Aging progressively decreases testosterone levels by about 1% per year after the age of 30 or 40. How does it interact with an individual’s diet?

A new study published in the Journal of the American Urological Association concludes that men who follow a more proinflammatory diet appear to have a higher risk of testosterone deficiency, indicating the important role of a healthy diet in male reproductive health.

Alejandro Monzó – Neolife Nutrition and Nursing Unit

Industrial food consumption and sedentary lifestyles in the spotlight

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Testosterone is an androgen or steroid hormone. It is produced mainly in the testes and ovaries (1). In men, it is the main male sex hormone and also an anabolic steroid. Testosterone fulfills different functions, which help to maintain:

• • Bone density
  • The distribution of fat
  • Muscle mass and strength
  • Facial and body hair
  • The production of red blood cells
  • Sex drive and sperm production

Hypogonadism impairs the ability to produce normal amounts of testosterone due to a problem with the testes or with the pituitary gland that controls the testes (1). Hormone replacement therapy with testosterone, administered as injections, tablets, patches or gels, may improve the symptoms of low testosterone in men, a very common treatment at Neolife

Nowadays, the average testosterone level in men has reduced significantly in recent decades. Although loss of testosterone is common as men age, scientific evidence shows that it is often associated with diabetes, abdominal obesity, sexual dysfunction, depression, and other adverse conditions (2).

According to new research published in the Journal of the American Urological Associationa diet rich in proinflammatory foods, including foods that contain refined carbohydrates and sugar, as well as polyunsaturated fats, may lead to testosterone deficiency in men (3). This study investigated the link between dietary inflammatory index and sex hormones in a representative sample of nearly 4,200 adult men. They provided a 24-hour dietary intake history and underwent sex hormone tests. For men on the more proinflammatory diet, the odds of testosterone deficiency were approximately 30% higher compared to men on the more anti-inflammatory diet.

The authors state that the study’s findings do not prove causality; however, they support previous research suggesting that this type of diet may contribute to testosterone deficits, in addition to other potential health problems. Men with low testosterone levels have higher levels of proinflammatory cytokines, small proteins released by cells during injury or infection or in response to inflammatory factors in the environment.

A proinflammatory diet is generally characterized by the consumption of refined carbohydrates, processed meats, trans fats, poor quality oils, and sugary drinks. In short, foods belonging to the fast food group, industrial and ultra-processed foods, all of them rich in fat, sugar, and salt. In an antioxidant diet, there is more consumption of vegetables, fruits, legumes, and nuts. New research published in the Journal of the American College of Cardiology shows that certain dietary patterns have the potential to significantly increase cardiovascular risk, so that appropriate intervention at this point may result in an effective disease prevention strategy (4, 5) (Figure 1).

Figure 1. Proinflammatory diet vs. anti-inflammatory diet: potential effects (5).

No isolated food ‘per se’ induces an increase in testosterone. However, an unhealthy proinflammatory diet, especially due to its effect on obesity and increased cardiovascular risk, may produce a decrease in testosterone(6). There is increasing evidence that poor eating habits are associated with a variety of chronic diseases, such as cardiovascular disease, type 2 diabetes or obesity, which is key to understanding their interaction with declining testosterone levels.

Therefore, a healthy, balanced, antioxidant diet may have a beneficial effect on testosterone levels. Intakes of complex carbohydrates, fiber, healthy fats, vitamins, and minerals, such as those mentioned below, have demonstrated the important role of a healthy diet in men’s health (6, 7, 8):

• A high consumption of vegetables, especially cruciferous vegetables, such as broccoli, Brussels sprouts, cauliflower, in addition to helping prevent cancer, favor the increase of testosterone levels.
• Restrictive diets, especially when it comes to fat, may also reduce serum testosterone levels in men. Cholesterol is necessary for the production of testosterone, so consuming natural fats, from quality meats, fish and eggs, nuts, extra virgin olive oil, coconut and avocado, may be a suitable option.
• In particular, minerals such as zinc, selenium, and magnesium play a relevant role in optimizing testosterone levels and fertility. Adequate consumption of nuts, liver, eggs, dark chocolate, seafood, and crustaceans may also be of interest.

Finally, there are several factors associated with a decrease in testosterone, such as advanced age, environmental pollution, lifestyle, the presence of structural alterations in the reproductive system, diseases such as obesity, and an unhealthy diet. At Neolife, our medical-nutritional team works with each individual and particular case; this is where dietary-nutritional advice is of special interest due to its great ability to prevent disease and potentially improve testosterone levels.

BIBLIOGRAFÍA

(1) Mayo Clinic. (2021). “Sexual health: testosterone”. URL: https://www.mayoclinic.org/healthy-lifestyle/sexual-health/in-depth/testosterone-therapy/art-20045728

(2) Kalvaitis, K. (2007). “Generational decline in testosterone levels observed”. Endocrinetoday. Healio. URL: https://www.healio.com/news/endocrinology/20120325/generational-decline-in-testosterone-levels-observed

(3) Zhang, C. y otros. (2021). “The Association between dietary inflammatory indcex and sex hormones among men in the United States”. Vol. 206, 1-7. American Urological Association. URL: https://www.auajournals.org/doi/10.1097/JU.0000000000001703

(4) De Luis Román, D.A. Bellido Guerrero, D. García Luna, P.P. Olivera Fuster, G. (2017). “Dietoterapia, nutrición clínica y metabolismo”. Tercera edición. Sociedad Española de Endocrinología y Nutrición. Grupo Aula Médica, S.L. Madrid, España.

(5) Li, J. y otros. (2020). “Dietary Inflammatory potential and Risk of cardiovascular disease among men and women in the U.S.”. Journal of the American College of Cardiology. Vol. 76 (19). URL:https://www.sciencedirect.com/science/article/abs/pii/S0735109720371904?via%3Dihub

(6) Camarero, A. (2019). “La alimentación insana puede producir un descenso de testosterona”. El Confidencial: Alimente. URL: https://www.alimente.elconfidencial.com/bienestar/2019-12-17/dieta-insana-descenso-testosterona_2379316/

(7) Guadalupe G-R, L. y otros. (2018). “Nutrición y fertilidad”. Nutrición hospitalaria. Vol. 35(6): 7-10. URL: https://scielo.isciii.es/pdf/nh/v35nspe6/1699-5198-nh-35-nspe6-00007.pdf

(8) Vázquez, M. (2013). “Aumenta tus niveles de testosterona, de manera natural”. Fitness Revolucionario. URL: https://www.fitnessrevolucionario.com/2013/05/19/aumenta-tus-niveles-de-testosterona-de-manera-natural-parte-ii/

La entrada Proinflammatory Diet and Testosterone se publicó primero en Neolife.

Aging, as we all know, is a set of processes that lead to the deterioration of the body over time. Today, we will talk about the role of inflammation.

Old age is associated with the development of chronic systemic (affecting the whole body) low-grade inflammation on a sustained basis. The term “inflammaging” is often used. This inflammaging state contributes to the onset of age-related diseases such as muscle wasting (sarcopenia) and frailty.

Dr. Celia Gonzalo Gleyzes – Neolife Medical Team

Inflammation Mechanisms

Acute inflammation is the set of processes that appear as a response to tissue damage in the body; this may be related to an external pathogen.

The aim of this mechanism is to limit microbial infection and repair damaged tissues.

An inflamed area is characterized by neutrophil extravasation. These cells are granulocyte-type leukocytes, and they contain lytic enzymes and phagocytin (a substance with antibacterial effects).

After extravasation, neutrophils and other inflammatory cells die in a programmed manner (called apoptosis), so their remains are captured (called phagocytosis) by macrophages (immune system cells derived from monocytes) to resolve the inflammation and return to tissue homeostasis.

This phagocytosis by macrophages is called “spherocytosis”. This is necessary because otherwise, apoptotic neutrophils could release molecules that are harmful to the tissue causing damage. Spherocytosis would also limit unnecessary extravasation of neutrophils once the pathogen is neutralized. In this way, the inflammation would be effective and self-limited over time.

Altered inflammation in aging

With age, the mechanisms that regulate inflammation are altered, and this has an impact in two ways: increased risk of infections and susceptibility to chronic diseases.

An increase in circulating inflammatory mediators (cytokines) is observed in the absence of infection, suggesting the presence of a chronic low-grade inflammatory state. A sustained inflammation will cause tissue damage and consequently pathologies such as atherosclerosis and dementia.

Dysfunction of certain processes due to aging

Neutrophils in older individuals would have a lower response to antiapoptotic stimuli. It is currently being investigated whether chemotaxis, attraction of the macrophage by the neutrophil, may be altered with age; further studies are still required to confirm this. Others point to an altered spherocytosis or a lack of monocyte maturation.

Macrophage polarization is another important point. The normal pathway would be for a macrophage to initiate spherocytosis and secrete anti-inflammatory interleukins to terminate the process. The opposite would be to have macrophages in the injured tissue that worsen the problem (secretion of inflammatory interleukins).

Polarization to a macrophage pro-resolving phenotype has been found to be induced by specialized pro-resolving mediators (SPMs), a superfamily of bioactive substances synthesized from essential fatty acids. SMPs include lipoxins, resolvins, protectins, and maresins. Again, it is possible that aging alters the biosynthesis of SMPs.

Conclusions and new horizons

Inflammaging may be understood as the combination of the inappropriate onset of inflammation and the poor resolution of inflammation, all linked to aging.

