Q: Why is it important to monitor cortisol and testosterone levels?
A: Cortisol levels reflect stress and inflammation, significantly influencing aging, muscle health, and immune function. Testosterone is linked directly to mortality risk, cardiovascular health, and overall vitality. Regularly testing these hormones helps detect and manage imbalances early, protecting your long-term health.
Q: How can you accurately assess your thyroid health?
A: Traditional testing methods, like TSH levels or basal body temperature alone, often fail to identify underlying thyroid conditions such as Hashimoto’s thyroiditis. Testing thyroid antibodies (TgAb and TPOAb), along with a comprehensive panel (TSH, T3, T4, reverse T3, cholesterol), provides a clearer picture and helps target autoimmune-related thyroid issues.
Q: How do NAD+ and gut microbiome tests contribute to overall wellness?
A: Measuring NAD+ indirectly through redox balance markers provides critical insights into mitochondrial and cellular health, influencing energy and metabolic functions. Gut microbiome testing identifies beneficial and harmful bacterial strains, guiding informed dietary and lifestyle adjustments. Both tests are designed to be affordable, accessible, and offer actionable results for improving overall wellness.
High Blood Sugar — Are We Missing Half the Story? The Role of Reductive Stress
Reproduced from original article:
https://articles.mercola.com/sites/articles/archive/2025/03/15/high-blood-sugar-reductive-stress.aspx
Analysis by Dr. Joseph Mercola March 15, 2025
STORY AT-A-GLANCE
- High blood sugar in Type 2 diabetes overwhelms cellular machinery like a chaotic factory, creating not just oxidative stress as previously thought, but also a more fundamental problem called reductive stress. Reductive stress occurs when there’s an oversupply of electron-carrying molecules in cells, creating a “traffic jam” of electrons that can’t be processed efficiently by the mitochondria’s electron transport chain
- While traditional views focused on oxidative stress alone, scientists now understand that reductive stress actually triggers oxidative stress. It’s the initial spark that sets off a chain reaction of cellular damage in diabetic conditions
- When the main pathway for processing glucose becomes blocked due to reductive stress, sugar molecules get diverted into harmful alternative pathways, creating additional toxic byproducts and inflammation
- The combination of reductive and oxidative stress explains many serious complications of diabetes including neuropathy, retinopathy, nephropathy and cardiovascular problems — all stemming from this initial electron overload
- Understanding reductive stress offers new therapeutic possibilities. Instead of just focusing on lowering blood sugar or fighting oxidative damage after it occurs, effective treatments target the electron transport chain efficiency and/or help cells recycle NADH more effectively
Visualize a huge workshop in your body that never stops working. Every second of the day, this workshop — your cells — transforms the food you eat into the energy and building blocks you need to survive. Picture endless supplies of raw materials being delivered to this workshop. When the workshop receives exactly what it needs, it hums along smoothly, producing vital components and discarding waste at a comfortable pace.
But when it is flooded with more resources than it can handle, chaos develops that reminds you of an old “I Love Lucy” episode. Conveyor belts clog, half-finished products pile up and machines begin malfunctioning. That chaos mirrors what happens inside your cells when you have chronically high blood sugar or otherwise known as Type 2 diabetes.
Scientists once focused on how too much sugar in your bloodstream creates damage through something called oxidative stress — an onslaught of destructive, oxygen-containing molecules. While that is important, a more serious stealth problem — reductive stress — turns out to be the main problem.1 For an easy-to-understand overview of what reductive stress is, and how it’s caused, see “Redox Simplified, Part 1.”
Reductive stress was first reported in the literature just before 1990 and is only relatively recently appreciated.2 It is at least as significant as oxidative stress for explaining why your cells lose their balance under conditions of prolonged high blood sugar. Reductive stress is the hidden spark that sets off a harmful chain reaction, eventually leading to severe problems for cells, tissues and organs.
Type 2 diabetes is frequently described as a disease of “overnutrition.” People consume more caloric energy than their bodies know what to do with, so cells try to cope with that oversupply. Insulin is the hormone that helps move sugar from the bloodstream into cells for use or storage.
This sugar is primarily glucose — a simple sugar that is chemically identical to what’s sometimes called dextrose, especially when you find it as a commercially available product in a store or used in IVs. In the early stages of Type 2 diabetes, cells grow resistant to insulin’s signal, making them slow to remove excess sugar from circulation.
However, in the late 1980s, scientists began to understand that there was another, more significant explanation beyond overnutrition. They couldn’t fully explain the observed pathologies solely based on excessive nutrient intake.
While overnutrition can contribute to health problems, more commonly, we see a disruption in the cellular machinery responsible for metabolizing fuel. Essentially, the “furnaces” within cells, the mitochondria, become less efficient at burning fuel. This diminished capacity to use fuel effectively leads to a buildup of harmful byproducts and, ultimately, cellular damage.
Why Overly High Sugar Leads to Reductive Stress
Many researchers once blamed only oxidative stress for the damage caused by chronic elevated blood sugars, but the story is far more complex. A less publicized culprit called reductive stress occurs when there is an oversupply of special electron-carrying molecules in your cells.
• Too much electron-carrying molecules in your cells — One of the key carriers is NADH, which picks up electrons when sugar is broken down for energy. Ordinarily, NADH unloads its electrons in the electron transport chain (ETC) of your mitochondria. When you have too much sugar around, your metabolic pathways generate more NADH than your cells can handle. This oversupply forms a traffic jam of electrons stuck in your mitochondrial ETC.
• The impact of excess NADH — During normal metabolism, oxygen in your mitochondria eventually accepts electrons from carriers like NADH, letting ATP and water form. However, if NADH is piling up too fast or is not being recycled quickly enough, your mitochondria reach a bottleneck and start leaking electrons onto oxygen in erratic ways. That partial reaction creates a reactive oxygen species called superoxide.
• Having excess NADH causes reductive stress — This sets off a cascade that leads to excessive oxidative stress. The two stresses work hand in hand — they both push the system toward an oxidative meltdown. Realizing that they are connected helps explain many of the complications tied to long-term high blood sugar.
Cells also have backup carriers like NADPH and glutathione, which help defend against or fix routine oxidative damage. But when you have high blood sugar, these carriers are also thrown off balance, sometimes contributing further to reductive stress. So, what should be a finely tuned assembly line of electrons becomes a crowded, poorly managed factory.
How Mitochondria and Enzymes Suffer Under Excess Sugar
Under healthy conditions, most sugar flows through glycolysis and then the Krebs cycle in your mitochondria, leading to a steady generation of NADH for ATP production. In a state of chronically high blood sugar, a steady flood of sugar pours in, leading to overly high rates of NADH production.
• Influx of sugar creates electron pressure — Pancreatic beta cells and liver cells are particularly vulnerable because they possess an enzyme called glucokinase, which does not slow down as sugar accumulates. It just keeps stuffing sugar into the mill, generating more pyruvate and acetyl-CoA, and eventually too much NADH.
This leads to what some researchers call electron pressure. Think of it as building water pressure in a dam. The more NADH, the more “water” is pushing against the gates of the electron transport chain. If the gates can’t relieve that pressure quickly enough, water (electrons) spills out in harmful ways, forming superoxide and other reactive oxygen species (ROS).
• Rethinking the accepted causes of oxidative stress — Though we typically consider fat metabolism or the lack of antioxidants to be reasons for oxidative stress, it is actually an overabundance of these electron carriers, like NADH, that triggers these chains of events.
• Low oxygen consumption occurs — Low oxygen usage in cells, sometimes referred to as pseudohypoxia, can also happen under these conditions. Even though oxygen might be physically present, the cell’s ability to use that oxygen effectively stalls when electron carriers accumulate. It’s the same effect as having enough workers on an assembly line but not being able to move products forward because the packaging stations are jammed.
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When Reductive Stress Morphs Into Oxidative Damage
Too much NADH sets the stage for oxidative stress, but how does that transition really happen?
• The process behind excess NADH creation — The mitochondria’s Complex I tries to oxidize NADH — basically convert it back to NAD+ — but an overwhelming influx of NADH leads to partial electron leaks onto oxygen, generating superoxide.
• Superoxide transforms into more harmful substances — The superoxide easily transforms into other even more hazardous molecules, such as hydrogen peroxide or hydroxyl radicals, intensifying the cell’s damage. Hence, reductive stress is the fuse that ignites oxidative stress.
Researchers used to think of oxidative stress and reductive stress as opposites, but in fact, you can’t get a huge wave of oxidative molecules without first bottling up too many electrons somewhere upstream. The meltdown occurs when all these unwanted oxygen-based molecules assault proteins, lipids and genetic material within cells, blocking regular functions and straining the system further.
How Key Enzymes Become Blocked, Triggering Toxic Side Routes
Glyceraldehyde 3-phosphate dehydrogenase, or GAPDH, is an important enzyme in glycolysis. You can think of it as a traffic cop, directing the flow of carbon units down the main route for energy production.
• Reductive stress roadblocks GAPDH — In reductive stress conditions, superoxide and other reactive molecules can chemically inactivate GAPDH, jamming the normal route. That means partially digested sugar fragments accumulate, searching for an escape route. If the main road of glycolysis is blocked, these fragments slip into alternative pathways — often called branching pathways.
• Examples of branching pathways — One of the branches is the polyol pathway, where sugar is first turned into sorbitol and then into fructose. This route increases NADH and drains NADPH, leaving the cell less capable of defending against oxidative threats. Another branch is the hexosamine pathway, which decorates proteins with sugar-like attachments and can promote even more harmful byproducts.
A third branch leads to the creation of advanced glycation end products, lumps of sugar stuck onto proteins that distort them and spark inflammation.
Each of these side roads ends up producing or amplifying reactive oxygen species, so the cell quickly finds itself in an escalating cycle — high sugar leads to reductive stress, which leads to oxidative stress, which damages enzymes, forcing leftover sugar into toxic detours, fueling even more oxidative stress.
• Diabetes is the result — The cyclical meltdown causes the hallmark problems of diabetes — nerves lose function (neuropathy), eyes develop vision problems (retinopathy), kidneys fail (nephropathy) and blood vessels clog or weaken (leading to strokes, heart attacks and amputations). It’s a chain reaction that starts from too much sugar and too many electrons in the wrong place at the wrong time.
