#53 COVID-19 Q&A #1 with Rhonda Patrick, Ph.D.

Posted on April 14th 2020 (over 4 years)

covid-19 vitamin d vitamin c virus melatonin sauna autoimmunity

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A little over a week ago, subscribers to my newsletter were asked to share some of their biggest questions regarding the on-going COVID-19 pandemic.

Hundreds of questions were submitted, ultimately laying the groundwork for what we think might become an on-going series. Today's episode will feature just a few of the more interesting ones.

Below you can find a summary of the topics Dr. Rhonda Patrick addressed in the Q&A. However, there are many more details discussed in this episode that are not summarized here.

Some of the questions we selected from the batch to cover in this episode include:

Are children and infants susceptible to COVID-19? Are some more susceptible to a more severe form of the disease? Are they carriers of it and possibly spreading transmission?
Can you explain a little about hydroxychloroquine as possibly treating COVID-19? How does it work? Does it have to do with it being a zinc ionophore?
Can you talk about quercetin's role as a zinc ionophore?
Is there any indication blood type influences COVID-19 risk?
Would you shed light on the conversation regarding vitamin D upregulating ACE2 receptors and vitamin D's influence on susceptibility to COVID19 infection?
Can you discuss whether sauna use might help prevent COVID19?
Is it true that high dose intravenous vitamin C might help treat COVID-19?
What are your thoughts on melatonin being a potential factor to impacting the severity of the virus via its effects on inflammation and oxidative stress?

Summary

On December 31, 2019, public health experts in China's Hubei province reported a cluster of unexplained pneumonia-like infections to the World Health Organization's China Country Office. That early report of a small, local epidemic of lower respiratory illness has since evolved into a global pandemic now known as coronavirus disease 2019, or COVID-19, an infection attributed to SARS-CoV-2, a novel coronavirus.

Coronaviruses are members of the Coronaviridae family. SARS-CoV-2 is one of seven coronaviruses known to infect humans. Others include SARS-CoV-1 (which causes severe acute respiratory syndrome, or SARS) and MERS-CoV (which causes Middle East respiratory syndrome, or MERS). COVID-19 is a respiratory disease with a clinical spectrum that ranges from no or few symptoms to acute respiratory failure, sepsis, and multiple organ dysfunction syndrome.

At the time of this writing in early April 2020, the worldwide death toll from COVID-19 has exceeded 115,000 people. Epidemiologists, public health experts, and infectious disease specialists expect that number to grow at a nearly exponential rate over the coming weeks before peaking. The disease has rocked global health, economic, and political systems.

Gaining a viral foothold in cells

SARS-CoV2 exploits the angiotensin-converting enzyme 2, or ACE2, receptor to gain entry into cells. The ACE2 receptor is widely distributed among the body's tissues but is particularly abundant in lung alveolar epithelial cells and small intestine enterocytes. The virus binds to a cell's ACE2 receptor and injects its genetic material – RNA – into the cytosol. Once inside, the viral RNA molecules are translated to produce RNA-dependent RNA polymerase (also known as replicase), the enzyme critical for the reproduction of RNA viruses. Essentially, the virus hijacks the body's natural replicating processes to promote viral reproduction. The viral RNA is then packaged into infective virion particles and released from the cell to infect neighboring cells.

Association between blood type and COVID-19

A question that is perhaps at the forefront of the public's mind is this: What factors increase the risk for developing COVID-19? As with any viral infection, older age and the presence of underlying health conditions are known risk factors for COVID-19. But some evidence suggests that a person's blood type might make them more susceptible to developing the disease. Blood types have previously been implicated in the susceptibility to other viral infections. For example, in the related SARS-CoV-1 virus, type A antibodies (as found in O and B blood types) can provide protection by inhibiting the interaction between the virus and ACE2 receptors. Similarly, data suggest that people with blood type A might have a higher risk of developing COVID-19, but people with blood type O have a lower risk.