As for possible therapies to treat these problems, the usefulness of statins (3-hydroxyl-3-methylglutaryl coenzyme A inhibitors) is being studied. Lovastatin has been shown to enhance spherocytosis in alveolar macrophages in patients with chronic obstructive pulmonary disease (COPD), a pathology characterized by chronic inflammation of the lungs.

Another line of research involves modulating treatments of SPMs to promote the resolution of inflammation. (1)

BIBLIOGRAFÍA

(1) Sendama W. The effect of ageing on the resolution of inflammation. Ageing Res Rev. 2020 Jan;57:101000. doi: 10.1016/j.arr.2019.101000. Epub 2019 Dec 17. PMID: 31862417; PMCID: PMC6961112.

(2) https://pubmed.ncbi.nlm.nih.gov/31862417/#:~:text=Abstract,such%20as%20sarcopenia%20and%20frailty

La entrada Aging and Persistent Inflammation se publicó primero en Neolife.

It would be a shame to miss out on a preventive treatment that would protect us from cognitive decline or Alzheimer’s disease. We are talking about a hormone, estradiol (E2).

With menopause, estradiol levels drop, and this hormone loss is associated with brain changes (including cognitive functions), sleep disturbances, and mood disorders. Let’s see how estradiol interacts with the cholinergic and dopaminergic systems and with mitochondrial functioning, which “break down” with aging.

Dr. Celia Gonzalo Gleyzes – Neolife Medical Team

Estrogens and the cholinergic system

A drop in estrogen levels occurs during menopause in women, and in men, when they undergo hormone blocking treatments for prostate cancer.

There are three types of estrogens, the most relevant being estradiol (E2). The other two may be synthesized from it: estrone (E1) and estriol (E3).

Estradiol has a higher affinity for the intracellular estrogen receptors, ERalpha and ERbeta.

The ovary is the primary source of estrogen in women, synthesized from acetate and cholesterol through a series of steps involving cytochrome P-450 aromatase in the last stage. Aromatase is expressed not only in the ovaries, but also in the brain, testes, adrenal glands, fetal liver, skin, fat, breast and bone marrow, all of which act on circulating androgens.

In males, testosterone is aromatized to produce estradiol. This process occurs in large quantities in the testes, where estrogenic action is important for fertility, and also in the aforementioned areas. It should be noted that some steroids may also act through estrogen receptors.

The expression of one or the other receptor will vary according to the location; ERalpha is expressed in the epididymis, testes, uterus, pituitary gland, kidneys, and adrenal glands, and to a lesser extent in the thalamus and hypothalamus.

ERbeta is expressed more intensely in the ovaries and prostate.

There are differences between men and women in the expression of ERalpha in the hypothalamus. In women, estradiol levels will fluctuate throughout the menstrual cycle.

The menopausal transition usually lasts 5-8 years and is associated with numerous symptoms (sleep disturbances, pain, decreased processing speed, verbal memory, depression, etc.).

It is estimated that 50-80% of women experience vasomotor symptoms (hot flashes, night sweats) at this stage.

The decrease in estradiol also occurs in the male, but will be more gradual.

Cognitive and morphological changes associated with estradiol variations

Some very interesting findings have been detected in animal models: surgical menopause leads mice to reduce the dendritic spines of certain neurons, but this alteration is reversed when they are given a treatment with estradiol.

In macaques, menopause causes certain synapses (connections between neurons) to be lost; once again, estradiol treatment allows synaptic density in the prefrontal cortex to be increased.

Using imaging tests, such as magnetic resonance imaging (MRI), it is found that estradiol replacement in postmenopausal women is associated with an increase in hippocampal volume.

There is an improvement in attention span (demonstrated by MRI in dynamic tests) in postmenopausal women receiving estradiol.

The decrease in estrogen is associated with a reduction in dendritic spines, in the number of specific synapses, with changes in connectivity, and with a reduction in gray matter in some specific areas. All of this translates into unfavorable cognitive changes.

Sleep disturbances arising in menopause correlate with vasomotor symptoms. Estradiol is also known to modulate REM sleep.

In perimenopausal women, the decrease in estradiol may worsen depressive symptoms if there was a previous history of this type of disorder. This is because estradiol interacts with the brain’s serotonergic system.

In animal models, estradiol treatment in oophorectomized rats (that had their ovaries removed) was shown to increase the expression of serotonin 5-HT2A receptors in different brain regions.

On the other hand, changes in estrogen levels alter cortisol responses.

Estrogens and the cholinergic system

Bartus’s theory from 1982 regarding brain aging was based on changes in the cholinergic system (typical in Alzheimer’s disease). In fact, drugs such as acetylcholinesterase inhibitors are used to increase acetylcholine levels at synapses. Estrogens would again be involved; there is expression of estrogen receptors (ERalpha) in these neurons with choline acetyltransferase activity.

Combined hormone therapy (estradiol/progesterone) initiated early in menopause is associated with increased cholinergic activity in the hippocampus and posterior cingulate cortex.

Estrogens and the dopaminergic system

Aging also leads to reductions in dopamine binding, dopaminergic receptors, and dopamine transport.

In oophorectomized rats, estradiol and progesterone therapy was associated with increased dopamine reuptake by dopaminergic neurons. In primates, the treatment favored the preservation of dopamine-producing neurons. A retrospective study shows that Parkinson’s disease is more frequent in women with early menopause or in those who have postponed hormone therapy beyond 6 months after the onset of menopause.

Estrogens and mitochondrial dysfunction

Another explanation for cognitive aging comes from mitochondrial DNA damage that occurs over time. It would lead to an increase in reactive oxygen species and a reduction of mitochondrial activity.

There are studies that confirm the hypothesis that estradiol helps maintain good mitochondrial function. In post menopausal women without hormone replacement therapy, there is a lower glucose uptake in the prefrontal, parietal, cingulate, and temporal lobes. This hypometabolism translates into a shift to more anaerobic behavior that is associated with a decrease in brain volume.

Inflammation and cognitive aging

We’ve already covered this in another blog post. Well, in menopause, there is an increase in inflammatory cytokines such as IL-1, IL-6, and TNF-alpha. Treatment with hormone therapy would normalize these altered levels.

Estrogens and Alzheimer’s disease

Certain observational studies have shown a reduction in the risk of Alzheimer’s disease with hormonal treatment initiated during menopause.

Recent research indicates that transdermal estradiol treatment reduces beta-amyloid accumulation in women with recent menopause, suggesting a role for E2 in modulating beta-amyloid plaque formation. E2 also regulates beta-amyloid degradation by metalloproteases and neprilysin. Finally, treatments with E2 would reduce Tau phosphorylation. (1)

Conclusions

The key takeaways are:

• The involvement of estradiol in different brain areas and systems. The loss of estradiol leads to cognitive decline and promotes diseases such as Alzheimer’s and Parkinson’s disease.
• The big benefit of hormone therapy, if started early in menopause.
• Regarding the choice of the type of hormone treatment, the combination of estradiol and progesterone, always bioidentical hormones, are a safe bet.

BIBLIOGRAFÍA

(1) Russell JK, Jones CK, Newhouse PA. The Role of Estrogen in Brain and Cognitive Aging. Neurotherapeutics. 2019 Jul;16(3):649-665. doi: 10.1007/s13311-019-00766-9. PMID: 31364065; PMCID: PMC6694379.

(2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694379/

La entrada Estradiol and Brain Aging se publicó primero en Neolife.

The exposome is defined as the set of non-genetic factors to which we are exposed throughout our lives and which condition our state of health and disease.

The WHO estimates that approximately 25% of diseases are related to these non-genetic factors, which could be avoided. Therefore, it provides extremely valuable information in the design of preventive, diagnostic, and therapeutic strategies in the medicine of the future.

Dr. Débora Nuevo – Neolife Medical Team

What is the EXPOSOME?

The set of traits presented by each individual is what we call phenotype, which is the product of each person’s gene combination (called a genotype) within a given environment.

What we understand as an exposome, a term coined by C. Wild in 2005, is the set of environmental (non-genetic) factors to which each individual is exposed from the moment of conception and which may condition the state of health or disease.

This name encompasses multiple factors, which also vary over time, and which we may group into 3 categories or domains:

• The General External domain includes social, economic, and psychological factors, such as education, climate, psychological stress, and the social or financial situation.
• The Specific External domain includes the influence of infectious agents, chemical and environmental contaminants, radiation, alcohol and tobacco use, profession or occupation and medical treatments.
• The Internal domain refers to metabolism, circulating hormones, microbiota, inflammation, lipid peroxidation, oxidative stress, and aging.

Variability and susceptibility windows of the exposome

In order for non-genetic factors to impact our health, they need to be able to alter biology at different levels (altering the microbiota, interacting in metabolic processes, decompensated the usual cellular pathways…).

That’s why the exposome is especially difficult to cover. Not only because of the variability of its nature but also because it is modified over time, that is, it is dynamic.

Its effect depends on the dose or the level of exposure, as well as the moment in which it occurs, so we are talking about intrapersonal variability.

And this effect does not turn out to be the same in all individuals, with population groups that are more susceptible than others, also leading to interpersonal variability.

On the other hand, it is worth mentioning the existence of windows of susceptibility, which are the specific periods throughout an individual’s life in which they are especially sensitive to certain exposures. An example is the special susceptibility to many factors at early stages of life, which may condition important events in later stages.

How do we study the exposome?

Due to the complexity of the term exposome, the approach must be multidisciplinary and comprehensive.