The following graph, Figure 4 from Liang-Jun Yan’s paper, “Pathogenesis of chronic hyperglycemia: from reductive stress to oxidative stress,”3 published in the Journal of Diabetes Research in 2014, illustrates this process.
Consequences for People with Diabetes and Recommended Solutions
As chronic hyperglycemia persists, cells get battered by waves of destructive molecules. This environment disrupts insulin secretion, lowers insulin sensitivity and robs tissues of normal functioning. Measuring such damage often shows high levels of oxidative stress in people with poor sugar control, reinforcing that the end result of reductive stress — excess electron carriers — translates into extensive oxidative harm.
• There is a glimmer of hope — If the fundamental problem is that NADH builds up too fast, then reducing or balancing that electron overload might prevent later catastrophes.
• Addressing the root problem of diabetes — While many diabetes treatments focus on lowering blood sugar in general, or on cleaning up ROS after they form, what we really need are strategies to either curb the production of extra NADH or help cells recycle NADH back to NAD+ more efficiently.
• Other strategies that help manage diabetes — Some researchers suggest that strengthening the electron transport chain, or using dietary or pharmaceutical interventions that enhance NAD+ regeneration, can short-circuit the entire cascade before oxidative stress goes wild.
In simpler language, controlling reductive stress means improving the traffic flow of electrons in the cell, ensuring they don’t stack up to dangerous levels. If you manage the electron flow at the front end, you reduce the chance of harmful chain reactions downstream.
Putting It All Together — Why Reductive Stress Matters So Much
Prolonged high blood sugar is definitely toxic to cells, but we now see that the toxicity operates through a two-phase process — first, reductive stress (an electron overload), then oxidative stress (excess oxygen-based radicals) finalizes the damage.
• Oxidative stress is just one piece of the puzzle — The statement above modifies the classic narrative that only oxidative stress is to blame. Recognizing how reductive stress kindles oxidative stress helps us see that lowering sugar might not be enough; we also need to keep watch on the entire electron-handling machinery within cells.
• Reductive stress must be detected earlier — One of the big questions is why reductive stress has been overlooked for so long if it’s so central. Part of the answer is that oxidative stress is easier to detect with standard lab tests and known chemical markers, whereas reductive stress is more subtle, only revealing itself in how the electron carriers build up.
Also, reductive stress was first documented decades ago and then largely forgotten, overshadowed by the simpler story of oxygen-based radicals. Only with improved technologies and a deeper dive into electron transport chain dynamics did researchers rediscover how an oversupply of NADH or NADPH can disrupt everything.
In everyday life, the main message remains consistent — keep blood sugar under control to protect your cells from a damaging cascade.
• Strategies to address reductive stress — Good nutrition, exercise and regular medical check-ups all form part of the frontline in preventing reductive stress from flaring into full-blown oxidative chaos.
• The importance of studying reductive stress — Long term, the real advantage in understanding reductive stress is that it offers a new angle — one that goes beyond the usual talk of high sugar and ROS. By targeting the earliest link in the chain, you can knock out multiple problems at once, safeguarding insulin production, reducing inflammation and preserving healthy organ function.
Supplements That May Help Address Reductive Stress
Several nutritional supplements can be helpful in this regard, including the following:
• Coenzyme Q10 (CoQ10) / Ubiquinol:
◦ Mechanism — CoQ10 is a vital component of the ETC in mitochondria. It acts as an electron shuttle, helping to move electrons along the ETC and facilitate ATP production. In its reduced form, ubiquinol, it can also act as an antioxidant.
◦ Relevance to reductive stress — By improving the efficiency of the ETC, CoQ10 may help to prevent the buildup of NADH and the subsequent leakage of electrons that leads to reductive stress.
• Alpha-lipoic acid (ALA):
◦ Mechanism — ALA is a potent antioxidant that can also regenerate other antioxidants, such as vitamin C and glutathione. It also plays a role in mitochondrial energy metabolism.
◦ Relevance to reductive stress — ALA’s antioxidant properties can help to mitigate the oxidative damage that results from reductive stress. It may also indirectly support the ETC by regenerating other antioxidants involved in the process.
◦ Note — ALA exists in two forms (R-lipoic acid and S-lipoic acid), and the R form is generally considered more biologically active.
• Methylene blue:
◦ Mechanism — Methylene blue acts as an alternative electron acceptor in the ETC, effectively bypassing Complex I and III. It can cycle between its oxidized and reduced forms, shuttling electrons directly to cytochrome c and oxygen, improving mitochondrial function even when the standard electron transport chain is impaired.
Methylene blue’s ability to accept electrons makes it particularly useful in conditions where the standard ETC is overwhelmed or dysfunctional.
◦ Relevance to reductive stress — By providing an alternative route for electron flow, methylene blue helps relieve the electron congestion that characterizes reductive stress. It effectively acts as an “electron pressure release valve,” helping to prevent the buildup of NADH and reducing the likelihood of electron leakage and subsequent oxidative damage.
• Pyrroloquinoline quinone (PQQ):
◦ Mechanism — PQQ is a potent antioxidant that has been shown to stimulate mitochondrial biogenesis (the creation of new mitochondria).
◦ Relevance to reductive stress — By increasing the number of mitochondria and improving their function, PQQ enhances the cell’s overall capacity to handle electron flow and reduce the likelihood of reductive stress.
• Riboflavin (B2), niacinamide (B3) and thiamine (B1):
◦ Mechanism — B vitamins play essential roles as coenzymes in various metabolic pathways, including those involved in energy production and the ETC. Riboflavin is a precursor to FAD, and niacin is a precursor to NAD. Both are electron carriers.
◦ Relevance to reductive stress — Adequate levels of B vitamins are essential for the proper functioning of the ETC and may help to prevent the buildup of reducing equivalents.
Frequently Asked Questions (FAQs) on Reductive Stress and Type 2 Diabetes
Q: What is reductive stress, and how does it relate to Type 2 diabetes?
A: Reductive stress occurs when cells accumulate too many electron-carrying molecules, such as NADH, due to prolonged high blood sugar levels. This overload creates a bottleneck in the mitochondria, leading to an imbalance that ultimately triggers oxidative stress. In Type 2 diabetes, excessive sugar intake overwhelms the metabolic system, causing a cascade of harmful effects that damage cells, tissues and organs.
Q: How does reductive stress contribute to oxidative stress and cellular damage?
A: When NADH builds up in cells, it overwhelms the electron transport chain (ETC) in mitochondria, leading to electron leakage. These leaked electrons react with oxygen to form harmful reactive oxygen species (ROS) like superoxide and hydrogen peroxide. This oxidative damage disrupts cellular processes, impairs insulin function and contributes to complications like neuropathy, retinopathy and kidney disease.
Q: Why is reductive stress often overlooked in diabetes research?
A: Traditionally, scientists have focused on oxidative stress as the primary cause of cellular damage in diabetes. However, newer research shows that reductive stress precedes oxidative stress and acts as the initial trigger. The difficulty in measuring reductive stress and its more subtle effects led to its underappreciation for decades, but advances in mitochondrial research have revived interest in its role.
Q: What strategies can help manage reductive stress in Type 2 diabetes?
A: Managing blood sugar levels through a healthy diet and exercise supervision is key to preventing reductive stress. Additionally, certain supplements, such as coenzyme Q10 (CoQ10), alpha-lipoic acid (ALA) and methylene blue may help manage reductive stress and prevent oxidative damage.
Q: How do supplements like CoQ10 and alpha-lipoic acid help with reductive stress?
A: CoQ10 improves mitochondrial function by facilitating electron transfer in the ETC, reducing the buildup of NADH. Alpha-lipoic acid (ALA) acts as an antioxidant and helps regenerate other protective molecules like glutathione. Both supplements aid in restoring cellular balance, reducing oxidative stress and improving insulin sensitivity in people with diabetes.
Redox Reactions Simplified, Part 1
Reproduced from original article:
https://articles.mercola.com/sites/articles/archive/2025/02/03/redox-reactions-simplified-part-1.aspx
Analysis by Dr. Joseph Mercola February 03, 2025
STORY AT-A-GLANCE
- Redox reactions are continuous exchanges of electrons between molecules in your body, similar to passing negatively charged water balloons, and these reactions are essential for basic functions like moving, thinking, and processing food into usable energy. When molecules gain electrons through redox reactions, they become “reduced” with a lower charge, while molecules that lose electrons become “oxidized” with a relatively higher charge. This process always happens in pairs, as one molecule must receive the electrons another gives away
- Your body maintains a delicate balance of electron exchanges. Too many electrons being passed around too quickly or incorrectly will damage cells, leading to a harmful condition called oxidative stress
- NAD+ is arguably the most vital molecule in your body, acting like a taxi service that carries electrons throughout your cells. Without NAD+, your cells cannot convert food into energy, repair DNA damage, or maintain proper cellular communication
- Mitochondrial damage from toxins like seed oils, microplastics, and EMFs create “reductive stress,” where electron carriers (like NADH) get stuck and cannot properly transfer their electrons, leading to reduced NAD+ levels and cellular dysfunction
- While expensive NAD+ boosting supplements exist, maintaining healthy NAD+ levels can be achieved more affordably through proper niacinamide (vitamin B3) supplementation and, most importantly, by avoiding substances that damage mitochondria
Have you ever seen someone walking on a tightrope in the circus, carefully keeping their balance so they do not fall off? That is a little like what happens inside your body every day, except instead of a person balancing on a rope, your cells are balancing something called redox reactions. The word “redox” might sound fancy, but it is just short for two smaller words: reduction and oxidation.
These redox reactions happen continuously to help you stay healthy, move around, think clearly, and even sleep. When you eat an apple or a sandwich, your body has to take the energy that is stored in your food and turn it into a form your cells can use. But before we go further, let’s talk about what an electron is, since it plays a big part in redox reactions.
Understanding Electrons
You can think of an electron as an extremely small particle that orbits around the center of an atom. Atoms are like tiny building blocks that make up everything around you, including your body, the water you drink, and even the air you breathe.
