#54 Vitamin C: Oral vs. Intravenous, Immune Effects, Cancer, Exercise Adaptation & More

Posted on May 12th 2020 (almost 5 years)

vitamin c exercise cancer depression dna damage immune system oxidative stress autoimmunity

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In 1970, double Nobel Prize laureate Dr. Linus Pauling published Vitamin C and the Common Cold, in which he posited that consuming large amounts of vitamin C could reduce the duration and severity of the common cold. The book effectively put vitamin C on the nutritional map, establishing it as a cure-all in the collective minds of the lay public. Nearly a decade later, Pauling published clinical data suggesting that high dose intravenous administration of vitamin C showed promise as a supportive treatment for cancer as well as a strategy to mitigate the side effects of chemotherapy. Pauling's work was heavily criticized in the scientific community, however, due to a lack of proper controls and standardization. Since then, countless studies have tested Pauling's theories about vitamin C, colds, and cancer (and many others), and a substantial body of evidence has emerged, identifying critical roles for vitamin C in immune function, cardiovascular and respiratory health, cognitive development and preservation, and many other aspects of human health.

Click here to view our nearly 30-page, 190 reference overview article on vitamin C.

Bioavailability of vitamin C

The absorption, distribution, metabolism, and excretion of vitamin C are complex and differ considerably from other low molecular weight compounds. Consequently, the bioavailability of vitamin C is both frequency- and dose-dependent. But the form of vitamin C impacts bioavailability, too. For example, oral vitamin C is absorbed in the small intestine via specialized transporters that are subject to saturation, but intravenous vitamin C bypasses the gut, achieving blood and tissue concentrations that are markedly higher than those achieved with the oral form. In fact, in healthy adults, intravenous administration of vitamin C can reach blood concentrations that are 30 to 70 times higher than equivalent oral doses.

Vitamin C as antioxidant

Much of vitamin C's effectiveness arises from its capacity to serve as an antioxidant – readily donating electrons to oxidized molecules, thereby quenching reactive oxygen species and preventing oxidative stress. This is perhaps best demonstrated in neutrophils, a type of immune cell that actively participates in eliminating pathogens from the body. Neutrophils generate large quantities of reactive oxygen species, putting them at risk for oxidative stress-induced DNA damage. Vitamin C is highly concentrated in neutrophils, however, with concentrations averaging roughly 50 times higher than plasma concentrations. In a strange paradox, the high levels of vitamin C present in neutrophils protect them from reactive oxygen species-induced DNA damage while simultaneously promoting the molecules' production.

Vitamin C as anti-infectious agent

After more than 50 years of research, the evidence supporting vitamin C's effectiveness against the common cold is still variable, likely due to widespread inconsistencies in study methodologies that span an extensive range of protocols. Despite these inadequacies, meta-analyses broadly demonstrate a protective effect, particularly with higher doses. However, even under the most rigorous testing, vitamin C likely shortens or lessens the duration of the common cold by hours, not days. Some populations, such as children and endurance athletes – who tend to have more colds than the average person – seem to benefit more from vitamin C's effects, especially when taken prophylactically.

Other data suggest that vitamin C reduces the risk of a litany of viral infections, from chickenpox to shingles to HIV. Perhaps more compelling are the data supporting vitamin C's use in the treatment of sepsis, a life-threatening condition that can arise when the body responds to a bacterial or viral infection. Sepsis ravages the body, provoking severe injury to multiple tissues and organs, often resulting in death. Recent evidence indicates that SARS-CoV-2, the novel coronavirus that causes COVID-19, induces sepsis. Interestingly, people who have sepsis often exhibit low vitamin C levels, which might be predictive of increased risk for organ failure. Vitamin C might be an effective treatment for sepsis because it modulates the proinflammatory state associated with sepsis and preserves organ function.

The beneficial properties of vitamin C extend beyond its ability to support immune function support and prevention of colds, conferring a wide range of salubrious effects on multiple organ systems, including respiratory, cardiovascular, neurological, and reproductive systems.

Vitamin C as lung defense

The innate immune system of the lungs is an integral component of the body's defense system, protecting the body against exposure to inhaled oxidants and pathogens. Vitamin C participates in this protective role by boosting immune cell function and reducing oxidative stress. Vitamin C's lung defense capacity is evidenced by robust data suggesting that vitamin C intake protects against chronic obstructive pulmonary disease, pulmonary fibrosis, and other respiratory illnesses, including lung cancer.

But this characteristic takes on special relevance in light of recent concerns about complications associated with COVID-19, such as pneumonia and acute lung injury, which often necessitate mechanical ventilation support. Epidemiological and observational data indicate that higher vitamin C intake is associated with a lower risk of developing pneumonia, and the vitamin has also proven to be effective at decreasing the duration for which patients are kept on mechanical ventilation, especially among patients who require more than 24 hours of breathing support.

Vitamin C as cardioprotective agent

Large, population-based studies have found that vitamin C confers protection against hypertension – a risk factor for cardiovascular disease and stroke, two of the leading causes of death among people living in the United States. Analysis of data from several randomized placebo-controlled clinical trials involving more than 1,400 participants indicates that oral vitamin C elicits significant reductions in blood pressure among people with hypertension. Furthermore, recent research suggests that intravenous vitamin C can reduce blood pressure in patients diagnosed with prehypertension, a risk factor for hypertension.

Vitamin C as mediator of brain health

Vitamin C is found in high concentrations in the brain, especially in the hippocampus and frontal cortex regions – areas involved in memory consolidation, learning, and aspects of executive function. In fact, in a classic example of the body triaging resources based on needs, the brain retains vitamin C during times of deficiency at the expense of other tissues. This is critical to our survival: Evidence suggests that vitamin C plays roles in the brain throughout the lifespan from development through older age.