Understanding how COVID-19 affects children

A huge concern for epidemiologists is the effect of COVID-19 in pediatric populations. Children are largely unaffected by COVID-19 illness, remaining disease-free or manifesting few or mild clinical signs and symptoms. Consequently, children, who account for nearly 5 percent of COVID-19 diagnoses, might be inadvertent vectors for the disease. Understanding how the infection affects children is critical to preventing the further spread of the disease. Evidence suggests that certain subgroups of children could be at greater risk for developing COVID-19, including those who are younger, have respiratory problems, or are immunocompromised.

Another concern is the risk of mother-to-child transmission of disease, also known as vertical transmission, which can occur during pregnancy. Several viruses, including hepatitis B, herpes varicella-zoster (chickenpox), and human immunodeficiency virus, can be passed via vertical transmission. However, case reports and retrospective studies indicate that SARS-CoV-2 is not transmittable from pregnant mothers to their infants at birth, but Caesarean delivery and quick isolation likely reduce exposure. While infants born to mothers with COVID-19 have not tested positive for the SARS-CoV-2, virus-specific antibodies have been detected in neonatal blood sera samples.

Hydroxychloroquine as a potential therapeutic for COVID-19

The emergence of a novel virus such as SARS-CoV-2 has challenged healthcare providers, who have sought equally novel means of treating COVID-19. Unfortunately, the data to support the use of treatments for COVID-19 are limited and inconclusive.

A great deal of attention has been focused on hydroxychloroquine, an old, inexpensive drug with a known safety profile and few interactions and side effects. Originally utilized as an antimalarial therapeutic, hydroxychloroquine is now also used to treat rheumatoid arthritis and lupus. The drug has demonstrated in vitro activity against several viruses, including coronaviruses and influenza, but previous randomized trials in people with influenza have been negative. Although the drug is well-tolerated, it does carry safety concerns, including the risk for retinal damage and cardiovascular complications such as irregular heart rhythms. Only well-designed randomized clinical trials will demonstrate hydroxychloroquine's true effectiveness as a treatment for COVID-19.

Another possible candidate is quercetin, a polyphenolic compound present in onions, green tea, apples, berries, and other edible plants. Quercetin exerts anti-inflammatory, antioxidant, and anti-viral properties and might improve immune function. It is safe, well-tolerated, and is already an FDA-approved drug ingredient. Although the compound has not been clinically tested against SARS-CoV-2, clinical trials are beginning, with outcomes expected in a few months.

The mechanism by which hydroxychloroquine and quercetin exert their beneficial effects might lie in their capacity to serve as ionophores. Ionophores are compounds that can transport ions across a lipid membrane. Of particular relevance in viral disease is the movement of zinc, an essential nutrient that inhibits the action of RNA-dependent RNA polymerase, described above. Essentially, zinc blocks the replication of viruses. However, zinc is a positively charged ion and cannot enter cells without a transporter. Hydroxychloroquine and quercetin are known ionophores.

For an interesting discussion on the zinc ionophore activity of chloroquine in the context of coronavirus, watch coronavirus update #34 from Medcram on YouTube.

Vitamin D and respiratory tract infections

Vitamin D is a steroid hormone. It is available in small quantities in food, but the primary source is via endogenous synthesis. This process occurs in a stepwise manner that starts in the skin following exposure to ultraviolet light and continues in the liver and kidneys, where the vitamin's active hormone form is made. Since ultraviolet light is required for vitamin D synthesis, reduced exposure to the sun or having dark-colored skin impairs vitamin D production. Approximately 70 percent of people living in the United States are vitamin D insufficient and ~30 percent are deficient.

Robust evidence suggests that vitamin D is protective against respiratory tract infections. Data from 25 randomized controlled trials from around the world demonstrate that daily or weekly supplementation of vitamin D reduced the risk of acute respiratory infection by more than 50 percent in people with low baseline vitamin D levels. People with higher baseline vitamin D levels also benefited, although the effect was more modest, with only a 10 percent risk reduction.

Vitamin D and the renin-angiotensin-system

SARS-CoV-2 virus enters human cells via the ACE2 receptor. Viral particles bind to the ACE2 receptor and together they are internalized into the cell. These viral particles can bind to a large number of ACE2 molecules, sequestering the ACE2 molecules from the cell surface and decreasing ACE2. This accompanying loss of ACE2 function can cause serious health consequences due to ACE2's participation in key physiological processes. This also occurs with infection via SARS-CoV-1, which also binds to the ACE2 receptor, decreasing cellular ACE2 expression levels and increasing disease severity.

