Did you also know that intermittent fasting appears to increase one’s lifespan? Let’s discuss!
Last week, I discussed the rationale for using melatonin based on what we know about how COVID-19 infections wreak havoc on the body’s tissues. This week and next, I want to focus specifically on it’s anti-inflammatory, anti-oxidative, and immunomodulatory role in health and wellbeing. I will also dive into how to put all of this into practice, as well as other supportive adjuvant agents. Because I’m spending almost a month on this topic, it tells you how important I think it is!
How Melatonin Works
Melatonin possesses anti-inflammatory action through various pathways. Let’s start with Sirtuin-1, which is a member of a protein family that functions in the cellular response to inflammatory, metabolic, and oxidative stressors. If your body senses danger, Sirtuin-1 (or SIRT1) is activated and goes in to assess the chemical damage. SIRT1 is one of the hallmark proteins in the body; it engages with your mitochondria and regulates the expression of genes key for ATP generation and proliferation. SIRT1 also increases mitochondrial biogenesis—the process by which cells increase mitochondrial mass—, thereby contributing to increased healthy life-span and reducing aging-related diseases (Yuan et al., 2016). It’s a protein you want hanging around, especially if you have increased inflammation!
This protein appears to mediate the anti-inflammatory effect of melatonin by inhibiting a protein called HMG-1 (or high-mobility group box 1 protein), which is secreted by immune cells like macrophages, monocytes, and dendritic cells. HMG-1 is a nuclear protein that organizes the DNA and regulates transcription (Klune et al., 2008). Thus, SIRT1, with the help of melatonin, downregulates the polarization of macrophages towards the pro-inflammatory type (Hardeland, 2018). In other words, melatonin flips the inflammation switch off in the immune system.
In sepsis-induced acute lung injury (ALI), the “proper” regulation of SIRT1 reduces lung injury and inflammation, and the application of melatonin adds to the therapeutic effect of SIRT1 (Wang et al., 2019). We know that SIRT1 plays a key role in chronic inflammation, and its expression and protein levels are reduced in several common (and chronic) inflammatory diseases in the U.S., including arterial inflammation, obesity, and Alzheimer’s disease (Hadar et al., 2017). Thus, melatonin works synergistically with SIRT1 to quell rising inflammatory markers. If there’s not enough melatonin available, the body has a harder time dealing with accumulating levels of inflammatory damage.
Nuclear factor kappa-B (NF-κB) is another essential pathway, and if there is anything you take away from this blog (besides the benefit of melatonin), it’s that we want to turn off NF-κB as much as we possibly can. This is the common final pathway for almost all inflammatory triggers. NF-κB, if it had its way, would never stop sending the danger signal, “Hey, Body, Wake Up! We Have Invaders! Generate Inflammation!”
Nuclear factor kappa B is an ancient protein transcription factor and a regulator of innate immunity (Salminen et al., 2008; Baltimore, 2009). The NF-κB signaling pathway connects pathogenic signals and cellular danger signals, thereby creating a system of cellular resistance to unwelcome pathogens. Myriad studies demonstrate NF-κB is like a central network hub, responsible for complex biological signaling to activate the immune system (Albensi and Mattson, 2000; Kaltschmidt and Kaltschmidt, 2009; Karin, 2009).
For that reason, NF-κB is the master regulator of evolutionarily conserved biochemical cascades (Mattson et al., 2000), not only in immunity, but also in inflammation, cancer, and nervous system function. Granted, the influence that NF-κB has on cell survival is an ever-evolving story; it can be neuroprotective or proinflammatory, depending on cell type, developmental stage, and pathological state (Qin et al., 2007), but this is beyond the scope of this post. For this discussion, NF-κB is generally (and closely) associated with pro-inflammatory and pro-oxidative responses, while at the same time being an inflammatory mediator in ALI. The anti-inflammatory effect of melatonin involves the suppression of NF-κB activation in acute respiratory distress syndrome (ARDS) (Sun et al., 2015; Ling et al., 2018). Melatonin downregulates NF-κB activation in T cells and lung tissue (Shang et al., 2009; da Cunha Pedrosa et al., 2010). This halts the build up of inflammation.