For example, studies in humans indicate that vitamin C concentrations are markedly higher in the fetal and newborn brain, and poor vitamin C status reduces hippocampal development. In older age, vitamin C's antioxidant capacity might be beneficial in decreasing the risk of neurodegenerative conditions like Alzheimer's disease, Parkinson's disease, Huntington’s disease, and multiple sclerosis by reducing oxidative damage – a key driver of neurodegenerative disease. Vitamin C is also important for the regulation of neurotransmitters, the formation of neural circuits, and many other key brain functions.

Vitamin C as chemoprotective agent

Vitamin C has been put to the test against many types of cancers, including glioblastoma, melanoma, and pancreatic, ovarian, colorectal, and non-small cell lung cancer. The findings from many of these studies suggest a trend in the overall survival rate for patients administered moderate doses of intravenous vitamin C in conjunction with standard therapies such as chemotherapy or radiation, even among patients with pancreatic cancer and ovarian cancer, two of the deadliest forms of cancer. These results have not been recapitulated with high oral doses of vitamin C, however.

Perhaps an equally important characteristic of vitamin C for people undergoing cancer treatment is its capacity to improve the patients' quality of life. Traditional therapies for cancer often ravage the body, eliciting both acute and chronic physical, emotional, cognitive, and sexual impairments. Terminal cancer patients who have received a combination of oral and intravenous vitamin C have noted marked improvements in their quality of life.

Vitamin C as performance enhancer – or hindrance

Vitamin C appears to enhance exercise performance by reducing the potential negative consequences of excess reactive oxygen species – highly reactive molecules produced during not only normal metabolic processes but also during exercise, as a consequence of exercise-induced immune activation. Excessive exercise-induced reactive oxygen species can promote muscle damage, fatigue, and immune dysfunction, but the extent varies according to the duration and extent of exercise. For example, high-intensity exercise such as long-distance running is linked to an increased incidence of upper respiratory infection.

Conversely, evidence suggests that reactive oxygen species might also mediate beneficial training adaptations as a part of a biologically useful signaling cascade. The downstream consequences of this cascade could blunt the beneficial training adaptations that reactive oxygen species might induce, such as increased mitochondrial number and function, improved insulin sensitivity and glucose utilization, and enhanced immune function, among others.

Vitamin C as potential kidney stone risk: a nuanced discussion

Although vitamin C is safe and well-tolerated in most healthy people, it has been implicated in an increased risk for developing kidney stones due to the formation of oxalate, an end product of vitamin C metabolism. The kidneys typically filter oxalate and excrete it in urine, but when high amounts of oxalate are present, it can form crystal structures with calcium and, in turn, promote the formation of kidney stones in high-risk people, such as those with existing kidney dysfunction. Yet large prospective cohort studies have found that high vitamin C intake increases the relative risk of kidney stones in healthy people. However, these findings were reached only after the creative manipulation of the data to predict theoretical risk, not actual risk. In reality, no association between vitamin C intake and kidney stones was identified.

Vitamin C as victim of less than rigorous study methodologies

The seemingly contradictory findings from much of the research on vitamin C arise from differences in study design, populations, dose, and delivery modalities, as well as a host of other factors. Resolving these inconsistencies presents a conundrum to the research community. Solutions might lie in simply ensuring that future studies utilize consistent, equivocal study designs, and in so doing, can elucidate the full potential of vitamin C in benefiting human health.