Vitamin D deficiency leads to overexpression of renin (an enzyme produced in the kidneys) and subsequent activation of the renin-angiotensin-system, a critical regulator of blood pressure, inflammation, and body fluid homeostasis. Disturbances in this system due to the loss of ACE2 function in the setting of SARS-CoV-2 infection can promote neutrophil infiltration, excessive inflammation, and lung injury. Once lung infection progresses to hypoxia, renin is released, setting up a vicious cycle for decreasing ACE2. Lower levels of ACE2 promote more damage, culminating in acute respiratory distress syndrome, or ARDS. Vitamin D acts as an endocrine repressor of the renin-angiotensin-system by downregulating the expression of renin, the rate-limiting enzyme of the renin-angiotensin cascade.

In a preclinical model of acute lung injury, administration of the active form of vitamin D provided protection against lung injury by balancing the renin-angiotensin-system via increasing ACE2 levels and decreasing renin production. It is important to note that the acute lung injury itself led to a decrease in ACE2 and this resulted in worse disease outcomes. The vitamin D increased ACE2 receptor levels only in conditions of acute lung injury where ACE2 levels decreased. When vitamin D was given to control animals, it did not cause an increase in ACE2 receptor levels. This means that vitamin D normalizes ACE2 receptor levels in situations where it is downregulated.

Since vitamin D insufficiency is widespread (and perhaps exacerbated in quarantine conditions, due to limited sunlight exposure), supplemental vitamin D might be a viable means to increase vitamin D to sufficient levels.

Intravenous vitamin C

Vitamin C, also known as ascorbic acid, is an essential nutrient, widely recognized for its antioxidant properties. For the past several decades, intravenous vitamin C has been used as an effective antiviral agent for the treatment of multiple types of viral infections such as herpes zoster (shingles), herpes simplex (cold sores), herpes varicella-zoster (chickenpox), influenza, measles, and mumps, among others.

Oral vitamin C uptake in the gut is limited due to saturable transport mechanisms. Intravenous vitamin C bypasses these mechanisms, however. Consequently, the bioavailability of intravenous vitamin C is 30 to 70 times higher than the same oral dose, which might translate to different biological outcomes. For example, 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 generate hydrogen peroxide, a type of reactive oxygen species produced by neutrophils to destroy pathogens such as viruses.

Intravenous vitamin C's effectiveness in treating viral infections is also likely due to its ability to enhance the immune system. Vitamin C is highly concentrated in immune cells, with neutrophils and leukocytes having 50 to 100 times higher vitamin C concentrations than plasma.

Furthermore, some studies have observed that in critically ill patients such as those with severe viral infections, plasma levels of vitamin C might be less than 25 percent of those observed in healthy people.

It is noteworthy that there are no published studies on the effect of intravenous vitamin C on COVID-19. However, some anecdotal evidence suggests that it might be beneficial in treating the disease. For example, intravenous vitamin C reduced mortality in patients with sepsis and ARDS, two complications associated with severe COVID-19. An ongoing trial in China will likely provide more evidence to support or discount the efficacy of intravenous vitamin C against COVID-19.

Possible links between melatonin and the NLRP3 inflammasome

Melatonin is a hormone produced in the pineal gland of the brain. It regulates the sleep-wake cycle and the expression of more than 500 genes in mammals. Melatonin production is markedly reduced in older adults. Some evidence suggests that melatonin modulates the NLRP3 inflammasome. Inflammasomes are large, intracellular complexes that detect and respond to internal and external threats. Activation of inflammasomes has been implicated in a host of inflammatory disorders.

SARS-CoV-1, the virus that caused the original SARS, activates the NLRP3 inflammasome, triggering NF-kB and a cytokine storm in the lungs. During a cytokine storm, an excessive immune response ravages healthy lung tissue and drives acute respiratory failure. Melatonin exerts anti-inflammatory and antioxidative properties that protect against respiratory failure associated with other viral pathogens in animal studies. For example, melatonin ameliorates respiratory syncytial virus‐induced lung inflammatory injury in mice via inhibition of oxidative stress and proinflammatory cytokine production. Additionally, two clinical studies have shown that melatonin exerts antioxidant and anti-inflammatory actions in the lungs of newborns with respiratory distress syndrome. Melatonin treatment reduced proinflammatory cytokines and improved the clinical outcome.