And since NF-κB is involved in cell survival, which works to our advantage in the acute sense, it’s clear why we find it turned on indefinitely in cancer cells. Besides melatonin, though, calorie restriction (or fasting) is one of the most effective ways to shut down NF-κB, thereby shutting down the entire inflammatory system that drives the progression of chronic and acute diseases. We can also turn off or modulate NF-κB with food (i.e. vitamin C and E, fatty acids EPA and DHA, N-acetyl cysteine (the precursor to glutathione), spices like rosemary and curcumin, flavonoids like quercetin, grape seed polyphenols, resveratrol, green tea catechins, soy isoflavones, and ellagitannins found in pomegranates). Imagine the one-two punch we’d get with the combination of both adequate nutrition and adequate sleep.
While some inflammation is actually good for us, we too often tip the scale and accumulate an excessive amount of reactive oxygen species (ROS) in our cellular environment. This is considered to give rise to an unfortunately unrecognized state plaguing our society: underlying oxidative stress (Sies, 1997). Left unbalanced, ROS can adversely damage DNA, RNA, and other proteins. Spontaneous mutations that stem from the uncontrolled oxidative stress lead to the initial stages of cancer; in fact, many cancers are known to exist in a constant state of oxidative stress, indicating the role of oxidative stress in cancer promotion (Klaunig et al., 2010; Tudek et al., 2010; Wu et al., 2010).
Thus, with the well-established link between oxidative stress and cancer, imagine the situation of an already inflamed body that has to deal with another novel infection that can release an enormous amount of inflammatory cytokines? It’s not good.
Fortunately for us, each cell in our body has its own internal defense mechanism to fight against oxidative stress. Chiefly, this is mediated by the transcription factor NF-E2-related factor 2 (Nrf2). If NF-κB is the master regulator of pro-inflammatory cascades, Nrf2 is the master regulator of anti-inflammatory cascades; it offers a battery of defensive mechanisms and regulates detoxification genes. Indeed, Nrf2 is stabilized and activated when ROS and electrophiles rise (Shelton & Jaiswal, 2013).
Furthermore, the stimulation of Nrf2 is vital in protecting lungs from injury. Thus, the Nrf2 pathway matters if you become infected with COVID-19. Once more, melatonin is implicated here. Melatonin stimulates the up-regulation of Nrf2 with therapeutic effects in hepatoprotection, cardioprotection, among other cells (Ahmadi & Ashrafizadeh, 2020). Time will tell if Nrf2 is implicated in decreasing CoV-induced ALI, but the close interaction of SIRT1, NF-κB and Nrf2 indicate their participation in the CoV-induced ALI/ARDS. As such, the findings do support the anti-inflammatory action of melatonin to fight infection.
Bottom line: Inflammation is associated with an elevated production of cytokines and chemokines, and melatonin is associated with a reduction in those pro-inflammatory cytokines (i.e. TNF-α, IL-1β, IL-6, and IL-8), with a concomitant elevation in the level of the anti-inflammatory cytokine IL-10 (Habtemariam et al., 2017; Hardeland, 2019). While there are a few concerns about the potential pro-inflammatory actions of melatonin when used in very high doses or under suppressed immune conditions (where it may induce an increase production of pro-inflammatory cytokines, IL-1β, IL-2, IL-6, IL-12, TNF-α, and IFN-γ) (Carrascal et al., 2018), it’s important to remember that in ALI-infection models, melatonin consistently demonstrates anti-inflammatory and protective action (Huang et al., 2010).
The Antioxidative Effect of Melatonin
The antioxidative effect of melatonin works in tandem with its anti-inflammatory actions by the following mechanisms (Wu et al., 2019; Reiter et al., 2020). Specifically, melatonin:
Superoxide dismutases (SODs) are a group of metalloenzymes, proteins that contain a metal ion cofactor such as iron, copper, zinc, manganese, among others. SODs are found in all kingdoms of life, forming the front lines of defense against ROS-mediated injury (Kangralkar et al., 2010). They catalyze the reaction of the superoxide anion free radical (O2-), which is very damaging, into molecular oxygen and hydrogen peroxide (H2O2), which is less damaging (Figure 1), thereby decreasing the concentration of O2- detrimental to cells at excessive concentration (Yasui & Baba, 2006).
Figure 1. (a) The catalytic mechanism for the conversion of O2- by superoxide dismutase (SOD). (b) Subunit structure of bovine Cu, Zn-SOD (Protein Data Bank Entry, 2 SOD).