Oral vitamin C has a threshold of 220 micromoles per liter in the blood while Intravenous vitamin C can reach up to 15,000 micromoles per liter. 1
Background on vitamin C.
Dietary sources of vitamin C.
Cooking fruits and vegetables can diminish the levels of vitamin C by 25%. 1
Recommended levels of vitamin C.
Smoking and alcohol consumption can cause vitamin C deficiency.
A single round of dialysis can reduce vitamin C levels by half. 1
Vitamin C deficiency causes scurvy.
Hospitalized patients are more likely to be deficient in vitamin C. 1
Vitamin C absorption and transport.
Organs like the brain and adrenal glands have a higher demand for vitamin C. 1
Bioavailability of vitamin C.
The maximum level of effective oral vitamin C is 2-3 grams given 4-6 times per a day. 1
Liposomal vitamin C can achieve blood levels nearly twice of what is capable with normal oral vitamin C. 1, 2, 3
Intravenous vitamin C can reach blood levels 30 to 70 times higher than oral vitamin C. 1, 2
Vitamin C is important for the immune system, reaching concentrations up to 100x higher in immune cells than blood serum. 1, 2,
The high levels of vitamin C present in immune cells protect them from reactive oxygen species, promote reactive oxygen species production, enhance immune cell survival, and modulates cytokines 1, 2, 3, 4, 5, 6, 7, 8, 9
Vitamin C for the use against the common cold
2 grams per day of vitamin C during a cold had a greater benefit compared to 1 gram per day. 1
Vitamin C is more effective for the common cold in those under the age of 16. 1
Taking vitamin C prophylactically was shown to decrease the common cold symptoms and duration 1, 2
Vitamin C supplementation reduced the percent of colds in endurance athletes by 50 percent. 1
Vitamin C and lung function
The people with the highest blood vitamin C concentrations were 15 percent less likely to develop respiratory conditions and were 46 percent less likely to die of lung cancer, compared to those with the lowest blood vitamin C levels.1
Vitamin C decreased the time needed to be on a ventilator for those over 24 hours of ventilation. 1
Vitamin C reduced the risk of pneumonia by 80% in those deficient in vitamin C.1, 2, 3, 4, 5, 6
Some studies have shown 1 gram of daily vitamin C to cause fewer and less severe asthma attacks but others have failed to show an effect. 1, 2, 3
For every 100-milligram increase in daily vitamin C intake among men, the risk of developing lung cancer decreased 7 percent. 1
Vitamin C improved lung function by 8% in those with exercise-induced bronchoconstriction. 1
Vitamin C may improve exercise in some ways but diminish physiological adaptations to exercise. 1, 2, 3, 4
Supplemental doses ranging from 400 milligrams to 3 grams per day decreased muscle damage and reduced muscle soreness after exercise. 1, 2, 3
But some studies using lower doses between 200 milligrams and 1 gram per day suggest that vitamin C has no effect on physical adaptations to exercise.1, 2, 3, 4
1 gram of vitamin C with 235 milligrams of vitamin E decreased mitochondrial biogenesis after exercise. 1
Low vitamin C levels might be linked to poor physical performance and increased oxidative stress. 1
There is mixed data for the effect of vitamin C and E on insulin sensitivity 1, 2
An antioxidant cocktail of vitamin C, E, and beta-carotene improved immune cell function in young athletes. 1, 2, 3, 4
Vitamin C and fatty acid oxidation
Vitamin C levels are inversely correlated with body fat, and reduced weight gain in animals fed a western diet 1, 2
Vitamin C prolonged life-span in mice genetically modified to premature aging. 1
Having marginally low vitamin C levels decreases the amount of fat burnt during exercise. 1
Vitamin C and the brain
Prenatal and postnatal vitamin C deficiency stunted hippocampal development in newborn guinea pigs by 10 to 30 percent. 1, 2
Compared to adults, vitamin C levels were up to 11 times higher at 11 weeks gestation and full term babies had at least three times higher vitamin C levels. 1, 2
For every 54-milligram increase in vitamin C intake there was an 18 percent reduction in the risk of Alzheimer's disease. In smokers, for every 54-milligram increase of vitamin C there was a 35 percent decrease risk of Alzheimer's disease. 1, 2
Intravenous Vitamin C and its use for the treatment of infection
Multiple case studies and observational reports suggest intravenous vitamin C might be useful in reducing pain in people who have shingles and in treating mononucleosis. 1, 2
A large meta-analysis showed that the addition of intravenous vitamin C to conventional therapy for myocarditis improves outcomes. 1
A recent paper has suggested SARS-CoV-2, the virus responsible for COVID-19, causes sepsis. 1
Experimental studies in mice have demonstrated that intravenous vitamin C lessens the proinflammatory state associated with sepsis and preserves organ function. 1, 2, 3
In clinical studies, intravenous vitamin C significantly reduced the number of hospital deaths, hospital days, and time on ventilation among patients with sepsis 1, 2
intravenous Vitamin C and cancer
Several clinical studies have shown trends that intravenous vitamin C in addition to standard treatment could improve survival in certain cancer patients. 1
10 grams of intravenous vitamin C twice a week and 4 grams of oral vitamin C daily for a week improved physical, emotional, and cognitive status as well as reduced fatigue, nausea, vomiting, pain, and appetite loss in terminal cancer patients. 1
Several other studies have shown intravenous vitamin C could improve quality of life in cancer patients. 1, 2, 3
Effect of Vitamin C on fertility and reproduction
One of the contributors to male infertility is excessive reactive oxygen species. 1, 2, 3
1 gram of vitamin C twice a day for 2 months improved sperm count by 58% and sperm motility by 48% in previously infertile men. 1
1 gram of oral vitamin C increased sperm quality in men exposed to lead and cigarette toxins. 1, 2
Intravenous vitamin C and cardiovascular health
Nearly half of all adults living in the US have high blood pressure, and only about one-fourth of those have their blood pressure under control. 1
A meta-analysis of 29 randomized placebo-controlled clinical trials involving more than 1,400 participants demonstrated that patients with high blood pressure who took an average of 500 milligrams of oral vitamin C per day for about eight weeks showed significant decreases in blood pressure compared to those who took a placebo. 1, 2
Vitamin C and inflammation
1 gram of vitamin C and 800IU of vitamin E for 2 months reduced CRP, an inflammatory biomarker for heart disease, roughly the same amount as statins. 1, 2
Intravenous vitamin C decreased CRP in women with rheumatoid arthritis. 1
Vitamin C's mechanisms of action
Studies in animals and in humans suggest that vitamin C plays an important role in facilitating neutrophil migration to sites of infection and overall neutrophil function. 1, 2, 3, 4
The high levels of vitamin C present in immune cells promote the neutrophils' reactive oxygen species production, while also protecting them from damage. 1, 2
Repleting vitamin C in vitamin C deficient mice normalized cytokine production including interferon 1, 2, 3
In vitro study showed that the import of vitamin C into cancer cells can cause oxidative stress and decrease cancer cell viability in a petri dish 1
While vitamin C acts primarily as an antioxidant at physiological concentrations of approximately 50 micromoles per liter, pharmacologic doses of intravenous vitamin C greater than 1 gram generates hydrogen peroxide which may be able to inhibit cancer cells. 1, 2, 3, 4
In vitro studies also show that vitamin C inhibits viral replication of multiple viruses such as influenza. 1, 2, 3
Safety of intravenous and oral vitamin C
For most people vitamin C intakes at doses above the RDA for oral vitamin C are well tolerated and safe. 1, 2
People who have hemochromatosis or whose iron levels are abnormally high should exercise caution when considering vitamin C supplementation due to its propensity to improve the absorption of dietary iron. 1
Intravenous vitamin C is well tolerated and has low toxicity. The most commonly reported side effects include mild to moderate nausea, headache, and dry mouth. Less common side effects include fatigue, hypertension, loss of appetite, and hyperglycemia.1, 2 3, 4, 5
People who have a deficiency in the enzyme glucose-6-phosphate dehydrogenase are at risk of hemolysis when given high doses of over 40 grams of vitamin C but can have decreased hemolysis when given doses of 1-10 grams. 1, 2, 3, 4, 5, 6
Vitamin C intake and kidney stone risk
A small number of case-reports indicate that oxalate nephropathy has been observed when patients with kidney impairment were given high dose intravenous vitamin C. 1, 2, 3
Two large prospective cohort studies found that after statistical manipulation of the data, vitamin C was associated with an increased risk of kidney stones. However without manipulation of the data those with higher vitamin C levels actually did not have any increased risk of kidney stones. 1, 2
A large prospective study of 48,000 Swedish men found a statistically significant increase in kidney stone risk, although the effects are clinically insignificant. 1
Conclusions