To obtain the data for the study of the exposome, biomonitoring is the most widely used strategy. There are two types of biomonitoring, which in turn complement each other by providing a more complete picture:

• Human biomonitoring: It consists of collecting biological samples, usually blood or urine. Concentrations of toxics or pollutants and their metabolites are analyzed. Other parameters that are compared to reference values are also measured.
• Environmental biomonitoring: It collects environmental samples that may include food, water, or air, and so their presence and the level of exposure are linked to the environment of the different population groups.

The biomarkers in turn may indicate:

• Exposure, indicating only the presence of a substance,
• Effect, the evidence of biochemical, physiological, or behavioral alterations that are associated with diseases,
• Susceptibility, in relation to the ability to respond to the exposure of a non-genetic factor.

The exposome in health and disease

According to the WHO, among the top 10 causes of death linked to a person’s life environment we find cardiovascular disease, cancer, and respiratory diseases.

Cardiovascular diseases

The role of an individual’s diet on the cardiovascular system is well known. For instance, a diet rich in salt or fat may lead to high blood pressure or dyslipidemia, which in turn are risk factors for atherosclerosis, myocardial infarction, or stroke.

The microbiota is also widely related to the risk of cardiovascular disease. Certain foods and components of the gut flora have been linked to a higher risk of atherosclerosis. An example is L-Carnitine, which is found in meats or dairy products and is metabolized by the gut microbiota generating, among other compounds, N-trimethylamine oxide, which promotes cardiovascular inflammatory processes.

Pollution, noise, or lifestyle habits are also factors that may be avoided and help lower the incidence of cardiovascular disease.

Early identification of these exposure factors and their elimination are key strategies in the development of preventive plans based on each individual’s exposome.

Cancer

Cancer is a multifactorial disease, and a large number of the factors involved are still unknown. However, it seems clear that some non-genetic factors are linked to the development of cancer,

One factor typically linked to skin cancer is exposure to the sun. UV radiation is known to cause mutations in skin cell DNA.

Additionally, some substances, like pesticides, some air pollutants, toxic substances that are present in certain foods or water (e.g. arsenic), as well as others like physical activity or circadian rhythm are also closely linked to skin cancer.

Breast cancer is also influenced by the exposome. Exposure to certain substances, like dichlorodiphenyltrichloroethane (DDT), polycyclic aromatic hydrocarbons (PAH), and heavy metals during certain susceptibility windows (such as the prenatal stage, gestation, or menopause) are strongly linked to the development of this pathology.

Lung cancer has smoking as its main non-genetic risk factor. Between 80 and 90% of lung cancers occur in smokers or former smokers.

Respiratory diseases

Once again, smoking is responsible for chronic respiratory pathologies such as COPD or asthma. Moreover, exposure to cigarette smoke during the prenatal phase also increases the risk of alterations in the fetus’ lung function and the development of diseases.

Allergies and asthma are closely linked to environmental pollutants. Climate change, urban pollution, and biodiversity loss are key to the development of allergies.

Endocrine diseases

The exposome also plays an important part in the development of endocrine pathologies. Some compounds have recently been shown to act as endocrine disruptors by altering hormonal pathways. These molecular compounds have structures that are very similar to some hormones, and through these, they can impersonate them at different steps in the operating pathway.

One example of these endocrine disruptors are the phthalates used as plastics, which are found in PVC, cosmetics, or hygiene and personal care products. These high lipid compounds, once in the bloodstream, may advance to any part of the body. In testes or ovaries, they are able to alter the secretion of hormones and cause fertility problems.

Additionally, an unhealthy diet, a sedentary lifestyle, or specific environmental components may play a key role in the development of DM II.

The exposome and the aging process

Aging is a natural and physiological process,

At the molecular level, it results in genomic instability, wear and shortening of telomeres, and a series of epigenetic changes that lead to an alteration in mitochondrial function and cellular senescence.

However, we don’t all age the same way. Aging is a biologically complex process, involving genetic and environmental factors. It is the exposome that is responsible for making a difference towards healthy aging with a similar genetic component. Some non-genetic factors have been associated with the maintenance of telomeres which is a great measure in the assessment of aging.

Pollution, smoking, obesity, and poor sleep quality are known to have a negative effect on the telomere length,

And so, the study of the influence of the exposome on cellular aging may be the key to the medicine of the future and to achieving a healthy aging process.

BIBLIOGRAFÍA

(1) Rappaport SM, Barupal DK, Wishart D, Vineis P, Scalbert A. The blood exposome and its role in discovering causes of disease. Environ Health Perspect. 2014;122(8):769-774. doi:10.1289/ ehp.1308015

(2) Wild CP. The exposome: From concept to utility. Int J Epidemiol. 2012;41(1):24-32. doi:10.1093/ije/ dyr236

(3) Olea N, Casas M, Castaño A, Mendiola J, Vrijheid M. Informe Anticipando. Exposoma. Fundación Instituto Roche. 2020. institutoroche.es

(4) https://www.vidasostenible.org/que-es-el-exposoma/

La entrada The Exposome and the Medicine of the Future se publicó primero en Neolife.

Neurological diseases have become one of the main health problems in developed countries due to their prevalence, clinical relevance, and impact. Evidence shows that nutrition is a promising approach to preventing age-related neurodegeneration.

With an increasingly aging population, there is evidence that points to how nutrition offers a promising approach to preventing neurodegeneration caused by aging and dementia. A new study published in the journal Ageing Research Reviews addresses new ways to explore the role of nutrition in healthy aging: the impact of nutrients, dietary manipulation, and microbiota.

Alejandro Monzó – Neolife Nutrition and Nursing Unit

The brain experiences neural development up to about 30 years of age

Nutrients play a fundamental role in the development and functioning of the human nervous system. Nutritional epidemiology has suggested a protective role for healthy diets and various nutrients, which affect brain aging outcomes. Older people who have a diet rich in fruits, vegetables, whole grains, and fish, like the Mediterranean diet, have larger brains than those with unhealthy diets (1, 2). The Mediterranean diet may be protective of cognitive impairment through various mechanisms (3):

• The intake of monounsaturated fatty acids would help preserve the cell membrane.
• The improvement of the metabolic pattern would lead to lower vascular deterioration,
• The intake of antioxidants would help decrease oxidative stress.

Therefore, the randomized clinical trial PREDIMED (PREvention with a MEDiterranean DIet) suggests that adherence to the Mediterranean diet decreases cardiovascular events including stroke, which directly and indirectly influences the development of dementia (3).

The bigger the size, the greater capacity

Additionally, it has been shown that people with bigger brains have better cognitive abilities, so any improvement in the quality of the diet may be a good strategy when it comes to maintaining elderly people’s cognitive abilities. There is evidence that shows that some nutrients or food ingredients, in particular vitamins and specific minerals, flavonoids, and omega-3 fatty acids are beneficial to cognitive function (Figure 1) (3, 4).

The importance of Omega3

In recent years, the role of omega-3 fatty acids has been studied in the development of cognitive decline and several mechanisms through which the risk of dementia may be diminished have been put forth. These polyunsaturated fatty acids exert their protective nature through their antithrombotic, vasodilator, anti-inflammatory, antiarrhythmic effects, and above all their effects on lipid metabolism. Since a direct link between cardiovascular disease and the onset of dementia, both Alzheimer’s and vascular, has been described, the reduction of cardiovascular risk may decrease the risk of dementia. These fatty acids, together with phospholipids, are part of cell membranes and may contribute to maintaining their integrity in neurons and their expression (2,3,4).

It is worth mentioning a paper published in the scientific journal Journal of Alzheimer’s Disease Reports, that shows that obesity may aggravate the effects of Alzheimer’s. This study revealed that obesity may contribute to the vulnerability of neural tissue, while maintaining a healthy weight in cases of mild dementia may help preserve brain structure (5). Therefore, overweight and obesity are additional burdens on brain health and may aggravate the disease,

Once again, the microbiota

Another new avenue of research regarding age is the study of human gut microbiome. This is the totality of the microorganisms that make up the gut microbiota, predominantly bacteria but also including fungi, viruses, and other organisms. The gut microbiome undergoes significant changes throughout life, presenting distinctive characteristics at different stages in life. The use of prebiotics and probiotics is presented as an interesting tool to address the microbiome-gut-brain axis and as an intervention to aid in the treatment of mental disorders. Prebiotics include dietary fibers that facilitate the growth of beneficial gut bacteria, and it has been suggested that they influence neurobiology, achieving good results in improving patients’ cognitive flexibility. However, the mechanisms through which the microbiota may influence brain function appear to be complex and multidirectional, and involve neural, endocrine, and immune pathways (4).

At Neolife, we develop a comprehensive health program, which includes the prevention of neurodegenerative diseases. And we have seen that nutrition plays an important role in both the cause of neurological disease and the treatment of many neurological processes. Therefore, an individualized dietary-nutritional plan is one of the keys in the prevention of disease in our patients, which also allows us to avoid premature brain aging and develop a state of optimal health.

BIBLIOGRAFÍA

(1) Otero. “La dieta mediterránea Evita que el cerebro se encoja con el envejecimiento”. Diario ABC. URL: https://www.abc.es/salud/habitos-vida-saludable/abci-dieta-mediterranea-evita-cerebro-encoja-envejecimiento-201805171223_noticia.html

(2) Redondo S., M.R. & González R., L.G. (2015). “Nutriguía: manual de nutrición clínica”. 2ªEdición. Editorial Médica Panamericana.