Sauna use and immunity

No data suggest that sauna use or other modalities of heat stress such as steam showers or hot baths will have any effect on COVID-19 illness. However, robust evidence suggests that sauna use promotes mild hyperthermia, which, in turn, induces a wide array of beneficial physiological responses. These responses reduce oxidative stress and inflammation and activate cellular defense systems such as heat shock proteins, which provide protection against many diseases. Data from a 2017 study suggest that sauna use reduces the risk of developing certain chronic or acute respiratory illnesses, including pneumonia, by up to 40 percent.

Sauna use reduced the incidence of common colds in 25 participants who used the sauna one to two times per week for six months compared to 25 controls who did not. It is noteworthy that it took three months before sauna use had a protective effect. The mechanism by which frequent sauna use reduces the incidence of pneumonia and colds is unknown but might be related to modulation of the immune system. Levels of white blood cells (especially lymphocytes, neutrophils, and basophils) are increased in both trained and non-athletes after sauna use. While these findings are interesting, they are still preliminary and larger studies are needed to confirm.

Increasing evidence suggests that certain heat shock proteins play a role in both innate and adaptive immunity. Heat shock proteins can directly stimulate innate immune responses, such as the maturation and activation of dendritic cells and the activation of natural killer cells. This indicates there may be a direct role for heat shock proteins in regulating the innate immune response, which plays an important role in the body's ability to fight off a disease that it has never been exposed to before.

Learn more about sauna use and immunity in our overview article.

Look for a second COVID-19-focused Q&A, coming soon.