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Alzheimer's disease

A neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes. The pathological hallmarks of Alzheimer's disease include amyloid-beta plaques, tau tangles, and reduced brain glucose uptake. Most cases of Alzheimer's disease do not run in families and are described as "sporadic." The primary risk factor for sporadic Alzheimer's disease is aging, with prevalence roughly doubling every five years after age 65. Roughly one-third of people aged 85 and older have Alzheimer's. The major genetic risk factor for Alzheimer's is a variant in the apolipoprotein E (APOE) gene called APOE4.

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Antioxidant

A molecule that inhibits oxidative damage to DNA, proteins, and lipids in cells. Oxidative damage plays a role in the aging process, cancer, and neurodegeneration. Many vitamins and plant-based compounds are antioxidants.

View carotenoids topic

Autoimmune disease

An immune disorder characterized by an immune response to and subsequent destruction of the body’s own tissue. The causes of autoimmune diseases are not known, but a growing body of evidence suggests they may be due to interactions between genetic and environmental factors. Autoimmune diseases affect approximately 7 percent of the population in the United States and are more common in women than in men. Examples include type 1 diabetes, Hashimoto’s thyroiditis, lupus, and multiple sclerosis.

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Bioavailability

The extent and rate at which drugs or other substances, such as plant-based dietary compounds, enter the body’s circulation. Bioavailability is influenced by a variety of factors, including dose, the presence of other foods or substances, and interindividual differences in metabolism due to gut absorptive surface and commensal microbial populations.

Biomarker

A measurable substance in an organism that is indicative of some phenomenon such as disease, infection, or environmental exposure.

Cholesterol

A waxy lipid produced primarily in the liver and intestines. Cholesterol can be synthesized endogenously and is present in all the body's cells, where it participates in many physiological functions, including fat metabolism, hormone production, vitamin D synthesis, and cell membrane integrity. Dietary sources of cholesterol include egg yolks, meat, and cheese.

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Cofactor

A substance whose presence is essential for the activity of an enzyme. Many minerals and vitamins are cofactors for enzymes.

Confounding factor

In statistics, a confounder (also confounding variable or confounding factor) is a variable that is correlated (directly or inversely) to both the dependent variable and independent variable.

Confounding factor

A variable that is related to one or more of the other variables in a study. A confounding factor can mask an association that exists between variables or demonstrate an association that does not exist. If confounding factors are not measured and considered, the findings of the study may be biased.

COVID-19

An infectious disease caused by the novel coronavirus SARS-CoV-2. COVID-19, or coronavirus disease 2019, was first identified in Wuhan, China, in late 2019. The disease manifests primarily as a lower respiratory illness, but it can affect multiple organ systems, including the cardiovascular, neurological, gastrointestinal, and renal systems. Symptoms include fever, cough, fatigue, shortness of breath, and loss of smell and taste. Some infected persons, especially children, are asymptomatic. Severe complications of COVID-19 include pneumonia, sepsis, acute respiratory distress syndrome, kidney failure, multiple organ dysfunction syndrome, and cytokine storm. Treatments currently involve symptom management and supportive care. Mortality varies by country and region, but approximately 6 percent of people living in the United States who are diagnosed with COVID-19 expire.[1] 1

C-reactive protein (CRP)

A ring-shaped protein found in blood plasma. CRP levels rise in response to inflammation and infection or following a heart attack, surgery, or trauma. CRP is one of several proteins often referred to as acute phase reactants. Binding to phosphocholine expressed on the surface of dead or dying cells and some bacteria, CRP activates the complement system and promotes phagocytosis by macrophages, resulting in the clearance of apoptotic cells and bacteria. The high-sensitivity CRP test (hsCRP) measures very precise levels in the blood to identify low levels of inflammation associated with the risk of developing cardiovascular disease.

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Creatine kinase

An enzyme present in the heart, brain, skeletal muscle, and other tissues. Creatine kinase participates in the conversion of creatine to phosphocreatine and adenosine diphosphate. Serum levels of creatine kinase can increase after a heart attack, skeletal muscle injury, strenuous exercise, heavy alcohol consumption, or intake of certain medicines or supplements. Levels of creatine kinase are reflective of muscle mass and are typically higher in males than females.

View creatine and cardioprotection topic

Crohn's disease

An inflammatory bowel disease that causes inflammation of the lining of the digestive tract, which can lead to abdominal pain, diarrhea, fatigue, weight loss and malnutrition.