(3) De Luis Román, D.A. Bellido Guerrero, D. García Luna, P.P. Olivera Fuster, G. (2017). “Dietoterapia, nutrición clínica y metabolismo”. Tercera edición. Sociedad Española de Endocrinología y Nutrición. Grupo Aula Médica, S.L. Madrid, España.

(4) Flanagan E. y otros. (2020). “Nutrition and the ageing brain: moving towards clinical applications”. Ageing Res Rev. Vol. 62 URL: https://pubmed.ncbi.nlm.nih.gov/32461136/

(5) Dake, M.D. y otros. (2021). “Obesity and brain vulnerability in normal and abnormal aging: a multimodal MRI Study”. Journal of Alzheimer’s Disease Reports. Vol. 5, nº1, pp: 65-77. URL: https://content.iospress.com/articles/journal-of-alzheimers-disease-reports/adr200267

La entrada Nutrition and Brain Aging se publicó primero en Neolife.

Despite its fundamental role, the mitochondrion has not been getting the attention it deserves when it comes to COVID-19. In this blog post, we’ll explain the part it plays in this disease.

Patients with COVID-19 mainly present a lower respiratory tract infection. Unfortunately, a significant number of patients develop what is called a “cytokine storm”, a hyper-inflammatory state associated with oxidative stress, deregulation of iron homeostasis, hypercoagulability, and clot formation.

Dr. Alfonso Galán González – Neolife Medical Team

The fundamental role that mitochondria play in platelet function and survival

In this new blog post, we wish to present the latest research, which links mitochondrial dysfunction and alterations of the gut microbiota with the pathogenesis of coronavirus disease; in other words, they are intimately involved in the way COVID-19 affects us and causes us harm.

In another blog post, we discussed how mitochondria are involved in the aging process (here) and gut microbiota and the causes and consequences of dysbiosis.

Some evidence, which we have already discussed here, was already pointing to the mitochondria and their energy production mechanisms as something that was affected in one way or another in COVID-19 disease. In this blog post, and as simply as possible, we will break down what we know about mitochondrial involvement and our gut flora in coronavirus disease, and how mitochondrial dysfunction in the disease may also affect platelet survival and apoptosis, and potentially increase the risk of clot formation.

A brief introduction

It is common knowledge that SARS-CoV-2 is a betacoronavirus that emerged in Wuhan, China in December 2019. Since then, the pandemic has spread rapidly, causing over 2.7 million deaths worldwide at the time of writing.

Essentially, patients with COVID-19 present a lower respiratory tract infection. Unfortunately, a significant number of patients develop what is called a “cytokine storm”, a hyper-inflammatory state associated with oxidative stress, deregulation of iron homeostasis, hypercoagulability, and clot formation.

During this time, several biomarkers have been associated with a worse prognosis and mortality in critically ill patients, mainly lymphopenia, increased D-dimer, and IL-6. A prospective study of large numbers of ICU patients reported a higher risk of death for every 10% increase in IL-6 or D-dimer, pointing to the close link between COVID-19 disease and systemic inflammation and endothelial damage.

Higher levels of Ferritin are also a predictor of mortality, as is oxidative stress. A great deal of evidence links inflammation with oxidative stress.

Despite its fundamental role in controlling oxidation and the formation of reactive oxygen species (ROS), not much has been said about mitochondria as an important part of COVID-19.

Next, we will explain the theoretical role of inflammatory signals when it comes to aggravating oxidative mitochondrial damage and how this contributes to alterations in coagulation, ferroptosis (cell death dependent on iron), and dysbiosis. We will also see how extracellular mitochondria, in particular platelet mitochondria, affect coagulation and clot formation.

Mitochondria, oxidative stress, and inflammation

Normally, our tissues require a large number of functioning mitochondria to provide energy and regulate cellular functions based on our needs. If there is a higher demand, we create more mitochondria through a process called mitogenesis, while excess mitochondria are eliminated through a process called mitophagy. Mitochondrial defects have been implicated in many pathologies, like diabetes, cardiovascular disease, gastrointestinal diseases, cancer, and the aging process. Mitochondria are the biggest source of reactive oxygen species (ROS), which on the one hand leads to normal cellular functioning, but on the other hand, has been associated with an increase in intracellular oxidative stress.

Pro-inflammatory cytokines induce an increase in mitochondrial ROS. These inflammatory cytokines, like TNF-alpha and IL-6, are found in the blood of COVID patients, affecting mitochondrial oxidative phosphorylation, which leads to the production of ATP (our energy currency) and to the formation of ROS. This affects mitochondria in many ways leading to cell death (apoptosis) in the worst case scenario. Additionally, when these damaged mitochondria release their contents into the cell’s cytosol or extracellular space, this leads to the production of pro-inflammatory cytokines, like IL-1 or IL-6. Both are markers in severe cases of COVID-19.

Many studies have also shown the impact of mitochondrial dysfunction on immune response. For example, the production of pro-inflammatory cytokines is greatly increased in lung cells with dysfunctional mitochondria.

Iron and mitochondrial dysfunction

Studies of markers in COVID-19 have shown without any doubt that excess ferritin is associated with the severity of the disease and a worse prognosis. Ferritin, in addition to being a marker of inflammation, is released by the cells that die.

One of the iron-mediated oxidative stress targets is none other than the mitochondria. The function of the mitochondria depends on the right amount of iron, and an alteration in its iron levels will alter its function, leading to stress and cell death.

Moreover, we know that non-protein circulating iron catalyzes the formation of higher levels of ROS that cause damage to cellular and mitochondrial components, as well.

Ferroptosis is a recently discovered phenomenon of programmed cell death associated with iron accumulation. It has been shown in numerous infections by different microorganisms. Peculiarly, ferroptosis causes irreversible alterations in mitochondrial morphology

.
This data provides a solid basis for the idea that mitochondrial dysfunction plays a key role in COVID-19 disease.

Thrombopenia and hypercoagulability in COVID

It is clear at this point that coagulation abnormalities are closely associated with COVID mortality. The comparison of coagulation parameters between survivors and non-survivors indicates a higher D-dimer, higher fibrin degradation products, higher prothrombin time, and higher activated partial thromboplastin.

Also, a decrease in the number of platelets has been associated with an increase in mortality and is more common in more severe cases especially associated with disseminated intravascular coagulation (DIC)

Extracellular mitochondria and platelet mitochondria

We may curiously find mitochondria outside the cells; this is something that is not well known. Extracellular mitochondria may be found cell-free, enclosed by a membrane such as inside platelets, or in vesicles. Out-of-cell mitochondria may induce paracrine or endocrine responses and regulate cell-to-cell communication, regeneration, hazard detection, and cause immune responses. In addition to extracellular mitochondria, the release of mitochondrial DNA (MDNA) has been described during apoptosis.

The potential role of cell-free circulating mitochondria or their blood derivatives in patients with COVID-19 has not yet been determined, but it is something that may have therapeutic implications, especially with the use of plasma obtained from recovered patients to treat sick patients. But let’s delve a little deeper.

A platelet is a small anucleate blood cell with the primary physiological and pathological function of hemostasis and wound healing. In the absence of an all-controlling nucleus, platelet health is largely determined by the health of its mitochondria.

The role that mitochondria play in platelet function and survival is fundamental. Mitochondrial dysfunction in the disease may also affect platelet survival and apoptosis, and potentially increase the risk of clot formation. More importantly, it has recently been shown that apoptotic platelets may induce clotting e”50 times faster than normal platelets.

An increase in mitochondrial ROS production in platelets leads to severe oxidative stress that alters ATP production and mitochondrial membrane potential, leading to increased platelet activation.

This may explain the small number of platelets in COVID-19 disease despite the onset of thrombosis. Additionally, patients with COVID-19 are likely to suffer from impaired mitophagy due to the stress caused by hyper-inflammation. In a healthy context, mitophagy protects platelets from oxidative stress and mitochondrial destruction by eliminating damaged mitochondria to prevent platelet apoptosis; when platelet mitophagy, which is involved in COVID-19 pathogenesis, is altered, there is an increase in platelet apoptosis that contributes to an increase in thrombosis.

Therefore, preserving the mitochondrial function of platelets may be an additional means of decreasing the risk of potentially fatal thrombotic events in COVID-19.

On the other hand, by linking this to the previous point of iron overload in COVID, evidence suggests that iron overload is an agent of platelet dysfunction. Excess iron alters mitochondrial function and promotes oxidative stress. It is believed that there is a link between iron overload and elevated ROS.

Moreover, activated platelets may release mitochondria into microvesicles into the extracellular medium when exposed to oxidative stress. These mitochondria may be lysed by generating inflammatory mediators that promote endothelial inflammation.

Therefore, extracellular mitochondria and their “derivatives” may represent critical mediators in the progression of the inflammatory environment that leads to coagulopathy associated with inflammatory response pathways.

Cell-free mitochondria and mitochondria in microvesicles are a major subset of extracellular vesicles released by activated monocytes, and their pro-inflammatory activity in endothelial cells is determined by the activation status of their parent cells. Therefore, mitochondria may be critical intercellular mediators in cardiovascular disease and other inflammatory environments.

COVID and dysbiosis

It is very important to consider the link between mitochondria and microbiota in COVID-19 for several reasons:

• First, some patients have concurrent gastrointestinal symptoms, including diarrhea.
• The virus’ genetic material has been detected in the feces of patients with COVID-19.

These observations indicate the ability of SARS-CoV-2 to colonize the gastrointestinal tract, which would disrupt the gut microbiota. Interestingly, fecal metabolomic analysis suggested possible pathways linking gut microbiota to inflammation, which would explain the predisposition of certain individuals to develop severe COVID-19. Addressing the impact of the COVID-19 microbiota on mitochondrial function would provide new avenues for therapeutic strategies.