Question: Are children and infants susceptible to COVID-19? Are some more susceptible to a more severe form of the disease? Are they carriers of it and possibly spreading transmission?
Most children have mild clinical manifestations of COVID-19. 1
Inactivated SARS-CoV-2 is detectable in feces suggesting a possibility of fecal to oral transmission. 1
Several studies have reported no transmission of COVID-19 from mother to baby in the womb or at birth. 1 , 2 , 3
How SARS-CoV-2 was not detected in the serum or throats in newborns but virus-specific antibodies were detected in neonatal blood. 1
The CDC recommends that breastfeeding is safe for mothers with COVID-19 and has guidelines for safety. 1
Question: Can you explain a little about hydroxychloroquine as possibly treating COVID-19? How does it work? Does it have to do with it being a zinc ionophore?
How a small open-label study found hydroxychloroquine resulted in nasal clearance of virus in 70 percent of patients by day 6 compared with 12.5 percent in the group receiving standard of care. 1
How a larger observational study using hydroxychloroquine and azithromycin saw clinical improvement in nearly all patients. 1
How two smaller studies saw no clinical difference in hydroxychloroquine and azithromycin. 1 , 2
Possible side effects of hydroxychloroquine including negative effects on cardiac function. 1 , 2 , 3
How the SARS-CoV-2 virus infects and replicates inside cells.
How zinc impedes viral replication by inhibiting RNA-dependant RNA polymerase of coronavirus virus. 1
How zinc requires an ionophore to effectively be transported inside of cells and how chloroquine acts as a zinc ionophore and increases intracellular levels of zinc. 1
How hydroxychloroquine is a less toxic derivative of chloroquine and is three times more effective in inhibiting SARS-CoV-2 infection in vitro. 1 , 2
Question: Can you talk about Quercetin's role as a zinc ionophore?
Quercetin has been reported to block the entry of SARS-CoV-1 into host cells. 1
A bioinformatics analysis screened for drugs that could be repurposed for treatment of SARS-CoV-2 and identified quercetin as one of the thirty potential drug candidates. 1
How quercetin has zinc ionophore activity in vitro. 1
Question: Is there any indication blood type influences COVID-19 risk?
Based on some small studies, people with blood group A may have a higher risk of acquiring COVID-19 compared with non-A blood groups. Whereas individuals with blood group O may have a significantly lower risk for the infection compared with non-O blood groups. 1
Wuhan patients with blood group A were more likely to die from COVID-19. 1
Question: Would you shed light on the conversation regarding vitamin D upregulating ACE2 receptors and its influence on susceptibility to COVID19 infection?
How 70% of the US has vitamin D insufficiency*, and 28.9% has vitamin D deficiency. 1
Older adults were 63 % more likely to have vitamin D deficiency and 46 % more likely to have vitamin D insufficiency than young adults. 1
Obese individuals have greater than 50% less bioavailability of vitamin D compared to non-obese individuals. 1
African-Americans have 24.6 times higher vitamin D deficiency and 3.7 times higher vitamin D insufficiency than caucasions. 1
In Stockholm Sweden, 40% of the COVID-19-related deaths are Somali immigrants, even though they only make up 0.84% of the population. 1
Supplementation of vitamin D reduced the risk of acute respiratory infection by more than 50% in people with the lowest baseline vitamin D levels. 1
ACE2 receptor is the entry point for SARS-CoV-2 virus but also is protective of acute lung injury.
SARS-CoV-1, which also enters the cell through the ACE2 receptor, decreases ACE2 expression levels and this has been shown to cause worse disease severity. 1
Decreased ACE2 levels are found in people with chronic conditions, elderly, and males. 1
Vitamin D normalizes the renin-angiotensin-system including ACE2 levels. 1 , 2
Vitamin D acts as an endocrine repressor of the renin-angiotensin-system by downregulating the expression of renin, the rate-limiting enzyme of the renin-angiotensin cascade. 1
Human recombinant soluble ACE2 reduced the SARS-CoV-2 infection in engineered human organoid tissues possibly by sequestering viral particles analogous to an antibody. 1
Vitamin D supplementation dosage
Question: Can you discuss whether sauna use may help prevent COVID19?
Men who used the sauna two to three times weekly were 27 percent less likely to develop pneumonia than those who used the sauna once weekly or not at all. Men who used the sauna four to seven times weekly were 41 percent less likely to develop pneumonia compared to infrequent or non-users. 1
Frequent sauna use decreases pulmonary congestion, and improves lung function including vital capacity, tidal volume, minute ventilation, and forced expiratory volume. 1
Far infrared ray dry saunas also has been shown to improve lung function in patients with chronic pulmonary disease, also called COPD. 1
Sauna bathing was shown to reduce the incidence of common colds in 25 participants that used the sauna 1-2 times per week for 6 months compared to 25 controls that did not. 1
Heat shock proteins have been shown to be increased by ~50% after 30 minutes in a 163 F (73 C) sauna in healthy young men and women. Once activated they can remain so for up to 48 hours. 1
Hsps can directly stimulate innate immune responses, such as the maturation and activation of dendritic cells, and the activation of natural killer cells. 1
Hsp 70 stimulates the immune system and confers protection against Herpes Simplex Virus and Influenza virus. 1 , 2
A 104ºF (40ºC) hot bath from the waist down for 1 hour is able to increase heat shock proteins. 1
Compared to the average of a 30-day hospital stay for all Covid-19 patients, those patients who received high dose IV Vitamin C had a hospital stay about 3-5 days shorter than the overall patients. 1
Intravenous vitamin C can reach blood concentrations that are 30 to 70 times higher than the same oral dose. 1 , 2
Intravenous vitamin C for the treatment of sepsis and acute respiratory distress syndrome.
In a randomized, double-blind, placebo-controlled, multicenter trial investigating the role of intravenous vitamin C for sepsis, vitamin C had a 30% mortality rate whereas the placebo-control group had a 46% mortality rate. Patients who received vitamin C had fewer ventilated days, spent less time in intensive care (seven days versus ten), and their hospital stays were approximately one week shorter than those who received the placebo. 1
Intravenous vitamin C alone or in combination with other treatments decrease the risk of organ failure and mortality in patients diagnosed with sepsis. 1 , 2
Intravenous vitamin C has been used for the treatment of viral illnesses such as viral myocarditis and epstein-barr virus. 1
Vitamin C blood levels during a viral infection can be less than 25% of normal, healthy values. 1
Vitamin C also boosts the immune system by promoting the proliferation of T cells and preventing T cell death. 1
High dose intravenous vitamin C leads to the formation of hydrogen peroxide but does not increase pro-oxidative markers. 1 , 2
Intravenous vitamin C is generally safe but may cause hemolysis in patients with G6PD deficiency. 1 , 2 , 3 , 4
Question: What are your thoughts on melatonin being a potential factor to impact the severity of the virus via its effects on inflammation and oxidative stress?
Potential role of melatonin as an adjuvant treatment for COVID-19. 1
Background information on melatonin. 1 , 2
Human lymphoid cells are an important physiological source of melatonin. The melatonin concentration increases up to five times the nocturnal physiological levels in human serum. 1
T-lymphocytes, natural killer cells, eosinophils, and mast cells possess melatonin receptors. Melatonin has the capability to regulate leukocyte function and contributes to the control of inflammation in tissues. 1
Melatonin administration increases the proliferative response of rat lymphocytes, increases the number of NK cells, stimulates the release of pro-inflammatory cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-α, enhances phagocytosis and modulates apoptosis. 1
Melatonin inhibits translocation of nuclear factor-kappa B (NF-kB) to the nucleus, thereby reducing pro-inflammatory cytokine production. 1
Melatonin has been shown to be protective against acute lung injury/ acute respiratory distress syndrome caused by other viral pathogens in preclinical animal studies. 1 , 2
Two clinical studies have shown that melatonin has antioxidant and anti-inflammatory actions in the lungs of newborns with respiratory distress syndrome. 1 , 2
Randomized controlled trials have shown melatonin is able to reduce proinflammatory cytokines TNF-α, IL-6, hs-CRP, IL-1β and lipoperoxides. 1 , 2 , 3 , 4 , 5)
SARS-CoV1 activates the NLRP3 inflammasome, triggering NF-kB and a cytokine storm in the lungs. Melatonin has been shown to reduce the infiltration of macrophages and neutrophils into the lung in acute lung injury models due to the inhibition of NLRP3 inflammasome. 1
A meta-analysis of 19 randomized controlled trials demonstrates that melatonin decreases sleep onset latency, increases total sleep time and improves overall sleep quality. 1
Melatonin has a high safety profile. 1 , 2 , 3