View intestinal permeability topic

Cytokine

A broad category of small proteins (~5-20 kDa) that are important in cell signaling. Cytokines are short-lived proteins that are released by cells to regulate the function of other cells. Sources of cytokines include macrophages, B lymphocytes, mast cells, endothelial cells, fibroblasts, and various stromal cells. Types of cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor.

Cytokine storm

A hyperinflammatory response to infection. Cytokine storm is characterized by the overproduction of immune cells and pro-inflammatory cytokines. A frequent complication of cytokine storm is multiple organ dysfunction. Cytokine storm is often present in severe cases of COVID-19.

Deoxyribonucleic acid (DNA)

A double-stranded molecule that carries the genetic material for an organism. Each strand of DNA is composed of nucleotides strung together by covalent bonds. Nucleotides are typically identified by the first letter of their base names: adenine (A), cytosine (C), guanine (G), and thymine (T). They form specific pairs (A with T, and G with C) via hydrogen bonds, which in turn provide the helical structure of the DNA strand. Specific sequences of the nucleotides comprise genes.

DNA is packaged around histone proteins in units referred to as nucleosomes. Each nucleosome contains 147 base pairs of DNA. Complexes of DNA, RNA, and histone proteins comprise chromatin. Chromatin’s primary function is to compress the DNA into a compact structure that can fit within the nucleus. Chromatin structure and DNA accessibility can be altered by epigenetic modifications, or “tags,” such as DNA methylation and histone modification. Epigenetic changes, which do not alter the overall sequence of DNA, are heritable and can regulate patterns of gene expression.

Depression

A mood disorder characterized by profound sadness, fatigue, altered sleep and appetite, as well as feelings of guilt or low self-worth. Depression is often accompanied by perturbations in metabolic, hormonal, and immune function. A critical element in the pathophysiology of depression is inflammation. As a result, elevated biomarkers of inflammation, including the proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha, are commonly observed in depressed people. Although selective serotonin reuptake inhibitors and cognitive behavioral therapy typically form the first line of treatment for people who have depression, several non-pharmacological adjunct therapies have demonstrated effectiveness in modulating depressive symptoms, including exercise, dietary modification (especially interventions that capitalize on circadian rhythms), meditation, sauna use, and light therapy, among others.

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DNA damage

A major contributing factor to aging, cellular senescence, and the development of cancer. Byproducts of both mitochondrial energy production and immune activity are major sources of DNA damage. Additionally, environmental stressors can increase this base level of damage. DNA damage can be mitigated by cellular repair processes; however, the effectiveness of these processes may be influenced by the availability of dietary minerals, such as magnesium, and other dietary components, which are needed for proper function of repair enzymes.

Enzyme

Any of a group of complex proteins or conjugated proteins that are produced by living cells and act as catalyst in specific biochemical reactions.

Exercise-induced bronchoconstriction

A narrowing of the airways that occurs in response to exercise. Exercise-induced bronchoconstriction occurs in approximately 10 percent of the general population and up to 50 percent in some competitive athletes. The condition is characterized as a 10 percent or greater decline in exercise-induced forced expiratory volume, or FEV1 (a measure of respiratory capacity).

Exerkines

Important for the endocrine enhancing properties of exercise. Exerkines are exercise-induced hormonal-like factors which mediate the systemic benefits of exercise through autocrine, paracrine, and/or endocrine properties.^[1]

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Fatty Acid

A molecule composed of carboxylic acid with a long hydrocarbon chain that is either saturated or unsaturated. Fatty acids are important components of cell membranes and are key sources of fuel because they yield large quantities of ATP when metabolized. Most cells can use either glucose or fatty acids for this purpose.

Glucose-6-phosphate dehydrogenase (G6PD)

An enzyme that participates in the pentose phosphate pathway, a series of chemical reactions that converts glucose to ribose-5-phosphate. G6PD also helps maintain red blood cells. G6PD deficiency is a genetic abnormality that causes low levels of G6PD. It occurs more commonly in men than in women.

Glutathione

An antioxidant compound produced by the body’s cells. Glutathione helps prevent damage from oxidative stress caused by the production of reactive oxygen species.

Glutathione peroxidase

An antioxidant produced within cells that enzymatically reduces hydrogen peroxide to water to limit its harmful effects. Glutathione peroxidase's primary role is to protect cells from oxidative damage, a key factor in many diseases.

Glutathione reductase

An antioxidant produced within cells that converts oxidized glutathione to reduced glutathione. Glutathione reductase is essential for protection against oxidative damage. Oxidative damage is a key factor in many diseases.

Glycolysis

A series of enzyme-dependent reactions that breaks down glucose. Glycolysis converts glucose into pyruvate, releasing energy and producing ATP and NADH. In humans, glycolysis occurs in the cytosol and does not require oxygen.

Hemochromatosis

Iron overload, also known as hemochromatosis, indicates accumulation of iron in the body from any cause. The most important causes are hereditary haemochromatosis (HHC), a genetic disorder, and transfusional iron overload, which can result from repeated blood transfusions. Affected individuals over the age of 40 or who have high serum ferritin levels are at risk for developing cirrhosis and have a higher risk of hepatocellular carcinoma as well.

Hippocampus

A small organ located within the brain's medial temporal lobe. The hippocampus is associated primarily with memory (in particular, the consolidation of short-term memories to long-term memories), learning, and spatial navigation. Amyloid-beta plaque accumulation, tau tangle formation, and subsequent atrophy in the hippocampus are early indicators of Alzheimer’s disease.