This reaction is accompanied by alternate oxidation-reduction of metal ions present in the active site of SODs (McCord & Fridovich, 1969; Tainer et al., 1983). You can see that in the figure when copper (Cu) gains an electron (going from Cu2+ to Cu+) and then loses an electron (going from Cu+ to Cu2+). If this all sounds foregin to you or you’re vaguely recalling your days with chemistry, it’s OK. Just know that the damage results from the exchange of millions and millions of electrons, but that damage can be cleaned up when SODs are activated (and the body has the right micronutrients and trace elements … and enough sleep!)
Based on the metal cofactors present in the active sites, SODs can be classified into four distinct groups (Youn et al., 1996; Miller, 2001):
The different forms of SODs are distributed throughout all biological kingdoms, albeit unequally, and are located in different subcellular compartments.
Why does this matter? Many scientific teams have revealed the therapeutic potential and physiological importance of SOD (Noor et al., 2002). While SODs constitute a vital antioxidant role for preventing excessive oxidative stress in the body (Landis & Tower, 2005), these enzymes serve as an anti-inflammatory agent and can prevent precancerous cell changes as well (Yasui & Baba, 2006). Natural SOD levels in the body decline as we age (İnal et al., 2001), and hence we become more prone to oxidative stress-related diseases. Because melatonin up-regulates antioxidative enzymes like SOD, we are better able to age gracefully, to fight infection easily, and prevent cancer development simply.
With respect to aging, this is why SOD is used in cosmetics and personal care products as an anti-aging ingredient and as an antioxidant due to its ability to reduce free radical damage to the skin, therefore preventing wrinkles, fine lines, and age spots. SOD also helps with wound healing, softens scar tissue, protects against UV rays, and reduces other signs of aging (Corvo et al., 2002). But SOD is useless if you are not getting enough sleep.
It’s worth mentioning that SOD is so powerful that drug developers are attempting to make a drug just like these metalloenzymes we naturally produce. These drugs are called “SOD mimetics” and are made synthetically. SOD mimetic are small molecule catalytic antioxidants that may offer the potential for treating an array of diseases resulting from oxidative stress (i.e. virtually any disease or infection). SOD mimetics mimic native SOD by effectively converting O2- into H2O2, which is further processed into water by catalase. They are of prime interest in therapeutic treatment of oxidative stress since it is underlying all chronic disease. Because of their smaller size, longer half-life, and similarity in function to the native enzyme, we will likely see their push into the market sooner than later for the battle against the ROS-mediated diseases. … Or we could commit to getting a better night’s sleep and letting the body heal in ways only it knows how.
Viral infections (and their replication) constantly produce oxidized products. We know this from SARS-induced acute lung injury (ALI) models, where the production of oxidized low density lipoprotein (LDL) activate the innate immune response by the overproduction of IL-6 lung (alveolar) macrophages via Toll-like receptor 4 (TLR4)/NF-kB signaling, thereby leading to ALI (Imai et al., 2008). TLR4 is a receptor for the innate immune system, and it is also a therapeutic target for melatonin. In cerebral ischemia (when an insufficient amount of blood flows to the brain), gastritis, and periodontitis disease models, melatonin has documented anti-inflammation actions via TLR4 signaling (Luo et al., 2018; Renn et al., 2018; Zhao et al., 2019).
The anti-oxidative effect of melatonin has also been identified in acute lung injury caused by radiation, sepsis, and ischemia-reperfusion (Chen et al., 2014; Wang et al., 2018; Wu et al., 2019). In ALI/ARDS patients, especially when this condition is advanced and in patients treated in ICUs, severe inflammation, hypoxemia, and mechanical ventilation with high oxygen concentrations increases oxidant generation locally and, inevitably, spills out to the rest of the body systematically (Sarma & Ward, 2011; Tamura et al., 2020). Melatonin could help clean a lot of this inflammatory damage up.
Melatonin’s use is not a novel idea. Its use as a therapy has been known for well over a decade, thanks, in part, to the extensive studies conducted by Gitto and his colleagues in 2004 and 20055 (during the aftermath of the first SARS pandemic). It was this team that used melatonin to treat newborn infants with respiratory distress that found the antioxidant and anti-inflammatory actions of melatonin in the lung. Thus, the application of melatonin would likely be beneficial in controlling inflammation and oxidation in those infected with coronavirus.
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