Summary: The clinical picture of SARS-Cov-2 infection is more severe and lethal in older people, and the seasonality of the severity and number of clinical cases, with a lower level of pathogenesis, is becoming evident in the summer months. In the search for the possible molecules involved in these differences in pathogenicity depending on age, temperature and environmental humidity, one molecule appears: Betaine (trimethylglycine). In this review, different scientific articles are collected that support the hypothesis of the important role that Betaine can play in the decrease of the pathogenicity of Covid-19, through the regulation of the factor NF-κB.
Keywords: Osmolites, Covid-19, Homocysteine, TMG, Trimethylglycine, Betaine
Introduction and methodology.
In the evolution of the SARS-Cov-2 pandemic, there are some clear and distinguishable characteristics of this virus, its action is
– Low clinical incidence in children and young people.
– There is a higher degree of pathogenicity in men than in women.
– Obesity or overweight and high levels of homocysteine in the blood increase the probability of more serious clinical conditions.
– After the start of the rise in temperatures in spring and with the summer, the severity of clinical cases and deaths fell considerably. With the arrival of autumn we can see the increase in deaths and admissions by Covid-19, in the northern hemisphere. Coronaviruses are seasonal viruses.
These characteristics of Covid-19, lead us to ask questions about what makes the degree of pathogenesis different, once a person is infected with SARS-Cov-2. In the absence of answers that explain these differences, which are due to immunological actions, we can think of the existence of a natural component or molecule in our organism, which varies according to age and environmental conditions.
In this search for possible molecules we find Betaine.
The articles for this review were compiled using the PubMed.gov Frontiers search engine and other scientific means, searching for the term “Betaine” alone and together with, “Viruses” “Osmolites”, “Homocysteine”, “Immune”, “Stress” The following are some of the most common diseases: “Inflammation” and “Apoptosis”.
Betaine, also known as trimethylglycine (TMG), is a derivative of the amino acid glycine, present in living beings, with three reactive methyl groups and a dipole structure, containing an equal number of positively charged and negatively charged functional groups (Zwitterion).
Betaine can be synthesized endogenously through the metabolism of choline or exogenously through the intake of foods rich in betaine, such as spinach, whole grains, beetroot, quinoa. . Lycium barbarum , has a long tradition in natural oriental medicine and has been attributed multiple health benefits, and among the supposed properties attributed to it, the use of its berries (goji berries) to prevent colds stands out as they are an important source of Betaine and vitamin C.  
Betaine nutritional supplements for humans are available in two forms : Hydrochloric Betaine and Anhydrous Betaine. Anhydrous Betaine is the most appropriate format for supplementation, currently used by athletes to improve their sporting performance and people with high homocysteine levels. Hydrochloric Betaine (Betaine Hcl) is used as a dietary supplement in humans to increase gastric acidity. The main indications for this supplement are treatment of hypochloriosis and gastric malfunction: improvement of heavy digestion, reduced reflux and gas have been reported with this supplement.
Anhydrous Betaine (TMG) is a food additive widely used in poultry, pig and aquaculture production, for its positive results in productivity, especially when stress situations occur that affect cell osmolarity, for example in situations of heat stress or bacterial and viral infections.
The main functions of Betaine are osmoprotection and transmetallization.
The main physiological function of Betaine is to act as an organic osmolite. Osmolites are organic molecules which intervene in the regulation of intracellular liquid concentrations and cell volume, protecting cells from dehydration . Betaine improves the water retention of the cells and reduces the central body temperature by reducing the activity of the ion pumps necessary for osmoregulation, thus allowing more energy for growth .
The regulation of the state of cell hydration, and therefore of cell volume, is important for the maintenance of the correct functioning of biochemical processes, especially DNA replication and protein formation-folding. The main role of Betaine in plants and micro-organisms is to protect cells against osmotic inactivation. Exposure to drought, high salinity or temperature stress triggers Betaine synthesis in the mitochondria, resulting in its accumulation in the cells. Betaine is an osmolite which increases the water retention of cells, replaces inorganic salts and protects intracellular enzymes against osmotic or temperature-induced inactivation. For example, spinach if grown in saline soil, Betaine can accumulate in quantities of up to 3%. of fresh weight. This allows chloroplasts to carry out photosynthesis in the presence of high salinity. 
Betaine increases its concentration in functional cells subject to greater osmotic pressure, for example in kidney cells or in intestinal epithelium. In the absence of data on the variation of Betaine levels in respiratory epithelium according to environmental temperature and humidity, it is assumed that Betaine plays an active role in reducing water loss during respiration under environmental conditions of high temperature and low relative humidity. In such a way, that Betaine is widely used in animal feed, for its positive effects in situations of saline [fish farming] or thermal stress due to high temperatures. It is added to the diet in animal and fish feeding as a natural anti-stress through different routes [water / feed] to overcome the problem of heat stress. 21] In ruminants it reduces the effect of heat on rectal temperature and respiration rate and improves cell heat tolerance by increasing the production of heat shock proteins [HSP] in vivo in mammary epithelial cells and white blood cells. 