Electrons carry a negative charge, a bit like a tiny battery that has a minus sign on it. When one atom or molecule passes an electron to another, it is as if they are handing over a piece of that negative charge. This exchange of electrons happens continuously in your body, even though you cannot see, hear, or feel it.
Electrons might seem like they are too small to matter, but they are very important. They are involved in every chemical reaction that keeps you alive, from breaking down your food to helping your muscles move. In a way, electrons are the sparks that keep your body’s engine running. If you did not have these sparks, your body would not have the energy it needs to do everyday things, like walking up the stairs or even thinking about what you want to have for lunch.
Your Body’s Balancing Act
That is where redox reactions step in. Think of them as a super-organized chain of events, where one molecule passes along these tiny, negatively charged electrons to another molecule. Since electrons are negative, if a molecule gains electrons, its overall charge goes down, and we say it’s been reduced. It’s an easy way to remember it: gaining negative electrons = reduced charge.
On the other hand, the molecule that loses electrons has lost some of that negative charge, so its charge becomes relatively higher, or more positive, and we say it’s been oxidized. This process always happens in pairs: if one molecule is giving away negative charges (getting oxidized), another molecule has to receive them (getting reduced).
You can imagine if too many electrons get passed around too fast or in the wrong way, bad things will happen in your body. Just like Goldilocks, you need just the right amount of electrons being passed at the right time. The moment your body loses this careful balance, trouble can happen, and cells will get hurt.
Fortunately, you have many helpers that keep your redox balance under control, sort of like friends who take care of you when you’re in trouble. These helpers make certain that your cells do not get overwhelmed by too many or too few electrons flying around. Sometimes people refer to this important balance as your “redox status,” which simply means how healthy and stable your cells are when it comes to these tiny electron exchanges.
By understanding the basics of redox, you begin to see how your body manages energy and protects itself from harm. It is a lot like learning the ABCs or the multiplication tables: you need to know the words and understand their meanings before you can really comprehend the bigger picture. Once you grasp how redox works, you will also discover how things like good food, rest, and exercise help your body stay in tip-top shape.
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Understanding Redox in Simple Terms
Let’s dive a little deeper into redox reactions without making it too complicated. Picture a group of friends passing water balloons that have a negative charge and you are around a circle on a hot day. If someone hands you a water balloon, you have gained that the negative charge of balloon (reduction), and if you hand that balloon off to someone else, you have lost negative charge (oxidation).
Every time a water balloon leaves you, it goes to another person. There is always an exchange: you cannot have one friend lose a water balloon unless another friend is there to catch it. That is exactly how electrons move around when we talk about redox. In your body, these water balloons are electrons that carry energy from one place to another.
So why does this matter? Because the exchange of electrons is what gives you the energy to do everything from talking and reading to kicking a soccer ball. Every time you move a muscle, your cells are using energy that came from these redox exchanges.
Now, if too many electrons get lost in the wrong place, your cells can be harmed by something called oxidative stress.
Oxidative stress is like having too many bursting water balloons soaking everything around them. But your body has a team of special molecules called NAD+ and NADH to handle this. They scoop up extra electrons when needed and hand them out when cells are running low. These molecules work closely together, making sure things run smoothly and you do not have water balloon chaos. You might wonder: how does all of this help you in daily life?
Well, if you know about redox, you can choose foods and activities that help your body’s balance. When you make good choices, like eating fresh fruits, veggies, and protein, plus getting proper rest, these are like giving your water balloon team the perfect tools and instructions so the balloon passing never turns into a wet and wild mess.
Little by little, the more you learn about redox, the more you realize it affects everything from how awake you feel to how quickly you recover from a cold.
NAD+ and NADH — The Electron Taxis — Your Body’s Most Valuable Players
To keep things simple, think of NAD+ and NADH as a taxi service that travels around inside your cells. NAD+ is like the empty taxi, waiting for passengers, while NADH is like the taxi that is full of passengers. But who are the passengers? They are electrons, those tiny, negatively charged particles we talked about.
When NAD+ picks up electrons, it becomes NADH, fully loaded and ready to drive. Once those electrons are delivered to the right place, NADH goes back to being NAD+. This is like the taxi dropping off passengers, then returning to pick up more.
But here’s something really important to understand: NAD+ isn’t just any carrier molecule. It’s arguably the most important carrier molecule in your entire body, and one of the most important molecules, period! It’s like the MVP of your cell’s energy team. In fact, having high levels of NAD+ is one of the best signs of good health that you could possibly have.
Why Is NAD+ So Incredibly Important?
NAD+ is absolutely essential for your body to make energy. Without enough NAD+, your cells can’t efficiently convert the food you eat into the energy they need to function. It’s like trying to run a car with barely any gas — it just won’t work! Your mitochondria simply cannot make ATP without NAD+. No matter how much high-quality food you are eating, it is impossible to convert it to energy without NAD+.
While discussing the vital role of NAD+ in cellular energy production, it’s interesting to consider a theoretical scenario: what if you could magically completely and instantaneously remove NAD+ from your body? If your NAD+ levels were to suddenly drop to zero, the consequences would be even more immediate and catastrophic than cyanide poisoning.
Cyanide is of the most rapidly acting poisons as it stops ATP production and causes rapid cell death, typically within minutes. NAD+ depletion, however, would have a far broader impact. NAD+ is not only essential for multiple steps in energy production — including glycolysis, the Krebs cycle, and the electron transport chain — but it’s also vital for DNA repair, cellular signaling, and immune function.
A sudden loss of NAD+ would be like cutting off the entire city’s fuel supply and its ability to repair infrastructure, communicate, or defend itself.
Yes, NAD+ is also crucial for repairing your DNA. You can think of your DNA as the instruction manual for your body. This instruction manual gets damaged all the time, and NAD+ is essential for fixing that damage. It’s like having a construction crew constantly fixing potholes in the roads, keeping everything running smoothly.
Without enough NAD+, the damage builds up, which can lead to serious problems. There are enzymes called PARPS that repair DNA and they can’t work without NAD+.
NAD+ is also involved in communication within and between your cells. It helps cells talk to each other and coordinate their activities. It’s like a cell phone network that allows all the different parts of your body to stay in touch. The sirtuin enzymes use NAD+ to send signals throughout the cell. Finally, NAD+ plays a role in keeping your immune system strong and healthy, helping you fight off infections and stay well.
Because NAD+ is involved in so many vital processes, having high levels of it is like having a well-oiled, finely tuned machine. It means your cells have the resources they need to produce energy, repair damage, communicate effectively, and keep you healthy. Low NAD+ is like having a low battery.
Keeping Your NAD+ Taxis Running Strong and Avoiding Reductive Stress
Without these electron taxis, your cells would not have the fuel they need to run properly. Your body becomes tired and less able to fix problems. So how do you keep those NAD+ taxis running at full capacity? One of the best ways is to avoid the things that damage your mitochondria and lead to reductive stress. Remember that traffic jam of electrons we talked about? That’s reductive stress, and it’s a major drain on your NAD+ levels.
When your mitochondria are damaged by things like seed oils, microplastics, EMFs, and other toxins, the complexes can’t process electrons properly. The electron taxis (NADH) get stuck, unable to drop off their passengers (electrons) and turn back into empty taxis (NAD+).
When you have a lot of reductive stress, it forces NAD+ to accept electrons, turning it into NADH. But if there is nowhere for NADH to go, it can’t perform its useful functions and you run low on NAD+. This is like having a whole fleet of taxis stuck in traffic, unable to pick up new passengers. To avoid this, the most important thing you can do is to avoid those mitochondrial poisons.
By treating your body kindly — sleeping well, eating balanced meals, exercising, and, most importantly, avoiding things that damage your mitochondria — you can keep this taxi service in top shape and prevent those harmful electron traffic jams. That means more energy for you to learn new things, work and play, and stay healthy for a long time to come. NAD+ is truly a superstar molecule, and keeping its levels high is one of the best things you can do for your health.
A Word About NAD+ Boosters
You might hear about fancy new supplements, like NMN or NR, that claim to boost your NAD+ levels. These are like high-tech upgrades to the taxi system. While they might offer some benefits, they are also very expensive, and scientists are still learning about how well they truly work.
The truth is, you don’t need a high-tech upgrade to keep your NAD+ taxis running smoothly. A simple, much cheaper option is to make sure you have enough niacinamide, a form of vitamin B3. Niacinamide is the fuel that helps your body make its own NAD+. Taking a small amount of niacinamide a few times a day (around 50mg, three times a day is a good starting point for adults) can be a very effective way to support your NAD+ levels without breaking the bank.
It’s like making sure your taxis have enough fuel to keep running efficiently, rather than buying a whole new fleet of expensive cars. The most important thing is to keep your mitochondria healthy by avoiding those harmful toxins we talked about! That is what will keep your NAD+ levels high and your cells running smoothly.
More Players in the Redox Game — A Glimpse Into the Future
We’ve talked about the main players in the redox game — those electron taxis (NAD+/NADH) and how important they are. But just like any good team has backup players, your body has other molecules that help with carrying electrons and keeping things balanced.
There’s actually a whole team of these electron carriers, each with its own special job. We talked about the main one: the electron taxis (NAD+/NADH).
There are also helpers that build things in your body and clean up messes, like a different kind of taxi service (NADP+/NADPH) — you can think of them as specialized workers that keep your cells in good shape — and the super cleaners (GSH/GSSG), the quick responders that can recycle energy (lactate/pyruvate). There are even emergency fuel reserves (acetoacetate and beta-hydroxybutyrate).
All of these helpers are really important for keeping your redox reactions in balance. They are like the supporting cast in a play — they might not always be in the spotlight, but the show couldn’t go on without them!
Now, you don’t need to memorize all these names, but it’s good to know they exist. These are things you might learn more about later, especially if you’re interested in health and how your body works. In fact, if you ever decide to get your health tested in the future, these are some of the things you might look at to see how well your redox system is functioning.
It’s like checking the oil in your car — these tests can show if your cellular engines are running smoothly, or if there might be a traffic jam forming. It is important to know that the best way to keep these players working well is to avoid the things that damage your mitochondria, like those harmful seed oils.
NADP+ and NADPH — The Builders and the Cleaners
Now let’s meet the close cousins of NAD+ and NADH, called NADP+ and NADPH. You can think of these two as a slightly different taxi company, but instead of just carrying passengers to the powerhouse, they also deliver supplies to your body’s building crew.