Hypertension

High blood pressure. Hypertension, defined as a systolic pressure of 130 mm Hg or higher, or a diastolic pressure of 80 mm Hg or higher, is a robust predictor of future incidence of stroke, coronary heart disease, heart attack, heart failure, and cardiovascular-related death. Central to the pathophysiology of hypertension is the loss of arterial compliance, which can have far-reaching effects on multiple organ systems, including the brain and kidneys.

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Hypoxia

Condition in which the body or a region of the body is deprived of adequate oxygen supply. Hypoxia may be classified as either generalized, affecting the whole body, or local, affecting a region of the body.

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Inflammasome

A component of the innate immune system. The inflammasome is expressed in the myeloid cells and promotes the maturation of the pro-inflammatory cytokines IL-1B and IL-18. It is responsible for activation of inflammatory processes.

Inflammation

A critical element of the body’s immune response. Inflammation occurs when the body is exposed to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response that involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever. Chronic inflammation occurs on the cellular level in response to toxins or other stressors and is often “invisible.” It plays a key role in the development of many chronic diseases, including cancer, cardiovascular disease, and diabetes.

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Insulin

A peptide hormone secreted by the beta cells of the pancreatic islets cells. Insulin maintains normal blood glucose levels by facilitating the uptake of glucose into cells; regulating carbohydrate, lipid, and protein metabolism; and promoting cell division and growth. Insulin resistance, a characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response, which can lead to high blood glucose levels.

Interferons

A group of signaling proteins made and released by host cells in response to the presence of several pathogens, such as viruses, bacteria, parasites, and tumor cells. Interferons are named for their ability to interfere with viral replication and are critical components of the body's innate immune response to viruses. SARS-CoV-2, the virus that causes COVID-19, impairs the body's interferon response.

In vitro

Experiments that are performed using cells or microorganisms outside of their normal biological context and are often done in a test tube or petri dish.

Iron

An essential mineral present in many foods. Iron participates in many physiological functions and is a critical component of hemoglobin. Iron deficiency can cause anemia, fatigue, shortness of breath, and heart arrhythmias.

Ischemia

A restriction in blood flow to tissues which causes a shortage of oxygen and glucose needed to keep tissue alive. Ischemia usually occurs when blood vessels become clogged and dysfunctional.

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Lectin

A class of proteins present in many edible plants, such as grains or legumes. Lectins are carbohydrate-binding molecules. They have been referred to as antinutrients for their ability to impair absorption of some nutrients. Many lectins possess hemagglutinin properties, which means they can bind to blood cells and cause them to aggregate. Cooking typically denatures lectins in foods.

Leukocyte

A type of white blood cell. Leukocytes are involved in protecting the body against foreign substances, microbes, and infectious diseases. They are produced or stored in various locations throughout the body, including the thymus, spleen, lymph nodes, and bone marrow, and comprise approximately 1 percent of the total blood volume in a healthy adult. Leukocytes are distinguished from other blood cells by the fact that they retain their nuclei. A cycle of prolonged fasting has been shown in animal research to reduce the number of white blood cells by nearly one-third, a phenomenon that is then fully reversed after refeeding.^[1]

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Liposome

A lipid particle that can encapsulate water-soluble substances. Liposomes are commonly used as drug delivery systems because they enhance uptake in the gut and increase bioavailability of the delivered substance.

Mechanical ventilation

A respiratory intervention in which a mechanical ventilator assists or replaces a patient's spontaneous respirations.

Metabolism

The thousands of biochemical processes that run all of the various cellular processes that produce energy. Since energy generation is so fundamental to all other processes, in some cases the word metabolism may refer more broadly to the sum of all chemical reactions in the cell.

Mitochondria

Tiny organelles inside cells that produce energy in the presence of oxygen. Mitochondria are referred to as the "powerhouses of the cell" because of their role in the production of ATP (adenosine triphosphate). Mitochondria are continuously undergoing a process of self-renewal known as mitophagy in order to repair damage that occurs during their energy-generating activities.

View hallmarks of aging topic

Mitochondrial biogenesis

The process by which new mitochondria are made inside cells. Many factors can activate mitochondrial biogenesis including exercise, cold shock, heat shock, fasting, and ketones. Mitochondrial biogenesis is regulated by the transcription factor peroxisome proliferator-activated receptor gamma coactivator 1-alpha, or PGC-1α.

Mononucleosis

A highly contagious disease caused by Epstein-Barr infection. Mononucleosis (commonly referred to as "mono" or "kissing disease") is characterized by high fever, sore throat, and enlarged lymph nodes.

Multivariate analysis

A statistical method used to identify patterns and relationships between several variables simultaneously. Multivariate analysis is commonly used to analyze complex sets of data because it reduces the likelihood of type I errors.

Neurodegenerative disease

A broad range of disorders caused by the progressive death of neurons in the central and peripheral nervous systems. Common neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington’s disease, and multiple sclerosis. Although treatments are available for some neurodegenerative diseases, there are currently no cures.

Neutrophil

A type of white blood cell, also known as a granulocyte. Neutrophils are the most abundant form of blood cell, comprising approximately 60 percent of total cells. They ingest, kill, and digest microbial pathogens, and are the first cells recruited to acute sites of injury. Neutrophils can infiltrate brain structures, driving inflammation and increasing the risk for neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease.

Nucleotide

One of four nitrogen-containing molecules that comprise DNA. A nucleotide consists of one of four chemicals, called a “base,” plus one molecule of sugar and one molecule of phosphoric acid. Nucleotides are typically identified by the first letter of their base names: adenine (A), cytosine (C), guanine (G), and thymine (T). They form specific pairs (A with T, and G with C), and their bonds provide the helical structure of the DNA strand.