Another primary physiological activity of Betaine is to be a donor of methyl groups, through trans-methylation, for use in many biochemical pathways. As its name suggests, trimethylglycine has three methyl groups, which can serve as reagents for trans-methylation reactions. If this occurs, Betaine is converted into dimethylglycine [SAMe], or further catabolised into sarcosine, and finally added to the amino acid reserve as glycine. Data support that Betaine regulates transcription factors PPARα, NF-κB, FOX1, ChREBP and SREBP1 and this allows Betaine to play a role in protein synthesis. Betaine modulates gene expression by changing the degree of methylation in the target gene promoter. The exact mechanism by which Betaine modifies the methylation state of the promoter is not yet clear, but methyltransferases using SAM as a methyl donor and DNA methyltransferases are good candidates for this function. 
2.3 Betaine and growth.
Betaine, as a donor of methyl groups, is necessary in the phases of cell growth, and therefore in children and young people of growing age it is more dependent, due to its intervention in the processes of DNA replication, in the stabilisation of the proteins formed and in the formation of the cytoplasmic membrane of the new cells. In the process of growth, levels of betaine and methylation in the organism and cell are high, and with age and the decrease in their necessary participation in the processes of cell replication, levels of betaine drop. It is basic in foetal development, intervening in the regulation of gluconeogenesis and lipogenesis in the liver and in cholesterol metabolism .
In the methionine cycle (an essential component in protein formation), homocysteine is produced. This toxic component can be recycled back to methionine by trans-methylation and/or, in the case of excess methionine, it is recycled to cysteine by trans-sulphurisation. Excess plasma homocysteine is a factor predisposing to the ischaemic complications of arteriosclerosis, venous thrombosis and pulmonary thromboembolism. There is evidence of a relationship between homocysteine and hypertension, but the mechanisms of this relationship are unknown and are influenced by the different causes of hypertension. .
The recycling of homocysteine into methionine occurs by two possible routes:
3.1 Vitamin B12-dependent route
Methionine can be regenerated from homocysteine by re-methylation and by catalysis of the enzyme homocysteinamethyltransferase [HMT], which requires vitamin B12 and 5,10-methylenetetrahydrofolate. Deficiencies in vitamin B12 levels, lead to increased levels of homocysteine 
The main causes of vitamin B12 deficiency are the strictly vegetarian diet (without B12 supplementation), stomach hypochlorhydria, alcohol consumption, Crohn’s disease, taking proton pump inhibitors such as omeprazole and similar for a long time. The consumption of these antacids is common in elderly people and polymedicated adults, as a stomach protector together with the ingestion of other medicines, especially anti-inflammatory ones. Omeprazole belongs to the group of so-called proton pump inhibitors (PPIs), meaning that omeprazole inhibits or decreases acid production in the stomach. At the same time, the activity of intrinsic factor, which is essential for binding to ingested B12 and enabling intestinal absorption of vitamin B12, is also reduced    . An increase in the severity of Covid-19 disease has been reported in patients who ingested IPP . The consumption of these stomach protectors is remarkably high in countries such as Spain, where it is the most consumed drug, according to the Annual Report of the Spanish National Health System. As the route of transformation of homocysteine into methionine dependent vitamin B12 and folate is decreased, there is an increase in the route dependent on Betaine, with the consequent decrease in the available levels of Betaine for other physiological functions such as osmolysis .
3.2 Betaine dependent route.
As a methyl donor, Betaine recycles homocysteine in the methionine cycle, through the Betaine Methyltransfera-Homocysteine, obtaining Methionine and Dimethylglycine as a result. . Deficient intake of Betaine or its precursor Choline can lead to disorders in liver metabolism and high concentrations of homocysteine. Doses of Betaine in the range of dietary intake reduce fasting plasma homocysteine concentrations. . According to several studies, Betaine appears to be very effective in preventing an increase in plasma homocysteine concentration .