NADPH can carry electrons that help build important things in your body, like fats that you store for energy and hormones that help you grow. Then, once the job is done, NADPH can become NADP+ again, ready to pick up a new load of electrons.
But that is not all NADPH does. It is also part of your body’s cleaning crew. Sometimes, nasty molecules called free radicals pop up. Free radicals are like rowdy troublemakers who knock things over if left alone for too long. If these troublemakers are not kept in check, they can damage your cells.
NADPH steps in, giving electrons to special substances that neutralize the free radicals, turning them into calmer molecules that will not wreck your cell’s furniture. It is a bit like using a fire extinguisher to stop sparks from turning into a bigger fire.
Because NADP+ and NADPH do both building and cleaning, they are absolutely essential to keeping your body’s overall redox system balanced. Whenever you hear someone talk about getting enough vitamins and antioxidants, you can think of how these helpers team up with NADPH. With the right support, your body’s building projects go well, and your cleaning crew can handle any messes that arise.
When these processes work smoothly, you feel better, look healthier, and have the energy to handle all the fun and challenges life throws your way.
FAD and FADH2 — The Delivery Trucks
Next are FAD and FADH2, which you can imagine as big delivery trucks that move cargo around your body. FAD is like an empty truck, and FADH2 is the truck when it is loaded with electrons. While NAD+ and NADH are the main taxis, FAD and FADH2 help carry extra energy from important places like your food to the powerhouse in the cell.
FAD becomes FADH2 when it picks up electrons, then drives them to your mitochondria — often called the power plant of the cell because that is where most of your energy gets produced. After the delivery is done, FADH2 returns to being FAD, similar to a truck that empties its cargo and heads back for more.
You might ask, why do we need both NADH and FADH2? Think of them as two different lanes on the same highway. One lane might lead you to one part of the city, while the other lane leads you to another. Your body’s redox world is big, and there are multiple routes to deliver energy to where it needs to go. Each route is specialized for different tasks, making sure that everything is efficient. That is one of the reasons you can run fast in a soccer game or focus while reading a tough book.
FAD and FADH2 are also found inside enzymes that are part of your body’s bigger energy-making cycle. This cycle works best when you have good nutrition, enough rest, and moderate exercise. If you skip on these, your delivery trucks might slow down, leading to low energy and an imbalance in the redox system. This is yet another reason why daily choices about food and activity are so crucial. You want all your trucks on the road and ready for action, right?
GSH and GSSG — The Glutathione System
Up next, GSH and GSSG. Think of these molecules as a super cleaning solution and the dirty mop water after you have cleaned up a mess. GSH, which stands for reduced glutathione, is the cleaning solution. GSSG, which is oxidized glutathione, is what GSH becomes after it has cleaned up. Your body often uses GSH to tackle free radicals, those troublemakers that can damage cells if left unattended.
When GSH meets a free radical, it uses its electrons to calm it down. In the process, GSH gets transformed into GSSG, a bit like a mop that has soaked up all the dirt.
But do not worry — your body has a system to recycle GSSG back into GSH, so the cleaning can continue. This recycling mostly happens in your liver, which is like the big cleaning headquarters. If your liver runs low on supplies, your glutathione system might not work so well, and that means free radicals can start to run wild. That can lead to harm to cells and even more serious issues over time.
Why should you care about GSH and GSSG? Imagine never cleaning your home. Before long, you would be tripping over old mail and dirty clothes, and it would be hard to find anything. In a similar way, if your body does not stay on top of cleaning out free radicals, your cells get clogged with gunk and can’t function properly.
By knowing about glutathione, you get a peek into how your body fights off everyday stress and keeps everything running smoothly. Eating foods rich in nutrients can help your body produce more GSH, giving you a stronger cleaning crew.
Lactate and Pyruvate — The Energy Recyclers
Have you ever run really fast and felt your muscles start to burn? That burning feeling can happen when your body is making a lot of energy quickly, and it starts producing something called lactate. Lactate and pyruvate are like two sides of a coin in your body’s energy bank.
Pyruvate is created when your body breaks down sugar. When your muscles need energy super-fast — like during a sprint — pyruvate turns into lactate. This process helps keep the energy flowing even if you cannot get enough oxygen quickly enough.
Later on, when you calm down and breathe easier, lactate travels to your liver and transforms back into pyruvate. Your liver then uses pyruvate to make more glucose to keep producing energy. It is almost like the body’s own recycling center, collecting used materials (lactate) and turning them back into something useful (pyruvate or glucose). By switching between lactate and pyruvate, your cells also help balance the NAD+ and NADH system.
That is because every time pyruvate turns into lactate, NADH can let go of electrons, returning to NAD+, which is then ready to do more work.
If you had no way to recycle lactate back to pyruvate, your muscles would tire out quickly, and you would have trouble doing everyday tasks, let alone playing sports. Even though lactate can make your muscles feel a bit sore, it is a sign that your body is working hard. Once you rest and breathe deeply, your recycling system helps clear the lactate away, so you can get back to feeling normal.
This cycle shows that the body is amazingly clever at making the most of what it has, ensuring no energy goes to waste.
Acetoacetate and Beta-Hydroxybutyrate — The Emergency Fuel
Sometimes your body does not get enough sugar from food, especially if you have not eaten in a while or if you are following a low-carb diet. In these cases, your body turns to an emergency plan: it starts breaking down fat for fuel.
When fat is broken down, your liver makes molecules called ketone bodies. Two of the main four carbon ketone bodies are acetoacetate and beta-hydroxybutyrate. Think of them as emergency batteries that keep your brain and muscles going when glucose, your regular battery, is in short supply.
Your liver is the only organ that can make these ketone bodies. This means your liver acts like a factory that can produce spare batteries whenever you need them. Acetoacetate and beta-hydroxybutyrate can travel to your brain, which usually loves sugar, and give it an alternative form of energy. It is as if your body says, “No sugar? No problem! We have backup fuel right here.”
This can be a lifesaver when you are running low on carbohydrates. But while this strategy works well as a backup, you have to be careful not to use it long term because it can cause you to lose muscle mass. Why’s that? Because the only way it can be used is when you activate stress hormones that break down muscle protein and transform it into glucose.
Ketone bodies also affect the redox balance by helping shift NAD+ and NADH levels in your liver. If you have too many of certain byproducts hanging around, it can throw off your redox status. By making acetoacetate and beta-hydroxybutyrate, your liver keeps everything in balance.
Remember, though, that this is an emergency plan, not your body’s first choice. Your body likes having enough healthy carbohydrates so it does not need to rely on ketone bodies all the time. But it is comforting to know that if you skip a meal or do not have easy access to food, your cells can switch gears and keep going with help from these amazing emergency fuels.
Putting It All Together — Your Body’s Electron Dance
Throughout Part 1, we’ve explored the fascinating world of redox reactions — the continuous exchange of electrons that keeps your body running. We’ve met the key players: the electron taxis (NAD+ and NADH), the delivery trucks (FAD and FADH2), the builders and cleaners (NADP+ and NADPH), and even the emergency fuel system (acetoacetate and beta-hydroxybutyrate). Each of these molecules plays a crucial role in maintaining the delicate balance of electrons in your cells.
Remember that NAD+ is arguably the most important molecule in your body, acting like a tireless taxi service that ensures electrons get where they need to go. Without enough NAD+, your cells can’t convert food into energy, repair DNA damage, or maintain proper communication.
We’ve learned that while expensive NAD+ boosting supplements exist, the most effective way to maintain healthy NAD+ levels is through proper niacinamide supplementation and, most importantly, protecting your mitochondria from damage.
But what exactly damages these vital cellular components? And how can we protect them? In Part 2, we’ll dive deeper into understanding what happens when things go wrong with your body’s electron transport system.
We’ll explore how modern industrial changes, particularly the introduction of seed oils and other toxins, can cause your cellular engines to become clogged and inefficient. Most importantly, we’ll learn practical steps you can take to keep your redox system running smoothly, ensuring your cells have the energy they need to keep you healthy and strong.
So, keep an eye out for Part 2, which will be published next week. In it, you’ll discover how to protect and optimize your body’s incredible electron-handling machinery, and why loading up on antioxidants like vitamin C can do more harm than good.
Niacinamide — The Best Supplement to Prevent Skin Cancer
Reproduced from original article:
https://articles.mercola.com/sites/articles/archive/2024/10/01/niacinamide-skin-cancer-prevention.aspx
Analysis by Dr. Joseph Mercola October 01, 2024
STORY AT-A-GLANCE
- Niacinamide (vitamin B3) enhances DNA repair and reduces UV-induced immunosuppression in skin cells, preventing non-melanoma skin cancers
- A large-scale study found higher niacin intake associated with a 16% lower risk of squamous cell carcinoma. Another study showed niacinamide twice daily for 12 months reduced new nonmelanoma skin cancers by 23%
- Niacinamide works by preventing ATP depletion, boosting cellular energy and enhancing DNA repair. It’s particularly beneficial for those with multiple past skin cancers, showing 54% reduction in basal cell carcinomas and 52% in squamous cell carcinomas
- Many studies use 500-mg doses, but caution is advised. Small doses of 50 mg three times daily are better to optimize energy and boost cellular NAD+ levels. Excessive intake may lead to side effects or backfire
- Topical niacinamide offers benefits for acne treatment, sebum reduction, antiaging effects and rosacea management. Oral niacinamide also supports brain health, chronic pain relief, stress protection, vision health and may ameliorate damage from linoleic acid consumption
In the video above, board-certified dermatologist Dr. Andrea Suarez, known online as Dr. Dray, shares some fascinating insights about niacinamide, a water-soluble form of vitamin B3 (niacin), and its benefits for skin health.1
Niacinamide, also known as nicotinamide, is a precursor for NAD+, which is not only involved in the conversion of food to energy but is also important in the process of repairing damaged DNA. This is crucial because your skin faces constant environmental stressors, including ultraviolet (UV) radiation, which can damage DNA in skin cells and suppress your immune system.
Niacinamide shows promise for skin cancer prevention due to its ability to enhance DNA repair and reduce UV-induced immunosuppression in skin cells. These mechanisms are useful in preventing the development of non-melanoma skin cancers (NMSCs), which include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).