The interaction between the microbiota and the mitochondria appears to occur both ways through endocrine, immune, and humoral links

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The gut microbiota influences mitochondrial functions related to energy production, mitochondrial biogenesis, redox balance, and inflammatory cascades. On the other hand, mitochondrial functions may alter the composition and activity of the gut microbiota. In fact, as described above, under stressful conditions such as bacterial or viral infections, mitochondria may modulate immune responses that lead to increased inflammation. This unbalanced immune response may result in dysbiosis.

Conclusions

Let’s try to sum this all up in a few words and present some takeaways:

• COVID-19 disease involves an inflammatory state.
• This inflammatory state involves the production of large numbers of inflammatory cytokines and is linked to the presence of hyperferritinemia (iron overload), leading to higher oxidative stress and cellular damage.
• The mitochondrion is the fundamental organelle in the generation of reactive oxygen species (ROS).
• Higher levels of ROS lead to intra and extracellular mitochondrial damage.
• This mitochondrial damage leads to microbiota dysbiosis.
• Additionally, platelet dysfunction plays a fundamental role in clot formation.
• Mitochondrial damage leads to the release of its contents, which aggravates the inflammatory state in a vicious cycle that leads to the progression of COVID-19.

This evidence of the involvement of mitochondrial, platelets and dysbiosis in inflammatory processes and COVID opens up new avenues in the search for new therapeutic and preventive strategies in this serious disease and others that involve severe systemic inflammation.

BIBLIOGRAFÍA

(1) Saleh J, Peyssonnaux C, Singh KK, Edeas M. Mitochondria and microbiota dysfunction in COVID-19 pathogenesis. Mitochondrion. 2020;54:1-7. doi:10.1016/j.mito.2020.06.008

(2) Zhang, D., Guo, R., Lei, L., Liu, H., Wang, Y., Wang, Y., Dai, T., Zhang, T., Lai, Y., Wang, J., Liu, Z., He, A.O., Dwyer, M., Hu, J., 2020a. COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome. medRxiv 2020.03.24.20042655.

(3) Zhu, H., Santo, A., Jia, Z., Li, Y., 2019. GPx4 in bacterial infection and polymicrobial sepsis: involvement of ferroptosis and pyroptosis. React. Oxyg. Species 7, 154–160.

(4) Aguirre, J.D., Culotta, V.C., 2012. Battles with iron: manganese in oxidative stress pro- tection. J. Biol. Chem. 287, 13541–13548.

(5) Wang, L., Wu, Q., Fan, Z., Xie, R., Wang, Z., Lu, Y., 2017. Platelet mitochondrial dys- function and the correlation with human diseases. Biochem. Soc. Trans. 45, 1213–1223.

(6) Melchinger, H., Jain, K., Tyagi, T., Hwa, J., 2019. Role of platelet mitochondria: life in a nucleus-free zone. Front. Cardiovasc. Med. 6, 1–11.

(7) Gou, W., Fu, Y., Yue, L., Chen, G., Cai, X., Shuai, M., Xu, F., Yi, X., Chen, H., Zhu, Y., Xiao, M., Jiang, Z., Miao, Z., Xiao, C., Shen, B., Wu, X., Zhao, H., Ling, W., Wang, J., Chen, Y., et al., 2020. Gut microbiota may underlie the predisposition of healthy individuals to COVID-19. medRix 1–44.

(8) Green, D., Galluzzi, L., Kroemer, G., 2011. Mitochondria and the autophagy- inflammation-cell death axis in organismal aging. Science (80-.) 333, 1109–1112

(9) Lin S-J, et al. Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev. 2004;18:12–16.

(11) Imai S, Yoshino J. The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing. Diabetes Obes Metab. 2013;15(Suppl 3):26–33.

(12) Lin SJ, et al. Life span extension by calorie restriction in S. cerevisiae requires NAD and SIR2. Science. 2000;289:2126–2128.

La entrada Mitochondria and Dysbiosis at the Root of COVID-19 Disease se publicó primero en Neolife.

One study showed that men, black people, and older patients were more likely to catch COVID, while those taking melatonin, paroxetine, or carvedilol were less likely to do so.

In diseases with a high degree of inflammation, melatonin use is very promising, as it lowers circulating cytokine levels. Melatonin has also been shown to be beneficial in patients who have suffered a heart attack, or those with cardiomyopathy, hypertensive heart disease, and pulmonary hypertension.

Dr. Alfonso Galán González – Neolife Medical Team

SThere is a hypothesis that has been proposed that the RAS suffers two blows that lead to the progression of COVID-19 disease in patients with a history of inflammation.

The first would come from the low-grade inflammation associated with diseases that cause chronic inflammation, and the second blow is caused by COVID. This may explain the higher mortality rate in patients with this type of pathology.

In these blog posts, we have often referred to this incredible molecule (here), and we’ve even mentioned how beneficial it is in coronavirus disease (here).

This time, we will delve deeper (even at the molecular level) into what makes melatonin have these effects, presenting the research that supports these findings.

What are the effects of melatonin that may help us combat COVID-19?

They are summarized in this chart:

In this first part, we will talk about its antiviral, anti-inflammatory, antioxidant, chronobiotic, and immunomodulatory effects, leaving the rest, together with an explanation of the studies currently underway, for a second blog post.

ANTIVIRAL EFFECT

SARS-CoV-2 enters the pulmonary epithelial cells and others through the ACE2 receptor.

The glycoprotein spike on the surface of the virus is bound to the ACE2 receptor (angiotensin-converting enzyme 2); after membrane fusion, the viral RNA genome is released into the cytoplasm and results in two polyproteins that are split by the SARS-CoV-2 main protease, which results in the replication-transcription complex.

Melatonin has been shown to inhibit the virus protease more effectively than other ligands.

Another way in which it may regulate infection is by binding and inhibiting calmodulin, which regulates the expression and retention of ACE2 in the cell membrane.

One study showed that men, black people, and older patients were more likely to catch COVID, while those taking melatonin, paroxetine, or carvedilol were less likely to do so.

The relationship between COVID and melatonin and the Renin-Angiotensin System (RAS) goes somewhat further. In general, RAS induces inflammation, high blood pressure, vasoconstriction, fibrosis, and proliferation via the ACE2/angiotensin II/AT1R axis and the opposite effects via the ACE2/angiotensin (1-7)/MAS axis.

The RAS is activated by chronic inflammation in cancer, diabetes, high blood pressure, and obesity. SARS-CoV-2 induces the internalization and detachment of ACE2, which leads to the inactivation of the ACE2 / angiotensin (1-7) / MAS axis.

And so, there is a hypothesis that has been proposed that the RAS suffers two blows that lead to the progression of COVID-19 disease in patients with a history of inflammation. The first would come from the low-grade inflammation associated with these diseases that activate the ACE/angiotensin II/AT1R axis, and the second blow is triggered by COVID, as it renders the ACE2/angiotensin (1-7)/MAS axis inactive. This may explain the higher mortality rate in patients with this type of pathology.

Melatonin is an effective angiotensin II activation inhibitor and facilitates the action of angiotensin (1-7), thus acting on both “blows”.

Anti-inflammatory/Immunoregulatory Effect

Immunoregulation

T cells are the most advanced cells in our immune system. For a somewhat more complete explanation of how our immune system works, please read this blog post.

For the purposes of this blog post, we will mention a few types of white blood cells (a fundamental cell of the adaptive immune system). There are T helper cells (Th cells), also known as CD4+ cells, that include Th1, Th2, Th17, and T regulators (Treg) (CD4+ CD 25+).

Despite the complexity of the immune system, the fundamentals of its functioning are based on 3 white blood cell populations, the Th1, the Treg, and the Th17. Th cells activate Treg, inhibit Th17, and promote antigen-independent cytotoxicity by inducing the evolution of NK (Natural Killer) cells from our innate immune system into natural killer cells that are activated by lymphokines. Their actions are usually mediated by the secretion of IL-2, the main growth factor for white blood cells.

The relationships between these subtypes of white blood cells are markers for the main diseases suffered by human beings. And so:

• A low ratio of Th1 to Treg is typical in advanced neoplasia.
• A higher ratio of Th17 to Treg is typical in autoimmune diseases… and acute respiratory distress induced by coronavirus.

Anti-inflammatory

The main pathophysiological mechanism of SARS-CoV-2 infection is upward regulation of pro-inflammatory cytokines induced by the activation of neutrophils, macrophages, and mast cells. They increase IL-1, IL-6, and IL-17, C-reactive protein, and TNF alpha.

Melatonin exerts its anti-inflammatory effects through various mechanisms:

• One of these is the Sirtuin 1 mechanism, which prevents macrophages from becoming the pro-inflammatory type.
• It suppresses NF-kB activity.
• It stimulates the production of Nrf2 in studies of heart and liver protection.
• It reduces pro-inflammatory CK (TNF-alpha, IL-1, IL-6, IL-8, and IL-17) and increases anti-inflammatory ones such as IL-10.

Even though all these terms are too scientific, the charts helps us understand them, and it’s interesting to see the mechanism through which they exert their effects.

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And so, the charts below show how doses of 60 mg of melatonin inhibit the production of pro-inflammatory cytokines.

And increases the anti-inflammatory kind.