4. Betaine in infectious processes
Betaine has been shown in several studies to be useful in the treatment of infectious diseases. In viral infections, apart from its action in regulating the immune response, there are indications of possible actions at various levels: stabilisation of the cytoplasmic membrane by reducing viral penetration, destabilisation or blocking of viral proteins by preventing their replication or assembly in the capsid, interaction with viral RNA. The decrease in viral penetration in some types of virus may be due to an increase in the expression of claudine – 1, claudine – 4 and ocludine. . In porcine parvovirus, Betaine reduced infectivity by 4-logs in cell culture . Betaine decreased mRNA expression levels induced by Infectious Bursal Disease [Gumboro disease] in chickens (IL-6 RNA virus), and IFN and IRF7 were suppressed by its methylation, reducing lesions and lymphopenia caused.  . The addition of S-Adenosyl Methionine and Betaine to pegIFNα / ribavirin improves the early virological response in chronic hepatitis C  . Betaine suppressed the re-emergence of Hepatitis B virus with HBV resistance to lamivudine and decreased the mutation of HBV DNA resistance [rtM204V / I]. Betaine supplementation may enhance the anti-HBV effect of interferon-α [IFN-α] by increasing the expression of dsRNA-dependent antiviral protein kinase induced by the JAK-STAT signalling pathway. . In coccidiosis in broilers, Betaine improves the clinical picture by increasing intra-epithelial lymphocytes in the duodenum of coccidia-infected chickens and increasing the functional properties of phagocytes  .
5. Betaine in intoxication
Betaine is useful in improving cellular and organic response in situations of stress and in the presence of toxic elements. There are many studies, which we can mention, in which the protective and stabilizing character of Betaine is positively evaluated, such as protecting the cerebellum from oxidative stress after administration of levodopa and benserazide in rats , Betaine can protect the lung from oxidative stress induced by paraquat and pulmonary fibrosis most probably through improved antioxidant capacity and polyamine synthesis , improved airway inflammation of asthma-induced lung tissue in the liver and kidney of mice . It reduced alcohol and/or statin-induced muscle cell death in rats   . It decreased bile acid induced apoptosis in vivo and in vitro largely by inhibition of the proapoptotic mitochondrial pathway .
Oral administration of Betaine reduced the appearance of features associated with skin ageing caused by UVB irradiation  and significantly decreased burn-induced tissue damage, restored the level of GSH and Na+/K+-ATPase activity, and decreased the level of MDA and MPO activity . Betaine attenuates monocrotaline-induced pulmonary arterial hypertension in rats by inhibiting the inflammatory response .
6. Effects of Betaine on the immune system
Accumulated evidence has shown that Betaine has anti-inflammatory functions in numerous diseases. Betaine regulates energy metabolism to relieve chronic inflammation  Betaine treatment significantly reduced the production of IL-6 from dendritic cells in autoimmune encephalomyelitis . Decreased expression of inflammation-related adipocines in human adipocytes caused by hypoxia has been evidenced by the presence of physiologically relevant concentrations of Betaine .
Betaine has also been found to be effective in treating oxidative stress in some tissues of aged rats. Betaine may increase hepatic levels of GSH and vitamin E, which are useful in reducing oxidative stress in liver, heart and brain tissues, especially in older rats .
In recent years, several studies on betaine mediated antioxidant activities have focused on changes in the NF-κ pathway. Betaine improves the metabolism of sulphur amino acids against oxidative stress, inhibits the activity of the nuclear factor κB and the activation of the NLRP3 inflammasome, regulates energy metabolism and mitigates endoplasmic reticulum stress and apoptosis. Betaine may be useful as a preventive agent against NF-kappaB activation induced during inflammation and aging  and to relieve inflammation by reducing interleukin [IL] secretion -1β . The nuclear factor κB [NF-κB] is a nuclear transcription factor that regulates the expression of a large number of genes that are critical for the regulation of apoptosis, viral replication, tumour genesis, inflammation and various autoimmune diseases. It also plays an important role in antioxidant mechanisms. Betaine appears to be able to prevent vascular disorders by suppressing the expression of lysophosphatidylcholine-related AM [LPC] associated with the activation of NF-κB through the upregulation of an inhibitor of the nuclear factor kappa-B kinase .
Betaine provided protective effects on liver and kidney function against maternal diabetes in an animal model of induced diabetic pregnancy. 7] The beneficial effect of betaine on fatty liver disease (NAFLD) is associated with reduced hepatic oxidative stress, inflammation and apoptosis, and increased cytoprotective signalling of Akt/mTOR . Betaine treatment significantly reduced intestinal inflammation and accelerated tissue healing in a murine model of colitis .
7. Betaine and Covid-19.
Two of the great unknowns of Covid-19 are the causes of seasonal variation and the difference in pathogenicity between young and old, these variations coincide with the differences in the concentration of Betaine in the organism. The seasonal variation in the levels of Betaine in the lung epithelium, as a regulator of evaporation, responds to the variation in the evolution of the number of severe cases and lethality of Sars-COv-2 throughout the year. Analysis of statistical data on severe cases by number of inhabitants shows a great difference between countries according to their altitude, average temperature and above all relative humidity, such that the severity is lower in countries with low average relative humidity: North African countries: Morocco, Egypt, Algeria, Middle Eastern countries: Saudi Arabia, as opposed to countries or areas with high relative humidity: Brazil, Florida, New York, part of Texas, areas of Mexico.