Oxalate

A naturally-occurring substance found in many foods. Oxalate binds to calcium in the gut and is eliminated in the feces. Any unbound oxalate passes through the kidneys and is excreted in the urine. High levels of oxalate in the kidneys can contribute to the risk of developing kidney stones. Dietary sources of oxalate include dark green leafy vegetables, beans, potatoes, and bran, among others.

Oxidant

Highly reactive molecules that have the ability to oxidize other molecules and cause them to lose electrons. Common oxidants are oxygen, hydrogen peroxide, and superoxide anion.

Oxidation

A chemical reaction in which an atom, molecule, or ion loses one or more electrons. Oxidation of biological molecules is associated with oxidative stress, a key driver of many chronic diseases.

Oxidative stress

A result of oxidative metabolism, which causes damage to DNA, lipids, proteins, mitochondria, and the cell. Oxidative stress occurs through the process of oxidative phosphorylation (the generation of energy) in mitochondria. It can also result from the generation of hypochlorite during immune activation.

View cold exposure topic

Parkinson's disease

A neurodegenerative disorder that affects the central nervous system. Parkinson’s disease is caused by destruction of nerve cells in the part of the brain called the substantia nigra. It typically manifests later in life and is characterized by tremors and a shuffling gait.

View blood-brain barrier topic

Pathogen

In general, anything that can produce disease. Typically, the term is used to describe an infectious agent such as a virus, bacterium, prion, fungus, or other microorganism.

Pharmacokinetics

The movement of a drug or other xenobiotic substance into, through, and out of the body. Pharmacokinetics comprises absorption, distribution, metabolism, and excretion, often abbreviated "ADME." Many factors influence pharmacokinetics, including a person's age, gut health, and circadian rhythms, as well as the substance's bioavailability.

PPAR-alpha (Peroxisome proliferator-activated receptor alpha)

One of the three isotypes of a subfamily of nuclear receptor proteins (the PPARs) that functions as a transcription factor. PPAR-alpha is a major regulator of lipid metabolism in the liver and is activated under conditions of energy deprivation. It is necessary for the process of ketogenesis, a process that is a key adaptive response to prolonged fasting and is inducible by strict carbohydrate restriction. Activation of PPAR-alpha promotes uptake, utilization, and catabolism of fatty acids by upregulation of genes involved in fatty acid transport, fatty acid binding and activation, and peroxisomal and mitochondrial fatty acid β-oxidation. Expression of PPAR-alpha is highest in tissues that oxidize fatty acids at a rapid rate, especially the liver, but also brown adipose tissue (BAT), the heart, and kidney.

Prefrontal Cortex

The area of the brain located in the front portion of the frontal lobe, just behind the area commonly known as the forehead. The prefrontal cortex is involved in a variety of higher cognitive functions and behaviors such as executive function and expression of appropriate social behavior.

Prophylactic

A medication or treatment intended for the prevention of disease.

Prospective cohort study

A prospective cohort study is a type of study, e.g., in sociology or medicine, that follows participants for a particular future time period.

Reactive Oxygen Species (ROS)

Oxygen-containing chemically-reactive molecules generated by oxidative phosphorylation and immune activation. ROS can damage cellular components, including lipids, proteins, mitochondria, and DNA. Examples of ROS include: peroxides, superoxide, hydroxyl radical, and singlet oxygen.

A related byproduct, reactive nitrogen species, is also produced naturally by the immune system. Examples of RNS include nitric oxide, peroxynitrite, and nitrogen dioxide.

The two species are often collectively referred to as ROS/RNS. Preventing and efficiently repairing damage from ROS (oxidative stress) and RNS (nitrosative stress) are among the key challenges our cells face in their fight against diseases of aging, including cancer.

Recommended dietary allowance (RDA)

The daily nutrient goals for essentially all healthy people. RDAs are calculated by determining the Estimated Average Requirements (the average amount of nutrients that half of all healthy people in any given demographic need each day) and adding two standard deviations. This ensures that the RDAs exceed the requirements of approximately 97.5% of the population.

Reduction

A chemical reaction in which an atom, molecule, or ion gains one or more electrons.

Reverse transcriptase

An enzyme that facilitates the generation of complementary DNA. In viruses, reverse transcriptases convert viral RNA into a complementary DNA, which can then be integrated into the host’s genome. In humans, the reverse transcriptase telomerase maintains and extends the length of telomeres.

Rheumatoid arthritis (RA)

A long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involved. The underlying mechanism involves the body's immune system attacking the joints.

View cold exposure topic

Ribonucleic acid (RNA)

A molecule that participates in the flow of genetic information from DNA into proteins.

Scurvy

A disease caused by vitamin C deficiency. Scurvy is characterized by bleeding, swollen gums, poor wound healing, joint pain, and bruising. Clinical features of scurvy appear in a person in as little as 84 to 97 days of vitamin C depletion. As scurvy progresses, a person might experience shortness of breath, dry eyes, joint swelling, weakness, fatigue, and depression.

Sepsis

The body's overwhelming and life-threatening response to an infection which can lead to tissue damage, organ failure, and death.

Signaling molecule

A molecule that allows cells to perceive and correctly respond to their microenvironment, which enables normal cellular function, tissue repair, immunity, cognition, and more. Hormones and neurotransmitters are examples of signaling molecules. There are many types of signaling molecules, however, including cAMP, nitric oxide, estrogen, norepinephrine, and even reactive oxygen species (ROS).