The Promise of Niacinamide for Skin Cancer Prevention
Clinical trials show that taking 500 milligrams (mg) of niacinamide twice daily significantly reduce the incidence of NMSCs in high-risk individuals.2 This news was particularly encouraging for those with a history of skin cancer. However, while many studies for skin cancer prevention use 500-mg doses, caution is warranted.
Niacinamide at a dose of 50 mg three times per day is a better dose and will provide the fuel for the rate limiting enzyme for NAD+, NAMPT. I recommend getting niacinamide in powder form because the lowest available dose in most supplements is 500 mg, and that will decrease NAD+ due to negative feedback on NAMPT, which is the opposite of what you’re looking for.
Other research has shown a beneficial role of niacinamide intake specifically for SCC risk reduction. In one large-scale study involving the Nurses’ Health Study and the Health Professionals Follow-up Study, researchers found that total niacin intake was inversely associated with SCC risk. The pooled hazard ratio was 0.84, suggesting a 16% lower risk of SCC for those with higher niacin intake.3
Niacinamide: Your Skin’s New Best Friend
A study conducted in Australia and published in The New England Journal of Medicine also found that this simple supplement significantly reduces the risk of developing nonmelanoma skin cancers.4 The study, involving 386 high-risk patients, revealed that taking 500 mg of niacinamide twice daily for 12 months led to a 23% lower rate of new nonmelanoma skin cancers compared to those taking a placebo.
This effect was seen in both basal cell carcinomas and squamous cell carcinomas, the two most common types of skin cancer. Again, the benefits of niacinamide were most pronounced in patients who had a history of numerous skin cancers, suggesting it might be particularly helpful for those at higher risk. The best part? Niacinamide is inexpensive, easily accessible as an over-the-counter supplement and comes with minimal, if any, side effects.
In addition to reducing skin cancer risk, niacinamide showed impressive results in decreasing actinic keratoses — precancerous skin lesions that can develop into squamous cell carcinomas. Participants taking niacinamide had 11% fewer actinic keratoses at three months and 20% fewer at nine months compared to the placebo group. This translated to three to five fewer actinic keratoses on average.
The mechanism behind niacinamide’s protective effects lies in its ability to prevent adenosine triphosphate (ATP) depletion and boost cellular energy, enhancing DNA repair. Your cells need ATP for life, repair and regeneration. Niacinamide also reduces UV-induced immunosuppression without altering your baseline immunity, providing a two-pronged approach to skin protection.
Many conventional chemopreventive agents, such as oral retinoids, cause significant side effects like dry skin, increased lipid levels and even liver toxicity. However, niacinamide showed no clinically significant adverse effects in the study. While the study used a dose of 500 mg twice daily, the minimum effective dose for skin cancer prevention is unknown.
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Niacinamide Reduces Skin Cancer in High-Risk Individuals
If you’ve had multiple skin cancers in the past, niacinamide is particularly beneficial for you. A systematic review and meta-analysis revealed that niacinamide’s effectiveness in preventing skin cancers tends to increase for individuals with a higher number of previous skin cancers.5
Niacinamide was effective in reducing both BCCs and SCCs, with a 54% reduction in BCCs and a 52% reduction in SCCs compared to control groups. To reap the full benefits of niacinamide for skin cancer prevention, consistency is key.
Again, the studies showing significant reductions in skin cancers used a dosage of 500 mg twice daily, taken orally for at least 12 months. This regimen appears to be effective for both healthy individuals and organ transplant recipients, who are at higher risk for skin cancers due to immunosuppression.
Niacinamide: A Secret Weapon for Skin Cancer Prevention
Unlike sunscreen, which blocks UV rays, niacinamide works by repairing DNA damage that has already occurred in your skin cells. This means it helps reverse past sun damage and reduce your risk of developing skin cancer, particularly BCC and SCC. As noted in the journal Cureus:6
“By providing the precursor molecules for key components to produce adenosine triphosphate (ATP), nicotinamide also enhances DNA repair by replenishing cellular energy after UV damage. Current research also suggests that nicotinamide plays a role in blocking inflammatory cell activation and influences cell life span, survival, and cancer progression.”
Niacinamide’s skin-protective effects stem from its ability to boost your body’s natural defense mechanisms. When you take niacinamide supplements, you’re providing your cells with the building blocks they need to produce ATP, the energy currency of your cells. This extra energy empowers your skin cells to repair DNA damage more efficiently after UV exposure.
But that’s not all — niacinamide also helps block inflammatory cell activation and influences cell lifespan and survival. This multipronged approach makes it a powerful ally in your skin cancer prevention strategy. It’s a simple addition to your daily routine that could have significant benefits for your skin health.
It’s especially important if you have a history of skin cancer, as studies have shown that many patients with non-melanoma skin cancers often have vitamin deficiencies.7 By addressing these deficiencies, you’re giving your skin the tools it needs to protect itself.
Interestingly, a 2023 study found that patients who believed more strongly in niacinamide’s ability to reduce skin cancer risk were more likely to use it consistently.8 On average, patients perceived that niacinamide could reduce their risk of basal cell carcinoma by 31.2% and squamous cell carcinoma by 30.2%.
Those who were actually taking niacinamide had an even higher perception of its effectiveness, believing it could reduce their risk by 41.2% for BCC and 38.3% for SCC. The researchers noted, “Our results should encourage providers to educate patients and their families on nicotinamide and its link to skin cancer prevention.”9
Too Much Niacinamide Can Backfire
Keep in mind that the niacinamide dosages used in research studies vary widely and can be on the high side. As a general rule, I only recommend taking small doses of 50 mg of niacinamide three times a day.
This dosage has been shown to optimize energy metabolism and boost NAD+ levels, which are foundational for optimal health. It can be taken four times a day if you space them out. Take a dose as soon as you get up, before going to bed, and twice evenly spaced between those times.
The problem with taking too much vitamin B3, whether in the form of niacin or niacinamide, is that it might backfire and contribute to cardiovascular disease10,11 and other side effects. Dray stresses the importance of proper dosage and warned about potential dangers of excessive intake:12
“You can run into dangerous side effects when taking very high doses. You can get into toxic ranges if you take too much. Three and a half grams per day will definitely get you to toxic levels that can damage your liver.”
Other potential side effects of high doses include nausea, vomiting, headache, dizziness and fatigue. There’s also a risk of medication interactions, particularly with carbamazepine. I recommend getting niacinamide in powder form so you can control the dose. Niacinamide will only cost you about 25 cents a month if you get it as a powder. Typically, 1/64 of a teaspoon of niacinamide powder is about 50 mg.
Niacinamide: A Versatile Skincare Ingredient and Overall Health Remedy
While the focus of many studies is on oral supplementation, Dray also touched on the benefits of topical niacinamide in skincare products, noting, “It’s actually very beneficial for a variety of skin issues when applied topically because it’s anti-inflammatory, it’s an antioxidant.”13 She explains that niacinamide applied topically is useful for:14
1. Acne treatment — “Four percent niacinamide is as effective for moderate acne as 1% clindamycin.”
2. Sebum reduction — “Two percent niacinamide gel … decreases sebum production, reducing oiliness and shine.”
3. Antiaging effects — “It’s been demonstrated when applied anywhere from 2% to 4% to help improve the look of fine lines, red blotchiness … It also can improve the appearance of sunspots, help them fade.”
4. Rosacea management — “Niacinamide can improve barrier function and make the symptoms of rosacea … better.”
However, Dray notes that some individuals may find topical niacinamide irritating, especially at higher concentrations. In addition to helping your skin, oral niacinamide also benefits other aspects of health, such as:
- Brain health, including Alzheimer’s disease15
- Chronic pain16
- Stress reduction17
- Vision health, including glaucoma18
- Ameliorate damage caused by linoleic acid (LA) consumption
The last one is particularly important, as one of the most toxic metabolic byproducts of LA is 4 HNE, a toxic aldehyde that appears to play a causative role in heart failure.19 Fortunately, there is an enzyme system called aldehyde dehydrogenases that deactivates 4 HNE.
The best way to increase the activity of this enzyme system is to make sure you have sufficient NAD+, and the most efficient way to optimize your NAD+ level is to make sure you’re getting 50 mg of niacinamide three times a day.
Further, as niacinamide emerges as a promising and versatile compound for skin health and cancer prevention, its ability to enhance DNA repair, reduce UV-induced immunosuppression and decrease the incidence of non-melanoma skin cancers makes it a valuable tool in dermatological care.
While clinical trials have shown significant benefits at higher doses, it’s crucial to approach supplementation cautiously, as excessive intake can lead to adverse effects. The recommended dosage of 50 mg three times daily in powder form strikes a balance between efficacy and safety.
Beyond skin health, niacinamide offers benefits throughout your body, underlining its importance as a multifaceted supplement. As research continues to unfold, niacinamide stands out as a simple, cost-effective and generally safe addition to your health regimen, particularly for those concerned about skin cancer risk and overall skin health.