The variation in severity of clinical cases among children and young people with respect to adults and the elderly has an answer in the variation of levels of Betaine and its precursor Choline, which is essential in the formation of the cytoplasmic membrane by means of phosphatidylcholine, since in growing people the endogenous production of Choline by methylation of phosphatidylethanolamine is higher than in adults and the elderly.
The stabilising and protective action of Betaine on cells and tissues is undoubtedly positive in the face of infectious processes. In the case of Covid-19 this protection can be derived from the intervention of nuclear factor expression κB [NF-κB], Huang et al. show that type 2 alveolar cells [iAT2s] derived from pluripotent stem cells [iPSC], can be used for models of VOCID-19 infection. They find that iAT2 cells, in an air-liquid interface culture, are key to SARS-CoV-2 infection, which induces a rapid inflammatory response phenotype, activated by signalling of the transcription factor NF-kB, a protein complex that controls DNA transcription. 53] Betaine has been shown in studies to prevent vascular disorders by suppressing lysophosphatidylcholin [LPC]-related AM expression associated with NF-κB activation through the upregulation of a nuclear factor kappa-B kinase inhibitor .
On hospital admission of patients with Covid-19, high blood homocysteine levels are an indication of an increased risk of cardiovascular problems in the course of the disease. High homocysteine levels predict a higher degree of injury and severity of the clinical picture  . Homocysteine interacts with and activates Angiotensin II receptor type I, aggravating vascular damage ; Angiotensin II plays an important role in triggering the inflammatory and thrombogenic process of Covid-19 . High homocysteine levels can be negative not only because of their direct toxic action as such but also because they influence a decrease in betaine levels . In the review by Nancy Lord & Mary Ruwart, different implications of homocysteine are related to Covid-19, especially to the expression of the cytokines TNF-α, IL-1β, and IL-6 . The influence of high homocysteine levels on the severity of Covid-19 may be determined by the effects of homocysteine itself on the circulatory system, and also by the correlation between high homocysteine levels and low levels of betaine.
Another group with a higher percentage of severe cases by Covid-19 are adults, with obesity and preferably male, in a recent study were found significantly inverse correlations between serum levels of Betaine and all measures of obesity in men [r r ranged from -0.12 to -0.23 and p <0.01 for all] but not in women. In addition, obese men had the lowest serum levels of Choline and Betaine, followed by overweight men, and normal weight men had the highest serum levels of Choline and Betaine .
The decrease in Betaine levels may be triggered by Vitamin B-12 deficiency caused by the intake of antacids, proton pump inhibitors. Betaine increases its homocysteine reducing activity. Patients who ingest IPP are more likely to have more severe Covid-19 disease  .
In the regulation of the immune response to an infection, metabolic gears are activated in which Betaine, homocysteine, vitamin B-12, vitamin D and S- adenosyl methionine are included, together with many other molecules. The control and feedback mechanisms of these gears lead to the regulation of an optimal and not excessive response, especially of the enzyme ACE-2. Controlling the excessive response and triggering of the cytokine storm depends on the correct level of concentration of these molecules, the excessive response leads to an increase in the number of cells killed by apoptosis, Betaine has proven its effectiveness in reducing cellular apoptosis. 
In addition to this improvement in the response to Covid-19 infection due to the improved immune response and greater cellular resistance to apoptosis, which would already justify its use, direct actions of Betaine against this coronavirus cannot be ruled out, through a decrease in the rate of viral replication, due to a decrease in its penetration into the cell by decreasing the activity of the furan in the excision of the Spike protein and adaptation to the ACE2 receptor . Another possible target where Betaine acts directly or indirectly through its metabolites, could be the SARS-CoV-2 viral protein: Nsp16/Nsp10 RNA cap 2′-O-Methyltransferase, S-adenosyl L-homocysteine formed by the demethylation of S-adenosyl methionine [SAM] in the methionine cycle could have interaction with this protein affecting the activity of this viral protein .
Increasing the intake of Betaine through foods with a higher content of this amino acid or through supplementation with anhydrous Betaine [TMG] or its precursor Choline, especially in the elderly and in environments with high humidity, may be key to reducing the pathogenicity of Sars-cov2. Betaine’s enhancing effect may be due to its effects of increasing cellular resistance to apoptosis and improving control of the immune response, in addition to possible effects of decreasing viral replication. Betaine, as a safe drug and/or food supplement, may help, above all, to prevent or alleviate the respiratory and systemic clinical picture associated with COVID-19. It is necessary and urgent to carry out clinical studies to confirm this possibility.
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