Single nucleotide polymorphism (SNP)

A change in one nucleotide DNA sequence in a gene that may or may not alter the function of the gene. SNPs, commonly called "snips," can affect phenotype such as hair and eye color, but they can also affect a person's disease risk, absorption and metabolism of nutrients, and much more. SNPs differ from mutations in terms of their frequency within a population: SNPs are detectable in >1 percent of the population, while mutations are detectable in <1 percent.

Sodium-dependent vitamin C transporter (SVCT2)

A high-affinity transporter that regulates the uptake of vitamin C from plasma. SVCT2s are widely expressed in the body's cells, but they are most abundant in the gut enterocytes. SVCT2s are saturable; as such, uptake of vitamin C is tightly regulated.

Statins

A class of drugs that lower blood cholesterol levels by blocking the production of an enzyme in the liver called hydroxy-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). Taking statins may reduce the risk of cardiovascular disease in some people. Although statins are generally well tolerated, as many as 10 – 20 percent of people taking the drugs experience complications, including myopathy (muscle damage), liver damage, and cognitive problems, including issues with forgetfulness, memory loss, and confusion.

Superoxide dismutase

A class of powerful antioxidant enzymes produced in cells. Superoxide dismutases convert harmful superoxide radicals to harmless molecular oxygen and hydrogen peroxide, providing cellular defense against reactive oxygen species.

Univariate analysis

A statistical method used to analyze data involving only one variable.

Vitamin A

A fat-soluble vitamin. Vitamin A is a collective term that includes retinol, retinal, and retinyl esters. Vitamin A plays key roles in immune function, reproduction, and cellular communication. It is best known for its role in supporting eye health and the processes involved in vision. Vitamin A also supports cell growth and differentiation and participates in the normal formation and maintenance of the heart, lungs, kidneys, and other organs. Dietary sources of vitamin A include liver, fish oils, milk, eggs, leafy green vegetables, orange and yellow vegetables, tomato products, fruits, and some vegetable oils.

Vitamin B1 (Thiamine)

Thiamine is a water-soluble B-vitamin, also known as vitamin B1, and a cofactor for enzymes involved in the breakdown and metabolism of carbohydrates, certain amino acids, and fatty acids. These enzymes help to generate energy in the form of ATP and modulate levels of amino acids that can cause deleterious effects. Thiamine is highly water soluble and is not retained in the body. For this reason, it must be continually obtained from the diet. Dietary sources of thiamine include vegetables, whole grains, legumes, and pork livers. Deficiencies in thiamine result in neurological, muscular, and cardiac symptoms, and can occur in as little as 18 days of total dietary depletion.

Vitamin C

A potent water-soluble antioxidant found in citrus fruits. Vitamin C is an essential nutrient involved in tissue repair, neurotransmission, and immune system function. Also known as ascorbic acid.

View vitamin c topic

Vitamin E

A fat-soluble vitamin. Vitamin E is the collective name for a group of eight fat-soluble compounds (alpha-, beta-, gamma-, & delta-tocopherol and alpha-, beta-, gamma-, & delta-tocotrienol) with distinctive antioxidant activities. Of these eight, only alpha- (α-) tocopherol meets human requirements. Vitamin E serves as an antioxidant that breaks the chain reaction formation of reactive free radicals. In doing so it becomes oxidized and loses its antioxidant capacity. Vitamin E also protects LDL from oxidation and maintains the integrity of cell membranes throughout the body. Dietary sources of vitamin E include nuts, seeds, eggs, and fatty fish, such as salmon.

VO2 Max

The maximum rate of oxygen consumption as measured during incremental exercise and indicates the aerobic fitness of an individual, and plays a role in endurance capacity during prolonged, submaximal exercise.

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SWSL

05/14/2020

“assume that topsoil was more nutrient dense than it often is now, making fruit less nutrient potent.”
No doubt, and this is a prime argument for mineral supplementation. Might be true for C content also? I wonder if there’s any indication for what ancestral vitamin C levels were. Or healthy tribes we have studied in modern times.

In any case, if we are supplementing to the limits of what our bodies will actually accept in food, then the question is why do we have to work so hard to overcome our natural limits? Did we evolve to need liposomal C for optimal health? Are we forcing the issue with a “more is better” mentality without an adequate understanding of the larger dynamics?

The idea of going with food-sourced (super-foods included) nutrition versus isolated elements in supplements has been a key point with Rhonda. Not rigid, but an orientation that makes good sense.

Krudup

05/13/2020

I’m a long time Pauling fan, less so post Rath, however. I think whole C with all the co-factors is optimal. I think ascorbic acid is kind of like the molecular shell. If I’m sick (very rare) I’ll make liposomal C. Also, I assume that topsoil was more nutrient dense than it often is now, making fruit less nutrient potent.

SWSL

05/13/2020

Great, thanks! Two counter-point thoughts to consider-

1) We are starting to understand the ROS are not just terrible bad enemies of life, but like everything else, integral to our system. The ROS seem to play a role as signalers. A balance between ROS and anti-oxidant levels may promote better health than simply hammering our bodies with anti-oxidants with no regard for the value of ROS in the dynamic? Rhonda did address this to a degree here with the discussion on exercise and blunting of beneficial effects and the linked research.

2) How do we reconcile historical dietary levels of C in the course of evolution with the idea of forcing huge over-supplies of it on our systems? Again, are we so sure that pushing for higher than an ancestral diet would provide is better for us on a daily basis?

Krudup

05/13/2020

“are we so sure that pushing for higher than an ancestral diet would provide is better for us on a daily basis?” Great question. Would the maximum natural blood plasma level from oral intake be the optimal self-leveling amount?