- 1, 12, 13, 14 YouTube, Dr. Dray, The Skin Supplement You Need to Know About April 28, 2022
- 2 Nutrients. 2024 Jan; 16(1): 100, Discussion
- 3 Nutrients. 2024 Jan; 16(1): 100, Dietary Niacin Intake and NMSC
- 4 N Engl J Med 2015;373:1618-1626
- 5 J Cutan Med Surg. 2022 May; 26(3): 297–308
- 6, 7, 8, 9 Cureus. 2023 Aug; 15(8): e44403
- 10 Nature Medicine February 19, 2024; 30: 424-434
- 11 Memorial Sloan Kettering Cancer Center, Nicotinamide
- 15 Clinical Trials Nicotinamide as an Early Alzheimer’s Disease Treatment (NEAT) NCT03061474
- 16 Cell Reports Medicine November 8, 2023
- 17 Nutrients. 2022 Jun; 14(11): 2219
- 18 JAMA Ophthalmology 2022;140(1):11-18
- 19 Haidut.me February 21, 2024 (Archived)
Transforming Health — How to Navigate Reductive Stress and the Metabolic Impact of Dietary Fats
Reproduced from original article:
https://articles.mercola.com/sites/articles/archive/2024/05/26/monounsaturated-fats.aspx
Analysis by Dr. Joseph Mercola May 26, 2024
STORY AT-A-GLANCE
- Reductive stress, caused by an excess of electrons in the electron transport chain, decreases metabolism and leads to degenerative diseases
- Dietary fats, particularly the balance of saturated and unsaturated, have a direct influence on your metabolic rate and health
- Desaturase enzymes, which are affected by dietary fats, signal your body to adjust its metabolic rate for energy conservation
- High consumption of polyunsaturated fats (PUFAs) mimics signals for metabolic slowdown, thereby contributing to metabolic syndrome
- Strategies to improve your metabolic health include managing your dietary fat intake and understanding the role of specific nutrients like stearoylethanolamide (SEA) in counteracting the negative effects monounsaturated fats, particularly oleic acid. These fats are implicated in slowing down the metabolic rate and increasing reductive stress, which SEA helps to mitigate by influencing metabolic processes and reducing inflammation
In this interview, repeat guest Brad Marshall, a molecular biologist, explains how different dietary fats influence your metabolism and overall health. You may want to listen to this interview a couple of times. If you still find it hard to understand, copy and paste the corresponding sections of the transcript into ChatGPT and ask it to explain it to you in even simpler terms.
In our previous interview, Marshall explained reductive stress and how it causes damage that leads to virtually every degenerative disease and the most common causes of death. Molecular biology can be hard to understand which is why I created the best 2-D illustration of how your body creates cellular energy. It will be helpful for you to review this illustration during our discussion.
The other strategy that will help you learn this important information is to have a dialog with ChatGPT 4 or your favorite large language model and ask it to help explain any concepts you don’t understand. If the answer is something you still don’t understand ask Chat to simplify its answer. Continue asking questions so you understand everything.
In summary, reductive stress results from an excess of electrons that slow down your metabolism and energy production. It’s like your body’s systems are overwhelmed with energy they can’t properly use, which leads to decreased efficiency and damage over time.
Why is it so important to understand these concepts? Because they’re the central keys to your health. If you understand these foundational concepts, you can make choices that will move you out of disease and towards health — because your body wants to be healthy. It’s designed to be healthy and will achieve that automatically once you give it what it needs.
I’ve admired Brad’s work so much that I’ve hired him to be my research director and we’re developing a test to measure the redox potential of your body. At present, such tests are not commercially available, and those that do exist provide results that are questionable at best.
How Dietary Fats Affect Metabolism
As explained by Marshall, reductive stress and metabolic syndrome might be better understood through the lens of evolution and animal behaviors like torpor — a state of decreased metabolic activity.
Animals adapt by changing the types of fat in their bodies seasonally to prepare for periods of dormancy like hibernation. The thing that triggers this fat composition change is the composition of fats in the animal’s diet.
For instance, the consumption of insects with high saturated fat content indicates to mammals the need for a more active metabolism suitable for warmer climates. Conversely, diets high in monounsaturated fats signal the approach of winter, prompting animals to lower their metabolic rate in preparation for hibernation.
Key components of this process are desaturase enzymes, which are responsible for adjusting the types of fats within your cells. These enzymes — Delta-6-desaturase, Delta-5-desaturase, and Delta-9-desaturase — signal your body to slow down its metabolic rate in anticipation of periods when less energy will be required or available by converting saturated fats into unsaturated fats, including monounsaturated fats.
As animals approach colder months, they naturally increase the production of these desaturase enzymes. This increase leads to a higher concentration of monounsaturated fats in the body, which is more efficiently stored as fat. This accumulation is part of the body’s preparation to conserve energy and maintain survival during periods of scarcity.
Thus, you could say that desaturase enzymes act as a metabolic switch that turns on your body’s torpor mode. By modifying the fat composition within your body, they effectively lower your metabolic rate, thereby allowing your body to conserve energy.
And again, this switch is influenced by the type of fat you consume. Saturated fats are associated with a higher metabolic rate and less reductive stress, while monounsaturated and polyunsaturated fats (PUFAs) lower your metabolic rate and increase reductive stress.
In short, if you consume high amounts of PUFAs, you’re tricking your body into thinking you need to conserve energy for hard times, like a famine or long winter with scarce food supplies. This process of conservation, in turn, downregulates or shuts down various biological processes because your body doesn’t have enough energy for all of them.
Why LA Is So Destructive
While we typically don’t think of torpor applying to humans, most Americans are in this state. The increase in unsaturated fats in the human diet over the last century — particularly PUFAs — mimic the natural signal for animals to enter a torpid state, but since humans do not hibernate, this reduced metabolism is neither necessary nor healthy. The process is further exacerbated when these fats become oxidized, as this increases reductive stress.
“In the last 100 years, we’ve eaten more and more and more of these unsaturated fats,” Marshall says. “And, of course, the polyunsaturated fats contribute to this process as well because the Delta-6-desaturates is the limiting step in the oxidation of the polyunsaturated fats.
You’ve talked a lot about concerns with polyunsaturated fats, and what I see when I look at it is, linoleic acid (LA) … is okay if it stays as linoleic acid, but once it starts getting converted to oxidized fats, that’s when it becomes a real problem.”
Through a series of enzymatic steps, LA is transformed into arachidonic acid. Arachidonic acid, when oxidized, can form various types of hydroxyeicosatetraenoic acids (HETEs), which are signaling molecules involved in numerous physiological processes, including inflammation and the immune response.
Marshall believes that two HETEs in particular, 5-HETE and 12-HETE, control the shifting of metabolism towards torpor metabolism. These HETEs, in turn, appear to be controlled by highly destructive oxidative linoleic acid metabolites (OXLAMs) that are produced when LA is oxidized.
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The Link Between High-PUFA Diets, Metabolic Syndrome and Related Issues
When you oxidize a lot of PUFAs you also activate a nuclear receptor called the aryl hydrocarbon receptor (AHR), which controls your circadian rhythm. Marshall comments:
“If you give a mouse a drug that strongly activates the aryl hydrocarbon receptor, it shuts down the circadian rhythm of the mouse. The aryl hydrocarbon receptor controls your circadian rhythm. And people who have metabolic syndrome have issues with sleep.
If you trigger the aryl hydrocarbon receptor, you also get a dysregulated gut microbiome. If you are oxidizing a lot of polyunsaturated fat, you activate the aryl hydrocarbon receptor and all of a sudden you have overgrowth of bad gut bugs and you’ll have a decrease in the good gut bugs.”
The reason why AHR activation catalyzes a transition from beneficial to pathogenic gut bacteria is because the AHR is highly involved in controlling the immune system. If you activate the AHR, you see an increase in myeloid derived suppressor cells — immune cells that suppress your immune response.
Are Starches Good or Bad? It Depends
At this point in the conversation, Marshall brings up a crucial point. Many in the Ray Peat community believe that starches, especially resistant starches, will promote the growth of pathogenic bacteria that produce endotoxin, also known as lipopolysaccharide or LPS. LPS can get into your bloodstream and cause all kinds of problems, so you don’t want a high LPS response.
However, after looking at this issue for the last 18 months, I’ve started to understand the flaws in Peat’s work. One of the primary functions of the gut is to maintain an anaerobic environment (an environment without oxygen). The problem is, you need energy to keep oxygen out of there, and if that energy is not available, oxygen is going to seep in.
Most beneficial bacteria are gram-negative, and they’re called obligate anaerobes. They do not have LPS in their cell wall and hence will not produce endotoxin when they die off. However, when you don’t create enough cellular energy you are unable to create a low oxygen environment in your large intestine.
This kills the beneficial bacteria as oxygen seeps in and they are unable to survive. When they leave, they create a hole that allows endotoxin-producing bacteria — facultative anaerobes — to take over through competitive inhibition. Facultative anaerobes can tolerate oxygen and survive.
The primary obligate anaerobic bacterium in your gut is a species called Akkermansia, which makes mucin, the protective layer in your gut. When your Akkermansia die off due to lack of cellular energy to maintain the proper oxygen gradient in the large intestine, then your mucin barrier starts to break down and you end up with leaky gut.
Now, the reason starch CAN be problematic is because, if you are metabolically inflexible (and most are), then you’re not making enough mitochondrial energy to maintain a healthy gut. So, the idea that starch is problematic is likely true for most people, because most people have a disrupted microbiome. Starch is indiscriminate and will feed any bacteria. So, since most people have a preponderance of pathogenic gut bacteria, starch causes problems.
The flip side of this is that if you have a healthy microbiome, starch can be quite beneficial. So, the primary goal is to get your cellular energy up and improve your microbiome first. Then you can eat starch.
I now eat about 1.5 pounds of white rice a day and have cut down on my fruit consumption. In total, I consume over 500 grams of carbs a day, but I now get less fructose (as starch doesn’t contain fructose like fruit does). Ultimately, I suspect starch may be the ideal fuel once your microbiome is optimized. But again, it’s all dependent on your gut health.
I also added over 50 grams of collagen from homemade bone broth per day and added raw milk cheese with animal rennet. This experiment has resulted in gaining 4 pounds but my percent body fat dropped from 8.5% to 6.5%. So, I gained over 4 pounds of muscle and no fat. That’s a good trade from my perspective.
Other Feedback Loops That Push Us Toward Metabolic Syndrome
While Marshall agrees with my theory of why starches can cause problems, he points out that there are other feedback loops at work as well:
“This is all part of one sort of big complicated positive feedback loop. I 100% agree with you about the gut barrier function. But I also think that there’s a whole bunch of aligned systems that are pushing us towards this outcome [metabolic syndrome].
When you look at the hibernating animals, when they go towards winter and you see all those desaturase enzymes are increased, their gut permeability increases. One of the tricks that the animal does as the hibernating season is approaching is they increase gut permeability, and they let more LPS in.
That may also let more oxygen through. I’m not sure. One of the patterns that you see in obesity and metabolic syndrome is that branched-chain amino acids in your bloodstream increase and glycine goes down. In mice, if you supplement with glycine, it increases gut barrier function.
So, you have this pattern going into winter where AHR is activated, desaturases are activated, gut barrier function is decreasing and LPS is coming in that causes release of CD38, [which] breaks down NAD+. And so, anytime LPS is coming through, it’s decreasing NAD+ availability.