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Albumin

The primary protein present in human blood plasma. Albumin binds water, minerals, fatty acids, hormones, bilirubin, and many drugs. Its main function is to regulate the oncotic pressure of blood, a form of osmotic pressure exerted by proteins that tends to pull water into the circulatory system.

Ambien

A prescription drug used to treat insomnia (also known as Zolpidem). Ambien is in a class of medications called sedative-hypnotics. It promotes the activity of GABA receptors in the brain, which slows brain activity to allow sleep.

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

Apoptosis

Programmed cell death. Apoptosis is a type of cellular self-destruct mechanism that rids the body of damaged or aged cells. Unlike necrosis, a process in which cells that die as a result of acute injury swell and burst, spilling their contents over their neighbors and causing a potentially damaging inflammatory response, a cell that undergoes apoptosis dies in a neat and orderly fashion – shrinking and condensing, without damaging its neighbors. The process of apoptosis is often blocked or impaired in cancer cells. (May be pronounced “AY-pop-TOE-sis” OR “AP-oh-TOE-sis”.)

Atherosclerosis

A disease characterized by the deposition of fatty plaques on the inner walls of arteries. Something is said to be atherogenic when it promotes the formation of fatty plaques in the arteries. Atherosclerosis causes coronary artery disease.

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.

View thymic involution topic

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.

Blue light

A wavelength of light emitted from natural and electronic sources. Blue light exposure is associated with improved attention span, reaction time, and mood. However, exposure to blue light outside the normal daytime hours may suppress melatonin secretion, impairing sleep patterns. In addition, blue light contributes to digital eye strain and may increase risk of developing macular degeneration.

Chelator

A protein that can bond to free metals. Often the metal atom is used to lower activation energy for reactions and speed up reactions in the body. Common examples of chelators include porphyrin rings in hemoglobin and chlorophyll.