Coronavirus infection accumulates hyper-inflammatory monocytes and macrophages in the lower respiratory tract, where they play a key role in determining whether the disease will be severe. Infected monocytes and macrophages change their metabolism from oxidative phosphorylation in the mitochondria to glycolysis in the cytoplasm, generating reactive oxygen species; these monocytes that obtain their energy in this way produce more cytokines, causing the destruction of T cells and alveolar cells, thus aggravating the infection.

Melatonin converts these macrophages with modified metabolism back into M2 anti-inflammatory macrophages that use oxidative phosphorylation.

Antioxidant Effect

In both the cytoplasm and nucleus, melatonin has important antioxidant effects and purifies free radicals. These effects are achieved in 3 ways:

• Melatonin eliminates free radicals.
• Melatonin is metabolized into compounds with great antioxidant power.
• It is a direct antioxidant that stimulates the synthesis of antioxidant enzymes and inhibits pro-oxidants.
• It enhances the effects of other antioxidants such as Vitamin C.

As shown in this graphic, there is an intimate relationship, a kind of “vicious circle”, between the production of Reactive Oxygen Species (ROS) and free radicals and inflammation.

One feeds the other and vice versa. In diseases with a high degree of inflammation, melatonin use is very promising, as it lowers circulating cytokine levels. This has been documented in patients with DM2, periodontal disease, and severe multiple sclerosis, as well as in acute inflammation, such as surgical stress, cerebral or coronary reperfusion.

Generally speaking, these effects are achieved with doses that are higher than those used for a chronobiotic effect (2-3 times, of about 100-300 mg).

SEPSIS

Clinical data for COVID-19 disease show us that these patients are at higher risk of sepsis and heart failure.

Melatonin improves the septic shock by inhibiting the NLRP3 pathway, called inflammasome. What is this? The inflammasome is a complex that promotes the maturation of pro-inflammatory cytokines such as IL-1o and IL-18. The inflammasome is responsible for the activation of inflammatory processes, and there is evidence that shows it induces cellular pyroptosis, a highly inflammatory form of scheduled lytic cell death that occurs most often after infection with intracellular pathogens.

Melatonin has been shown, in rodents, to improve kidney, myocardial and liver damage in cases of sepsis, and in human neonatal sepsis, it improves clinical evolution.

In the study represented in these graphs, it was shown to increase the average lifespan of mice with peritonitis.

Melatonin has also been shown to be beneficial in patients who have suffered a heart attack, or those with cardiomyopathy, hypertensive heart disease, and pulmonary hypertension.

In critical patients, even those admitted to ICU, deep sedation increases long-term mortality. The use of melatonin in these patients lowers the use of sedation, pain, agitation, anxiety, and improves sleep quality.

A study of 10 patients admitted to the hospital with COVID-related pneumonia and poor prognostic risk factors administered melatonin, between 36 and 73 mg daily, along with standard treatment. Benefits were observed in all clinical variables (symptoms, regression of pulmonary infiltrates, inflammation markers), as well as in the need for ventilation, total hospitalization time, and final result (death vs recovery).

Another current article in the “preprint” phase shows data from 791 patients who required intubation from severe COVID lung disease and retrospectively analyses which treatments improved prognosis. Melatonin was the only treatment significantly associated with a better evolution.

Chronobiotic Effect

This refers to molecules that affect the physiological regulation of the body clock and specifically those capable of recovering unsynchronized circadian rhythms or preventing this from happening.

The elderly population is not only more susceptible to coronavirus infection but is more likely to have circadian rhythms that are altered by several causes, such as melatonin levels that decrease with age or an increase in stress from social isolation. The deregulation of circadian rhythms is believed to be involved in multiple pathologies suffered in the elderly, especially cardiovascular and neurodegenerative diseases.

It is worth noting that our immune system shows a significant circadian rhythmicity. Therefore, at the start of the day’s activity, there is greater expression of pro-inflammatory CK such as IL-1, IL-6 and IL-12 as well as macrophagic and leukocyte activity that leads to possible tissue damage. By contrast, anti-inflammatory mediators and other growth and angiogenesis factors are increased in the resting phase. As for immune cells; CD4 and CD8 activity against viral antigens reach their maximum levels in the resting phase, while cytotoxic activity of NK cells is more severe in the early hours of activity.

Indeed, these patterns may be altered in older people and should be taken into account when administering immunomodulators or anti-inflammatory drugs.

Delirium

Cases of delirium are found in 50% of hospitalized older patients and 80% of those in critical condition who require mechanical ventilation. Melatonin use is associated with lower ICU stay, lower prevalence of delirium, and improved sleep quality.

In COVID-19 disease, 15% of hospitalized patients have some degree of impaired of consciousness, from drowsiness to coma. Melatonin should be considered an effective agent for improving sleep and minimizing administration of BZD and antipsychotics.

With this, we end this first part of how melatonin may improve COVID disease. I hope it wasn’t too complicated to understand. I recommend you stay tuned for Part 2, which is very interesting, as well, and which provides insights into how its use is being integrated into the different fields and medical specialties.

BIBLIOGRAFÍA

(1) Gurwitz, D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev. Res. 2020, 81, 537–540.

(2) Hardeland, R. Melatonin and inflammation—Story of a double-edged blade. J. Pineal Res. 2018, 65, e12525.

(3) Xia, Y.; Chen, S.; Zeng, S.; Zhao, Y.; Zhu, C.; Deng, B.; Zhu, G.; Yin, Y.; Wang, W.; Hardeland, R.; et al. Melatonin in macrophage biology: Current understanding and future perspectives. J. Pineal Res. 2019, 66, e12547.

(4) Sánchez-López, A.L.; Ortiz, G.G.; Pacheco-Moises, F.P.; Mireles-Ramírez, M.A.; Bitzer-Quintero, O.K.; Delgado-Lara, D.L.C.; Ramírez-Jirano, L.J.; Velázquez-Brizuela, I.E. Efficacy of Melatonin on Serum Pro-inflammatory Cytokines and Oxidative Stress Markers in Relapsing Remitting Multiple Sclerosis. Arch. Med. Res. 2018, 49, 391–398

(5) Gitto, E.; Reiter, R.J.; Amodio, A.; Romeo, C.; Cuzzocrea, E.; Sabatino, G.; Buonocore, G.; Cordaro, V.; Trimarchi, G.; Barberi, I. Early indicators of chronic lung disease in preterm infants with respiratory distress syndrome and their inhibition by melatonin. J. Pineal Res. 2004, 36, 250–255.

(6) Gitto, E.; Karbownik, M.; Reiter, R.J.; Xian Tan, D.; Cuzzocrea, S.; Chiurazzi, P.; Cordaro, S.; Corona, G.; Trimarchi, G.; Barberi, I. Effects of melatonin treatment in septic newborns. Pediatr. Res. 2001, 50, 756–760.

(7) Castillo, R.R.; Quizon, G.R.A.; Juco, M.J.M.; Roman, A.D.E.; De Leon, D.G.; Punzalan, F.E.R.; Guingon, R.B.L.; Morales, D.D.; Tan, D.-X.; Reiter, R.J. Melatonin as adjuvant treatment for coronavirus disease 2019 pneumonia patients requiring hospitalization (MAC-19 PRO): A case series. Melatonin Res. 2020, 3, 297–310

(8) Ramlall, V.; Zucker, J.; Tatonetti, N. Melatonin is significantly associated with survival of intubated COVID-19 patients. medRxiv 2020

(9) Chellappa, S.L.; Vujovic, N.; Williams, J.S.; Scheer, F.A.J.L. Impact of Circadian Disruption on Cardiovascular Function and Disease. Trends Endocrinol. Metab. 2019, 30, 767–779.

(10) Zambrelli, E.; Canevini, M.; Gambini, O.; D’Agostino, A. Delirium and sleep disturbances in COVID–19: A possible role for melatonin in hospitalized patients? Sleep Med. 2020, 70, 111.

La entrada Melatonin in the Time of the Pandemic. Part 1 se publicó primero en Neolife.

An important way to activate our cellular immunity is by activating PARPs. These consume NAD, and when there is none or very little left, they can no longer be activated. They don’t activate our cellular immunity and the virus is free to continue replicating and damaging us.

NAD intervenes vitally in two very important pathways in humans, namely the sirtuin and PARP pathways. It is essential in functions that influence the aging process, such as mitochondria synthesis, apoptosis, autophagy, inflammation, intracellular and systemic signaling, DNA repair, genomic stability, programmed cell death… and our immunity.

Dr. Alfonso Galán González – Neolife Medical Team

The activation of NAMPT and providing NAM and NR dramatically lower the replication capacity of a coronavirus model that is sensitive to PARP activity.

Scientific knowledge has given us an incredible surprise very recently. Keep reading, and you’ll understand everything perfectly.

A few weeks ago, we posted in this blog an article on the importance of NAD in cellular metabolism, the aging process, gene expression, DNA repair, and other fundamental functions, and we showed you what we can do to improve its levels so that our body may function in the most optimal way. You may read this article here. I recommend it so you may better understand the results of the research that we will present below.

We said that there are two vital pathways in the human body in which the presence of NAD is essential: the sirtuin and PARP pathways.

Sirtuins are a group of enzymes that regulate functions that influence the aging process, such as mitochondria synthesis, apoptosis, autophagy, inflammation, intracellular and systemic signaling, DNA repair, etc. And PARP or poly (ADP-ribose) polymerase is a family of proteins involved in DNA repair, genomic stability, and programmed cell death.