The thing about that is, all three desaturases run off NADH and not NAD+. So, the gut inflammation leads to increased activity of these desaturases, which leads to increased monounsaturated fat production, which continues to push you further in that direction of reductive stress, which lowers glycine, which makes the gut leakier. To me, it looks like it’s all wrapped into the same process.
These processes all work together, and they all work in these feedback loops because if you are an animal in the right situation, you want to have a low metabolic rate, you want to have slow metabolism, and you want to be storing extra fuel.
It’s a very complicated process with a lot of different parts, and they’re all working together to achieve the outcome, which we call metabolic syndrome. Because in our situation, we don’t have to store extra fat for winter and we’re not going to hibernate.”
Tracing the Inflammatory Cascade to Its Root
Marshall also points out research showing mice that lack SCD1, and therefore cannot make monounsaturated fat, have very low inflammatory markers.
In autumn, hibernating animals increase SCD1, which increases production of monounsaturated fats, which in turn increases the inflammatory immune cells like TLR4 and NF kappa beta. At the same time, stearoylethanolamide (SEA) production is reduced. SEA is a bioactive lipid made from stearic acid that is noted for its effects on reducing appetite and inflammation.
However, if you decrease Delta-9 desaturase activity, you eliminate that whole inflammatory cascade. So, Marshall suspects that it’s the inflammatory cascade resulting in elevated C-reactive protein can be traced back to the activation of Delta-9 desaturase. Hence, the remedy needs to include the deactivation of Delta-9 desaturase.
SEA, which is available as a supplement, has the remarkable effect of drastically raising your metabolic rate if the negative feedback loops just described are in play. In animal studies, SEA has been shown to reduce inflammation, suppress production of TNF alpha, SCD1 and Delta-9 desaturase.
“So, it’s doing all of the things that you would predict would help your metabolic rate,” Marshall says. In the interview, he describes the effects his SEA supplement had on his morning body temperature readings, which is a simple way to gauge your metabolic rate, and how he was able to use that to fine-tune his dosage.
What Do Countries With Low Diabetes Rates Eat?
As noted by Marshall, West Africa has one of the world’s lowest diabetes rates, partially attributed to its diet, which is rich in starchy tubers like plantains, cassava, and African yams, as well as collagenous meats like beef skin. These foods are often used in stews, extracting collagen and gelatin.
This dietary pattern, emphasizing starchy tubers and collagen-rich meats, contrasts with diets higher in processed foods and may contribute to the region’s lower diabetes prevalence, which is below 3%.
My idea of a healthy meal would be white rice cooked in bone broth, topped off with a couple of egg yolks and a small amount of beef liver. This meal would be high in starch and collagen, and low in fructose and muscle meat, which has a very different amino acid composition than collagen. For a refresher on the difference between muscle meat and collagen, see “Why Collagen Is a Proven Necessity.” Marshall comments:
“One of the things about starch is, if you eat a bunch of starch, your NAD+ availability increases postprandially. After the meal, you have more NAD+ availability if you’re burning a lot of starch. And so, it all comes down to reductive stress.”
Why Olive Oil Isn’t as Healthy as It’s Made Out To Be
Marshall also recounts research showing the differences between saturated and unsaturated fats in terms of how they affect your metabolism.
“This experiment has been done in humans about four or five times. They feed people bread and butter or bread and olive oil, and measure how much oxygen they’re consuming and how much carbon dioxide they’re breathing out. That’s called respiratory exchange ratio.
If you look at those two numbers, you can determine how much carbohydrate and fat people are burning. And so, if people eat bread with butter, they’ll have a relatively high respiratory exchange ratio, and that means that they’re burning a lot of the carbohydrate in the meal. So, you eat bread and butter, you can burn that carbohydrate cleanly, which is the right way to do it.
If you eat bread and butter, you want to burn those carbs first. Then, as your blood glucose levels drop, then you’ll start to burn more of the fat from the meal. That’s the correct sequence. If you eat olive oil and bread, you burn less of the glucose right away.
I would argue that the olive oil makes you essentially acutely insulin resistant. Because the insulin, you eat that bread, the insulin is signaling, it’s trying to clear the other things out to allow that glucose to burn. But if you eat bread and olive oil, your respiratory exchange ratio will be lower, and that means you’re burning more fat.
And of course, if you read those articles, they say, ‘Oh, eureka. If you eat olive oil, you’ll burn more fat than if you eat butter.’ When I look at that, I say, ‘This is bad. This is not what you want.’”
Olive oil, if pure (and most aren’t) is mostly oleic acid, a monounsaturated fat, but PUFAs have the same effect. Both will inhibit glucose metabolism. What’s more, when you consume oleic acid, it creates oleoylethanolamide (OEA), which has the opposite effect of SEA.
OEA activates a nuclear receptor called PPAR-alpha, which directly turns off glucose metabolism. So, every time you eat monounsaturated fat, PPAR-alpha is activated and turns off your ability to break down glucose.
High Metabolism Is the Goal
Marshall continues:
“If you compare bread and butter to bread and olive oil, the bread and butter looks like that’s what you want … as you want to burn those carbs. Because if you burn those carbs, your NAD+ availability will go up. And I said this in the last show, but there’s this old saying that ‘fat burns in the flame of carbohydrate.’
You get that NAD+ availability up and you get that flywheel spinning, and now you can efficiently burn the fat in the meal and also your stored body fat, because the carbs are really driving that process.”
One way to accomplish that is by taking a SEA supplement, as that will increase your metabolic rate. Remember, the key goal is to increase your body’s ability to create cellular energy, which means improving your mitochondrial function and increasing your metabolic rate. If you can do that, it doesn’t matter what disease you have; most will begin to improve.
Again, to summarize, SEA helps counteract the effects of oleic acid by influencing your body’s metabolism and its response to fats. It does this, in part, by suppressing the enzyme delta-9 desaturase in the liver, which plays a role in converting saturated fats into monounsaturated fats like oleic acid.
By doing so, SEA helps reduce your body’s tendency to store fat, mimicking a condition where energy storage for winter is unnecessary. This, in turn, helps to improve your metabolic rate and reduce inflammation by affecting NF kappa beta, a protein complex involved in inflammatory responses.
Lab Test for Redox Status Is in the Works
As mentioned earlier, Marshall and I are developing a lab test to assess redox status by analyzing three pairs of compounds: lactate and pyruvate, acetoacetate and beta-hydroxybutyrate, and oxidized and reduced glutathione.
We believe this approach will offer more precise insight into cellular health than directly measuring NAD+. We want this test to be affordable and able to provide detailed information about your mitochondrial function to help you monitor your progress as you make various lifestyle changes.
In the interview we discuss, in detail, how and why evaluating these three redox pairs are crucial for understanding how your body processes fuel and manages oxidative stress. We also explain how the balance of these pairs in the mitochondria and cytoplasm can indicate overall metabolic health and the effectiveness of your body’s antioxidant defenses, such as glutathione.
In short, the test aims to provide insight into your mitochondrial function and how it can be overwhelmed by excessive or improper fuel intake, which has significant implications for your health.
Marshall also explains how antioxidants, like vitamin C, interact with free radicals, substances with unpaired electrons that can damage cells. When antioxidants donate an electron to free radicals, like superoxide or lipid peroxides, they neutralize them, preventing damage.
However, this process can be complex, as illustrated by glutathione, a crucial antioxidant that, when in its reduced form, helps eliminate harmful substances but can also indicate reductive stress in cancer cells. Thus, maintaining a balanced level of reduced glutathione is essential for health.
More Information
To learn more, please listen to the interview in its entirety. You may need to listen to it several times, even, to really understand it. Once you do, however, the answers to many of your health problems will become that much clearer. And, if you want to dive deeper into molecular biology, be sure to check out Marshall’s YouTube channel, Fire in a Bottle. Marshall also sells a SEA supplement that is available at his website.
The Best Nutrition Course Is NOW Available for You!
In closing, I have other good news. Shortly, I will be sending out invites to train individuals interested in becoming one of my health coaches. My health coaches will be some of the best trained coaches on the planet because they will understand how biology works and how to correct it to optimize health.
Many will apply but only a few will be accepted. Once they are accepted, they will be allowed to enroll in my nutritional biochemistry course at no charge. This course is based on the concepts of the late Dr. Ray Peat who popularized bioenergetic medicine. That’s a fancy word for optimizing diet choices to maximize cellular energy production.
Poorly functioning mitochondria is pervasive and probably exists in 98% of the population. Diligent application of the principles outlined by Peat will help your mitochondria recover so they can produce the amount of energy they were designed to. This is important because your body needs energy to activate its intrinsic healing capacity.
The foundation for the nutritional biochemistry course that will be taught to our health coaches is from a course that Ashley and Sarah Armstrong put together. In my view, it is the best health course I’ve ever seen.
I only wish I had had this course when I first started practicing medicine. It would have been a game changer. It’s hard to imagine how many additional hundreds of millions of people I could have helped with this knowledge. Not to worry though, as the knowledge is now available for you.
If you are seriously interested in understanding how your body works, and more importantly, what specific actions you can take to guide it to working the way it was designed to, then this is the course you need to take.
You can enroll for the course on their website. I take no commissions from recommending this course. All the funds go directly to the Armstrong sisters. They’re probably the most knowledgeable farmers on the planet when it comes to health. This is why they can produce some of the healthiest food possible. But you may realize that farmers don’t earn very much, so you can support their mission to provide the world with healthy food by purchasing their course.
I would encourage you to seriously consider taking advantage of the wealth of knowledge that has taken them many years to compile and make available to you in an easy to learn format.