Chloroquine

A medication used to prevent and to treat malaria. It is also occasionally used for amebiasis that is occurring outside of the intestines, rheumatoid arthritis, and lupus erythematosus. Currently it is being researched as an antiretroviral in humans with HIV-1/AIDS, an agent in chemotherapy for cancer, and its ability to inhibit lysosomal degradation of protein products during autophagy.

Chromosome

A tightly coiled molecule of DNA found in the nucleus of a cell. Chromosomes contain the genes and other genetic material for an organism. Humans have 46 chromosomes arranged in 23 pairs. Each chromosome is comprised of long stretches of DNA wrapped around proteins called histones, which provide structural support. At the end of each chromosome is a repetitive nucleotide sequence called a telomere. Telomeres form a protective “cap” – a sort of disposable buffer that gradually shortens with age – that prevents chromosomes from losing genes or sticking to other chromosomes during cell division.

CLOCK

A gene encoding a transcription factor (CLOCK) that affects both the persistence and period of circadian rhythms. CLOCK functions as an essential activator of downstream elements in the pathway critical to the generation of circadian rhythms. In humans, polymorphisms in the CLOCK gene have been associated with increased insomnia, weight loss difficulty, and recurrence of major depressive episodes in patients with bipolar disorder.

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.

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.

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.

View cold exposure 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.

Cytosol

The aqueous component of the cytoplasm of a cell, within which various organelles and particles are suspended.

Cytotoxic T Lymphocytes

A type of white blood cell that kills cancer cells, cells that are infected (particularly with viruses) or are otherwise damaged.

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.

Endothelium

The single layer of cells that lines the interior of the blood and lymphatic vessels. The endothelium participates in blood flow, platelet aggregation, and vascular tone. It also regulates inflammation, immune function, and angiogenesis. Endothelial dysfunction is a systemic pathological condition broadly defined as an imbalance between vasodilating and vasoconstricting substances produced by (or acting on) the endothelium. It is a robust predictor of heart attack and stroke risk.

View small vessel disease topic

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.

Fat-soluble vitamin

A vitamin that is readily dissolved in fats or oils. Fat-soluble vitamins are absorbed along with fats in the diet and can be stored in the body’s fatty tissue. Vitamins A, D, E, and K are fat-soluble. Dietary sources of fat-soluble vitamins include fatty fish (such as salmon), nuts, oils, and avocados, among others.

Flavonoid

Flavonoid are widely distributed in plants, fulfilling many functions. Flavonoids have been shown to have a wide range of biological and pharmacological activities in animal, human, and in-vitro studies. Examples include anti-allergic, anti-inflammatory, antioxidant, antimicrobial, anti-cancer, and anti-diarrheal activities.

Heat shock protein

A family of proteins produced by cells in response to exposure to stressful conditions. Heat shock proteins are expressed in response to heat as well as exposure to cold and UV light, and during wound healing and tissue remodeling. Many heat shock proteins function as chaperones by stabilizing new proteins to ensure correct folding or by helping to refold proteins that were damaged by cell stress. A 30-minute 73ºC sauna session in healthy young adults has been shown to cause a robust and sustained increase in the production of heat shock proteins for up to 48 hours afterward.^[1]

^ Shields, Richard K; Iguchi, Masaki; Littmann, Andrew E.; Chang, Shuo-Hsiu; Wester, Lydia A.; Knipper, Jane S. (2012). Heat Stress And Cardiovascular, Hormonal, And Heat Shock Proteins In Humans Journal Of Athletic Training 47, 2.

View sauna topic

Homeostasis

An organism’s ability to maintain its internal environment within defined limits that allow it to survive. Homeostasis involves self-regulating processes that return critical bodily systems to a particular “set point” within a narrow range of operation, consistent with the organism’s survival.

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.

View cold exposure topic

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.

View small vessel disease topic

Immunogenicity

The ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human or animal.

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.

View toll-like receptors topic

Interleukin 6 (IL-6)

A pro-inflammatory cytokine that plays an important role as a mediator of fever and the acute-phase response. IL-6 is rapidly induced in the context of infection, autoimmunity, or cancer and is produced by almost all stromal and immune cells. Many central homeostatic processes and immunological processes are influenced by IL-6, including the acute-phase response, glucose metabolism, hematopoiesis, regulation of the neuroendocrine system, hyperthermia, fatigue, and loss of appetite. IL-6 also plays a role as an anti-inflammatory cytokine through inhibition of TNF-alpha and IL-1 and activation of IL-1ra and IL-10.