We presented this chart of NAD synthesis to explain how our body is able to synthesize it and what we can do to improve this synthesis by providing various supplements or enhancing the activity of various enzymes with different strategies.

Well, this latest study by Dr. Charles Brenner’s team at the City Of Hope National Medical Center in California (USA) shows us that, within the PARP group, these enzymes that are primarily associated with DNA repair and that depend on NAD and therefore consume our reserves of it, there is a subgroup known as MARylating (mono-ADP-ribosylating) PARPs that are associated with antiviral cellular response. This study shows that:

• COVID-19 infection (SARS-CoV-2) produces robust upward regulation of these MARylating PARPS by inducing the expression of genes that encode for the enzymes of the salvage pathway (see chart) of NAD synthesis from Nicotinamide (NAM) and Nicotinamide Riboside (NR).
• They show that PARP 10 overexpression is sufficient to lower cellular NAD levels and that PARP 7, 10, 12, and 14 activity is limited by NAD availability.
• That this availability of NAD may be increased by pharmacologically activating NAD synthesis.
• That infection by a coronavirus model causes a very severe attack on the NAD of the host cell.
• And finally, that the activation of NAMPT (see chart and significance here) and providing NAM and NR dramatically lower the replication capacity of a coronavirus model that is sensitive to PARP activity.

I hope I didn’t lose you with this hard and more technical data, and I’ll summarize it in the simplest way possible.

What does all this mean? Well, SARS-CoV-2 causes our NAD levels to drop. How does it do that? To defend against it, we make our cellular immunity work at full throttle, and now we know that an important part of how we manage to activate our cellular immunity is through activating PARPs. These PARP 7, 10, 12, and 14 that influence immunity consume NAD like all the PARPs, and when there is none or very little left, they can no longer be activated. They don’t activate our cellular immunity and the virus is free to continue replicating and damaging us.

If we increase our NAD levels by taking Nicotinamide (NAM), Nicotinamide Riboside (NR), or increasing the activity of the NAMPT enzyme that is responsible for converting NAM into NAD, we will improve PARP activity, our cellular immunity, and lower virus replication.

I hope that this explanation clarifies the importance of this finding.

Can this explain, in part, why older people have more serious COVID disease? Well, we know that our NAD levels drop over the years and because of the aging process.

And while this has not yet been studied, it could be a very logical conclusion.

BIBLIOGRAPHY

(1) Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014;24(8):464-471. doi:10.1016/j.tcb.2014.04.002

(2) Lin S-J, et al. Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev. 2004;18:12–16.

(3) Imai S, Yoshino J. The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing. Diabetes Obes Metab. 2013;15(Suppl 3):26–33.

(4) Lin SJ, et al. Life span extension by calorie restriction in S. cerevisiae requires NAD and SIR2. Science. 2000;289:2126–2128.

(5) https://m.jbc.org/content/early/2020/10/13/jbc.RA120.015138

La entrada COVID, NAD, and Our Immune System se publicó primero en Neolife.

We look for pleasant scents in our perfumes, cosmetics, air fresheners, and cleaning products… But have we stopped to think about what these perfumes contain and what effects they may have on our body and health?

Anti-perfume activists or aromatherapy advocates? Where do we stand? Some components have been classified as endocrine disruptors, others as carcinogens, or environmentally toxic, but the truth is that the beneficial effects of certain molecules in the central nervous system have also been described.

Dr. Celia Gonzalo Gleyzes – Neolife Medical Team

Perfume: man’s companion through the ages, for better or worse

Human metabolism generates unpleasant odors through sweat, fat (sebaceous glands), and breathing. If we analyze them from a biochemical point of view, these odors are composed of fatty acids, steroids, amino acids, and biogenic amines.

From the beginning, man has always tried to disguise or mitigate them. Even ancient cultures used perfumes, which they made from mixtures of plants (flowers, leaves, fruits, resins, seeds, barks etc.) or from animal glands (musk, civet musk, ambergris, etc.). Oils (olive, almond, coconut, grapeseed, etc.) were used to facilitate absorption and application.

A secret recipe

Oftentimes, there is no way to find out the components of a perfume, which are only listed as “fragrance” or “scent”. This is what we call a “trade secret” to limit imitation. It’s a real shame. We have no information about the molecules used (good or bad) and their concentrations. Sometimes, we may see a list of ingredients.

The age of chemistry

As already mentioned, only natural components were used before, but since the development of chemistry this has changed. This is sometimes done to improve stability and prevent the oxidation of the perfume. On the other hand, some manufacturers resort to the use of fixing agents, dyes, and preservatives, such as alcohol, parabens, phenoxyethanol, methylisothiazolinone, nickel sulfate, etc.

Fragrances are all around us, from the air freshener they pump into shopping malls, to the scent in our hair gel, car air freshener, laundry detergent, deodorant, incense, or scented candles…

Researchers warn us about the potential harmful effects of fragrance compounds. They may alter hormonal circuits, be responsible for pathologies such as depression or autism, certain types of cancer (prostate and breast cancer), endocrinopathies (gynecomastia), liver damage, etc.

Air fresheners (or scented candles or incense) affect the air quality of our homes and release hundreds of toxic volatile organic compounds (VOCs), such as limonene, alpha and beta-pinene, ethanol, acetone, etc.

Compounds present in some fragrances

Most fragrance compounds belong to one of three families: phthalates, synthetic musks, and sensitizers.

1. Phthalates

These are phthalic acid esters, they have numerous applications, and in perfumery, they are used to improve the fixation of perfume (which makes it last longer), through the use of dimethyl phthalate (DMP) and diethyl phthalate (DEP).

Phthalates are considered to be endocrine disruptors and may affect bone mineral density and sperm quality, and contribute to the development of obesity…

In children, DEP and DMP are connected to behavioral and developmental disorders.

In trials with adult animals, it was observed that exposure to these substances may lead to the apoptosis (death) of neurons in the hippocampus.

      2. Synthetic musks

These are odorous synthetic chemicals. Natural musk is obtained from the secretion of a gland found in musk deer.

The categories of synthetic musks are: nitro, polycyclic, macrocyclic, and alicyclic musks. The last two categories are thought to be somewhat safer.

Several nitro musks are carcinogenic and have estrogenic activity (their use is banned or restricted, but once again, if the components of our perfume are not specified, it is difficult to identify them).

Ambrette (muskmallow), a type of nitro musk, may cause limb weakness and peripheral demyelination.

Galaxolide and tonalide (polycyclic musks) inhibit a specific enzyme (PMPMEase), predisposing individuals to degenerative problems.

      3. Sensitizers

These compounds are substances that are able to produce allergic reactions in unaltered tissues after repeated exposures.

As we will see below, they are present in plants (essential oils):

• Citral: present in citrus fruits. It may cause skin problems, benign prostatic hyperplasia, inhibit the synthesis of retinoic acid, and in animal models, modify behaviors.

• Linalool: present in lavender. It causes estrogenic and antiandrogenic activity. Use not recommended in children. It may cause problems such as gynecomastia.

  Beneficial actions: neuroprotection through antioxidant and anti-apoptotic pathways; anticonvulsant, anxiolytic, and antinociceptive (pain control) properties.

• Limonene: lemon scent. Exposure to this compound may cause sedative, anxiolytic, antinociceptive, and antioxidant effects. The neuromodulation of the GABAergic, adrenergic, and dopaminergic systems has also been described.

  Here are some examples; the list is long: geraniol, citronellol, eugenol, and farnesol also have various effects, from anticonvulsant and anesthetic to anti-inflammatory (1).

  Of course, these effects will depend on the concentrations, administration routes, and guidelines, but they leave an interesting field for their use. Some pharmaceutical companies are already producing them (see Pranarom with its capsules for relaxation).

Perfume-related pathologies

• Effects on the nervous system

Intense smells may cause headaches and even migraines. There is also an influence on the risk of depression on the basis that aromatic components (some) have a similar effect to pesticides, altering hormonal secretions and affecting neurotransmitters.

Human skin and organs have numerous odor receptors (approximately 400). Exogenous odor molecules attach themselves to these olfactory receptors belonging to the G protein-coupled receptor family (GPCR). These receptor proteins are expressed on cell surfaces including that of neurons.

Olfactory neurons with specific receptors also express estrogen receptors, which explains the link between smell and sex hormones. In animal models, smell has been found to influence social behaviors such as solitary or gregarious behavior. The vomeronasal organ, the vascularized region of the olfactory system, interacts with peptides or steroid hormones, modulating behavioral activities.

• Skin and airway hypersensitivity

Some perfumes may cause contact allergies or asthma. There is talk of photosensitivity with some compounds, such as bergamot oil. Exposure to sunlight produces photo activation releasing toxic components that may also cause hemolysis.

Perfuming an environment with incense is not a good idea. The smoke generated by combustion releases toxic gases such as CO, CO2, NO2, SO2, benzene, toluene, xylenes, aldehydes and polycyclic aromatic hydrocarbons. Clearly, it may be a risk factor for lung cancer.

• Polycystic breast and ovarian cancer

Fragrances with estrogenic compounds (parabens, phthalates, and nitro musks) may cause breast cancer. To sum up the metabolic pathway: they would act by favoring aromatase activity, an enzyme that allows the conversion of androgens into estrogens. It is also connected to breast tissue hyperplasia and polycystic ovary syndrome (the production of endogenous progesterone probably does not counteract the effects of the estradiol).

A high level of aromatase activity induces the production of growth factors (TGF-beta, EGF, and bFGF).