Chronic Pain Due to Mitochondrial Dysfunction, Niacinamide Can Treat It
Reproduced from original article:
https://articles.mercola.com/sites/articles/archive/2024/05/14/chronic-pain-mitochondrial-dysfunction.aspx
Analysis by Dr. Joseph Mercola May 14, 2024
STORY AT-A-GLANCE
- Chronic pain may not be a disorder of its own but a symptom of underlying mitochondrial dysfunction
- Nicotinamide riboside (NR) — a form of vitamin B3 and precursor to nicotinamide adenine dinucleotide (NAD+) — helps relieve chronic pain in mice by improving mitochondrial function
- Niacinamide, another form of vitamin B3 involved in similar cellular processes as NR, may also be useful for relieving chronic pain
- Linoleic acid (LA) in vegetable and seed oils causes mitochondrial dysfunction
- Lowering your intake of LA, which is common in ultraprocessed foods, is one of the most straightforward ways to improve mitochondrial health and, thus, potentially relieve chronic pain
About 21% of U.S. adults suffer from chronic pain, with new cases occurring more often than new cases of other common conditions like diabetes, depression and high blood pressure.1 Pain is considered chronic if it occurs every day or most days over a period of three months or more.
For about 8%, the chronic pain is considered high-impact,2 meaning it limits life or work activities, demonstrating the heavy burden this condition places on those affected. Many reach for dangerous opioid drugs for relief, which suppress mitochondria3 — the last thing you want if you’re struggling with chronic pain.
Chronic Pain Is a Symptom of Mitochondrial Dysfunction
Researchers with Utrecht University in the Netherlands revealed that nicotinamide riboside (NR) — a form of vitamin B3 and precursor to nicotinamide adenine dinucleotide (NAD+), a molecule involved in DNA repair and healthy aging — helps relieve chronic pain in mice4 by improving mitochondrial function.
“Previous research has linked chronic pain to dysfunctional mitochondria, particularly those in specialized nerve cells, called sensory neurons, which detect changes in the environment,” New Scientist reported.5
For the study, an inflammatory substance was injected into the paws of 15 mice, which led to changes in mitochondrial function, even a week later after the inflammation had resolved. The mitochondrial changes were associated with greater pain in the mice, which also had lower levels of NR in the mitochondria of their sensory neurons compared to mice that didn’t experience inflammation.6
NR plays an important role in mitochondrial function, so researchers gave the mice a high dose, which alleviated pain.
“Together these findings indicate two things: first, that inflammation can impair mitochondrial function in sensory neurons and that these impairments increase the risk of chronic pain, even after inflammation has resolved. Second, that taking nicotinamide riboside supplements may help treat this chronic pain by restoring mitochondrial function,” according to New Scientist.7
The study may help shed some light on why some people continue to experience pain even after inflammation has healed, which remains a largely unanswered question. The researchers noticed that even after the initial pain from inflammation goes away, the nerve cells involved in sensing pain still show changes in their mitochondria that disrupt the balance of certain chemicals in the cells.
However, adding the NAD+ precursor NR helped mice recover from pain, even when it was chronic. This suggests that managing mitochondria function in these nerve cells is crucial for overcoming persistent pain after inflammation.
Vitamin B3 for Chronic Pain
As noted in the blog To Extract Knowledge From Matter, which is inspired by the work of the late Ray Peat, niacinamide, another form of vitamin B3 involved in similar cellular processes as NR, may be useful for relieving chronic pain:8
“The study … is one of the first to demonstrate that chronic pain is not an organic disorder of its own, but a symptom of an underlying mitochondrial dysfunction. This not only explain why the intervention with niacinamide worked in alleviating the pain (by improving mitochondrial function), but also why treating chronic pain with opioids is about the worst intervention one could choose.
Why? Because opioids are among the most potent suppressors of mitochondria, which means that as soon as one stops taking them the chronic pain will be much worse, leading to more opioid use and so on — a vicious cycle with usually lethal outcome (overdose).”
In fact, one study found that people who use opioids tend to have fewer mitochondria in their blood. Further, being exposed to the synthetic opioid fentanyl before birth was found to change the number of mitochondria in the blood and the activity of genes related to mitochondria in the nucleus accumbens, a brain area important for feeling pleasure, in young offspring.9
To Extract Knowledge From Matter continued explaining why the featured study’s use of vitamin B3 is superior to opioids for chronic pain:10
“The niacinamide dose used in this study was on the high-side (HED [human equivalent dose] ~35mg/kg daily), but considering it was administrated only once and the pain was completely resolved, it is a low-risk intervention in such doses for humans, especially compared to opioids.
Also, there are prior animal studies showing that lower doses (HED 3mg/kg daily) taken for a few weeks can also relieve chronic pain, which lowers the risk of such intervention even more.”
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Your Mitochondria Need Niacinamide
Niacinamide, also known as nicotinamide, is a form of niacin (vitamin B3) that plays a vital role in energy metabolism. It’s essential for the mitochondrial electron transport chain to function. Without it, your mitochondria cannot make energy.
Niacinamide is so important because it is a precursor for NAD+, which is involved in the conversion of food to energy, maintaining DNA integrity and ensuring proper cell function. NAD+ is also a primary fuel for sirtuins, longevity proteins that become depleted with age.
Niacinamide at a dose of 50 milligrams (mg) three times per day will provide the fuel for the rate limiting enzyme for NAD+, NAMPT. Niacinamide also has potent antiobesity effects, can help prevent neurodegeneration and heart failure, and reverse leaky gut.
Niacinamide may also help prevent neurodegeneration by allowing for higher energy levels through energy metabolism in the mitochondria. “There are many studies, going back decades, demonstrating that a drop in NAD+ levels, and thus of NAD/NADH, is a common feature of virtually all neurodegenerative diseases,” writes Peat’s student Georgi Dinkov, a bioenergetic researcher.11
I recommend getting niacinamide in powder form because the lowest available dose in most supplements is 500 mg, and that will decrease NAD+ due to negative feedback on NAMPT, which is the opposite of what you’re looking for. Niacinamide will only cost you about 25 cents a month if you get it as a powder. Typically, 1/64 of a teaspoon of niacinamide powder is about 50 mg.
I also recommend taking one aspirin tablet daily. Aspirin plays a role in mitochondria function12 and also has other health benefits. Importantly, it helps increase the oxidation of glucose as fuel for your body while inhibiting the oxidation of fatty acids, specifically linoleic acid (LA). Dinkov adds:13
“Since aspirin is known to modulate autophagy (raise it when it is abnormally low and lower it when it is abnormally high) and niacinamide is a very effective NAD precursor, it is reasonable to try them in combination that should be synergistic when it comes to protecting the brain (and the entire organism) from diseases and even aging.”
Why Avoiding LA in Ultraprocessed Foods Is Important for Pain Relief
Lowering your LA is the single most important strategy you can take to not only lower reductive stress in your mitochondria but improve your overall health, including relief of chronic pain. LA is an omega-6 fat found in the vegetable oils and seed oils common in most ultraprocessed foods.
The main reason why excess LA causes disease is that it prevents your mitochondria from working well. Mitochondria produce most of your cellular energy in the form of ATP, and without ATP, your cells cannot function and repair themselves normally.
Polyunsaturated fats (PUFAs) such as LA are easily damaged by oxygen in a process called oxidation,14 which triggers the creation of damaging free radicals.15 These, in turn, give rise to advanced lipoxidation end products (ALEs)16 and in the case of omega-6 fats, oxidized LA metabolites (OXLAMs).17,18
These ALEs and OXLAMs then go on to cause mitochondrial dysfunction, which is a hallmark of most chronic disease. In addition to oxidation, inflammation and mitochondrial dysfunction, processed seed oils can also inhibit cardiolipin, an important fat in the inner membrane of your mitochondria.
Cardiolipin is important because it influences the structure of the cristae inside your mitochondria, which is the area where energy production occurs. If cardiolipin is damaged, then the complexes will not be close enough together to form supercomplexes, and thus the mitochondrial energy production will be impaired.
Cardiolipin also works like a cellular alarm system that triggers apoptosis (cell death) by signaling caspase-3 when something goes wrong with the cell. If the cardiolipin is damaged from oxidative stress due to having too much LA, it cannot signal caspase-3, which means apoptosis does not occur.
As a result, dysfunctional cells are allowed to continue to grow, which can turn into a cancerous cell. The type of dietary fat that promotes healthy cardiolipin is omega-3 fat, and the type that destroys it is omega-6, especially LA.
The good news is that dietary changes can improve the composition of fats in your cardiolipin in a matter of weeks, or even days. So, even though it will take years to lower your total body burden of LA, you will likely notice improvements well before then.
How to Optimize Your Mitochondrial Function
To optimize your mitochondrial function, you want to avoid LA as much as possible and increase your intake of omega-3s. Primary sources of LA include seed oils used in cooking, ultraprocessed foods and restaurant foods made with seed oils, condiments, seeds and nuts, most olive oils and avocado oils (due to the high prevalence of adulteration with cheaper seed oils).
Animal foods raised on grains, such as conventional chicken and pork, are also high in LA. Another major culprit that destroys mitochondrial function is excess iron — and almost everyone has too much iron. You can learn more about the health risks of excess iron in my interview with Christy Sutton, D.C. The most effective way to lower your iron is to donate blood two to four times a year.
As mentioned, I also recommend taking 50 mg of niacinamide three times per day. It’s also helpful to make sure you’re getting all the other B vitamins, as they too are crucial for mitochondrial function, especially regular niacin, riboflavin and folate.
Oftentimes, decreased mitochondrial function is due to a deficiency in B vitamins, and that’s easy to fix with a low-dose, high-quality B complex. Usually, when this is the case, improvement can be seen — and felt — within two to three weeks.
- 1, 2 National Institutes of Health May 16, 2023
- 3, 9 Front Psychiatry. 2021 Nov 18:12:737389. doi: 10.3389/fpsyt.2021.737389. eCollection 2021
- 4 Cell Reports Medicine November 8, 2023
- 5, 6, 7 New Scientist November 8, 2023
- 8, 10 Haidut.me February 23, 2024, Chronic pain due to mitochondrial dysfunction, niacinamide can treat it (Archived)
- 11, 13 Haidut.me May 11, 2023, Niacinamide may prevent neurodegeneration (Archived)
- 12 Biochem Biophys Res Commun. 2017 Jan 8; 482(2): 346–351
- 14 Oxid Med Cell Longev. 2014;2014: 360438. doi: 10.1155/2014/360438
- 15 Pharmacognosy Review. 2010;4(8):118-126
- 16 Biochemical Journal. 1982;208(1):129-140
- 17 Nephrol Dialysis Transplant. 2001;16(8):1598-1606
- 18 Free Radical Biol Med. 1992;13:341-390