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.

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]

^ Cheng CW; Adams GB; Perin L; Wei M; Zhou X; Lam BS, et al. (2014). Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell 14, 6.

Macrophage

A type of white blood cell. Macrophages engulf and digest cellular debris, foreign substances, microbes, cancer cells, and oxidized LDL in a process called phagocytosis. After phagocytizing oxidized LDL, macrophages are referred to as foam cells.

View thymic involution topic

Mechanical ventilation

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

Melatonin

A hormone that regulates the sleep-wake cycle in mammals. Melatonin is produced in the pineal gland of the brain and is involved in the expression of more than 500 genes. The greatest influence on melatonin secretion is light: Generally, melatonin levels are low during the day and high during the night. Interestingly, melatonin levels are elevated in blind people, potentially contributing to their decreased cancer risk.^[1]

^ Feychting M; Osterlund B; Ahlbom A (1998). Reduced cancer incidence among the blind. Epidemiology 9, 5.

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.

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.

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.

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

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.

Pineal gland

A small endocrine gland found in the brain of mammals. The pineal gland secretes melatonin, a hormone that regulates the sleep-wake cycle as well as other metabolic processes.

Polyphenol

A class of chemical compounds produced in plants in response to stressors. Polyphenols contribute to the bitterness, astringency, color, flavor, and fragrance of many fruits and vegetables. They often serve as deterrents to insect or herbivore consumption. When consumed in the human diet, polyphenols exert many health benefits and may offer protection against development of cancers, cardiovascular diseases, diabetes, osteoporosis, and neurodegenerative diseases. Dietary sources of polyphenols include grapes, apples, pears, cherries, and berries, which provide as much as 200 to 300 mg polyphenols per 100 grams fresh weight.

View small vessel disease topic

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.

Quercetin

A bioactive compound found in many edible plants. Quercetin demonstrates a wide range of health-promoting characteristics, including antioxidant, anti-inflammatory, and anti-cancer properties. It scavenges reactive oxygen and nitrogen species, inhibits activation of the proinflammatory molecule nuclear factor kappa B (NF-κB), and downregulates the inflammatory response of macrophages. When used in conjunction with the chemotherapy drug dasatinib, quercetin shows promise as a senolytic (anti-aging) compound, effectively clearing senescent cells and promoting improvements in a variety of age-related diseases. Dietary sources of quercetin include onions (most abundant), apples, berries, leafy vegetables, herbs, spices, legumes, tea, and cocoa.

View senescence topic

Randomized-controlled trial (RCT)

A study in which people are randomly allocated to receive one of several clinical interventions. One of these interventions is the standard of comparison or control. The control may be a standard practice, a placebo, or no intervention at all.

Reduction

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

Sepsis

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

Sudden cardiac death

A sudden and unexpected lethal failure of the heart to pump blood effectively. Sudden cardiac death is typically caused by malfunction of the heart’s electrical system. It accounts for approximately 15 percent of all deaths in Western countries.

Sulforaphane

An isothiocyanate compound derived from cruciferous vegetables such as broccoli, cauliflower, and mustard. Sulforaphane is produced when the plant is damaged when attacked by insects or eaten by humans. It activates cytoprotective mechanisms within cells in a hormetic-type response. Sulforaphane has demonstrated beneficial effects against several chronic health conditions, including autism, cancer, cardiovascular disease, diabetes, and others.

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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.

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Vitamin D

A fat-soluble vitamin stored in the liver and fatty tissues. Vitamin D plays key roles in several physiological processes, such as the regulation of blood pressure, calcium homeostasis, immune function, and the regulation of cell growth. In the skin, vitamin D decreases proliferation and enhances differentiation. Vitamin D synthesis begins when 7-dehydrocholesterol, which is found primarily in the skin’s epidermal layer, reacts to ultraviolet light and converts to vitamin D. Subsequent processes convert D to calcitriol, the active form of the vitamin. Vitamin D can be obtained from dietary sources, too, such as salmon, mushrooms, and many fortified foods.

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