• Disorders in the fetus and newborn

Some synthetic aromas (such as nitro musks) are lipophilic substances, i.e. they can be absorbed and accumulated within the body’s adipose tissue, even reaching breast milk and then passing on to the nursing baby. Studies conducted on animals show that synthetic musks may cause growth problems.

Another study links genital abnormalities in newborn (undescended testicle, unclosed penis – hypospadias-) with exposure to compounds such as phthalates present in cosmetics.

Numerous studies show that several fragrances cause fetal neuromodulation (even though they’re in the womb).

It is believed that exposure to chemicals (through the placenta or breast milk) may contribute to diseases such as autism (a disorder that presents alterations in the mirror neuron system of the parieto-frontal region).

• Liver toxicity

Polycyclic musks that have entered the bloodstream reach the liver and may block certain enzymatic activities, altering the body’s detoxification systems. Cases of hepatitis with elevated transaminase levels (also described with exposures to toluene, used in perfumes and dyes) (2) may then occur.

Recommendations

That clean smell starts with proper hygiene and ventilation (so important in times of COVID), which will prevent us from inhaling other toxic substances. Let’s avoid combustion (particle-generating incense), have more plants (with or without scented foliage), discard scented candles, and perfume diffusers that might contain synthetic musks. Let’s carefully select our perfumes (good quality or with non-harmful components) and not abuse scented cosmetics (there’s a risk of synergy between various molecules). And finally, as with food, we should read labels and continue to inform ourselves. Our knowledge is constantly evolving.

BIBLIOGRAPHY

(1) Pinkas A, Gonçalves CL, Aschner M. Neurotoxicity of fragrance compounds: A review. Environ Res. 2017 Oct;158:342-349. doi: 10.1016/j.envres.2017.06.035. Epub 2017 Jul 3. PMID: 28683407.

URL: https://pubmed.ncbi.nlm.nih.gov/28683407/

(2) Patel S. Fragrance compounds: The wolves in sheep’s clothings. Med Hypotheses. 2017 May;102:106-111. doi: 10.1016/j.mehy.2017.03.025. Epub 2017 Mar 22. PMID: 28478814.

URL: https://pubmed.ncbi.nlm.nih.gov/28478814/

La entrada An Intoxicating Scent se publicó primero en Neolife.

The way our genetic material works is that some genes are transcribed, that is, that their information is read and used to create a protein with a particular function, and that other genes, however, are not read, are not transcribed despite being encoded in our DNA.

Whether a cell becomes a neuron, a skin cell, or a muscle cell is determined by which genes are being read in each case. DNA methylation, in fact, regulates which genes are expressed and which are not. Simply put, methylated regions silence genes, and nonmethylated regions express genes. As previously mentioned, as we age, our DNA methylation levels decrease, and we have less control over our DNA.^.

Dr. Alfonso Galán González – Neolife Medical Team

Unlike the permanent mutations in our genes, which we cannot change, we do have the ability to change this epigenome.

In this blog post, we’ll present one of the famous 9 “Hallmarks of Aging”, or factors that determine aging, which are, in fact, reversible. We’re talking about epigenetic alterations.

Epigenetics is not the easiest thing to explain, but we’ll give it a try. If we consider the word “epigenetics”, we may see it means something that is “epi” or “over” or “on top of” our genes. Something that is not written in our genes, in our DNA, but that impacts how our genes are going to work. The way our genetic material works is that some genes are transcribed, that is, that their information is read and used to create a protein with a particular function, and that other genes, however, are not read, are not transcribed despite being encoded in our DNA. Whether a cell becomes a neuron, a skin cell, or a muscle cell is determined by which genes are being read in each case, even though all these cells have the same genetic material. So, our genome is the complete list of all the genes that we can potentially read or not read, activate or not, turn ON or OFF, and what determines this? Our epigenome.

Our epigenome are a series of markers added to our DNA without modifying its sequence, but which determine exactly that, what should be expressed and what should not.

All our cells have 23 chromosomes. Chromosomes are a tangle of chromatin, formed by nucleosomes, which look like the beads of a necklace, which are in turn made up of DNA coiled around proteins called histones. This is how structural support is given to the chromosomes and they fit in the nucleus of the cell.

Epigenetic alterations consist of changes in this chromatin and may be changes in both the histones and chromatin structure, as well as the addition of methyl groups to the DNA. These alterations may be inherited by daughter cells and therefore perpetuated.

Let’s delve deeper into the issue of DNA methylation (1).

DNA methylation, in fact, regulates which genes are expressed and which are not. Methylation patterns change over time. Simply put, though it’s actually a bit more complicated, methylated regions silence genes, and nonmethylated regions express genes. As previously mentioned, as we age, our DNA methylation levels decrease, and we have less control over our DNA (3).

This influences the function of the cells, harming them and predisposing them to the appearance of a pathology. Yes, indeed, we’re talking about the often mentioned diseases associated with aging. We now know that these epigenetic alterations, namely this change in DNA methylation patterns predispose to cancer, neurodegenerative diseases, obesity, diabetes, insulin resistance, inflammation, cardiovascular disease, immune disorders, etc. (2). These epigenetic alterations accumulate as we age, and we can measure them. Multiple “epigenetic clocks” such as Horvath’s and more complete current ones have been designed, which are used to measure just how methylated a series of genes are, giving us an idea of our biological age as opposed to our chronological age. Tests are now available that measure the methylation of millions of sites in the genome when initially only a few hundred (4) were available.

Unlike the permanent mutations in our genes, which we cannot change, we can modify this epigenome, and there are multiple studies that show how we can make these clocks start working backwards and rejuvenate our biological age, based on what they measure.

How can we do this?

Well, you’ve probably heard all this before: exercise, a balanced diet, and supplementation.

A systematic review of the scientific literature published in January this year shows us that strength training in humans induces epigenetic alterations in pathways associated with energy metabolism and insulin sensitivity, contributing to skeletal muscle health. Aerobic exercise also causes modifications in biomarkers associated with metabolic alterations through changes in specific DNA methylation and mRNA expression. It seems that the best strategy is a combination of both types of exercise (6).

Calorie restriction, which we’ve already discussed in previous blog posts, prevents a decrease in DNA methylation levels, even in different organs (5).

Calorie restriction mimetics, like metformin or resveratrol have also demonstrated these benefits.

Smoking and psychological trauma lead to changes in methylation patterns.

The availability of methyl group donor molecules influences our methylation levels. Betaine (trimethyl glycine –TMG-) is a safe supplement that helps us with this task (7). Additionally, it lowers homocysteine levels; you may see why this is important here.

In short, a decrease in DNA methylation leads to pathology and aging. This process may be reversed through exercise, a proper diet, and supplements like TMG.

We cannot emphasize enough how important it is to exercise and maintain a good diet. This is just more scientific proof of their incredible benefits.

BIBLIOGRAPHY

(1) Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013 Jan;38(1):23-38. doi: 10.1038/npp.2012.112. Epub 2012 Jul 11. PMID: 22781841; PMCID: PMC3521964.

(2) Sallustio F, Gesualdo L, Gallone A. New findings showing how DNA methylation influences diseases. World J Biol Chem. 2019 Jan 7;10(1):1-6. doi: 10.4331/wjbc.v10.i1.1. PMID: 30622680; PMCID: PMC6314879.

(3) Heyn H, Li N, Ferreira HJ, Moran S, Pisano DG, Gomez A, Diez J, Sanchez-Mut JV, Setien F, Carmona FJ, Puca AA, Sayols S, Pujana MA, Serra-Musach J, Iglesias-Platas I, Formiga F, Fernandez AF, Fraga MF, Heath SC, Valencia A, Gut IG, Wang J, Esteller M. Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10522-7. doi: 10.1073/pnas.1120658109. Epub 2012 Jun 11. PMID: 22689993; PMCID: PMC3387108.

(4) Bell CG, Lowe R, Adams PD, Baccarelli AA, Beck S, Bell JT, Christensen BC, Gladyshev VN, Heijmans BT, Horvath S, Ideker T, Issa JJ, Kelsey KT, Marioni RE, Reik W, Relton CL, Schalkwyk LC, Teschendorff AE, Wagner W, Zhang K, Rakyan VK. DNA methylation aging clocks: challenges and recommendations. Genome Biol. 2019 Nov 25;20(1):249. doi: 10.1186/s13059-019-1824-y. PMID: 31767039; PMCID: PMC6876109.

(5) Gensous N, Franceschi C, Santoro A, Milazzo M, Garagnani P, Bacalini MG. The Impact of Caloric Restriction on the Epigenetic Signatures of Aging. Int J Mol Sci. 2019 Apr 24;20(8):2022. doi: 10.3390/ijms20082022. PMID: 31022953; PMCID: PMC6515465.

(6) Barrón-Cabrera E, Ramos-Lopez O, González-Becerra K, Riezu-Boj JI, Milagro FI, Martínez-López E, Martínez JA. Epigenetic Modifications as Outcomes of Exercise Interventions Related to Specific Metabolic Alterations: A Systematic Review.

Lifestyle Genom. 2019;12(1-6):25-44. doi: 10.1159/000503289. Epub 2019 Sep 23. PMID: 31546245; PMCID: PMC6921698.

(7) Zhao G, He F, Wu C, Li P, Li N, Deng J, Zhu G, Ren W, Peng Y. Betaine in Inflammation: Mechanistic Aspects and Applications. Front Immunol. 2018 May 24;9:1070. doi: 10.3389/fimmu.2018.01070. PMID: 29881379; PMCID: PMC5976740.

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