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The cytokine storm is a consequence of mitochondrial dysfunction

The cytokine storm is a consequence of mitochondrial dysfunction

The cytokine storm is a consequence of mitochondrial dysfunction

The cytokine storm is a consequence of mitochondrial dysfunction

Lipoic acid, Methylene Blue and Chlorine dioxide relieve COVID-19 spike protein toxicity

Lipoic acid, Methylene Blue and Chlorine dioxide relieve COVID-19 spike protein toxicity

Lipoic acid, Methylene Blue and Chlorine dioxide relieve COVID-19 spike protein toxicity

Lipoic acid, Methylene Blue and Chlorine dioxide relieve COVID-19 spike protein toxicity

most diseases display a form of anabolism due to mitochondrial impairment

most diseases display a form of anabolism due to mitochondrial impairment

most diseases display a form of anabolism due to mitochondrial impairment

infection by Covid-19 follows a similar pattern

chronic inflammation

Long-term effects include redox shift and cellular anabolism as a result of the Warburg effect and mitochondrial dysfunction

Long-term effects include redox shift and cellular anabolism as a result of the Warburg effect and mitochondrial dysfunction

Long-term effects include redox shift and cellular anabolism as a result of the Warburg effect and mitochondrial dysfunction

Long-term effects include redox shift and cellular anabolism as a result of the Warburg effect and mitochondrial dysfunction

infection by Covid-19 follows a similar pattern

unrelenting anabolism leads to the cytokine storm,

unrelenting anabolism leads to the cytokine storm,

unrelenting anabolism leads to the cytokine storm,

chronic inflammation

chronic inflammation

infection by Covid-19 follows a similar pattern

Lipoic acid and Methylene Blue have been shown to enhance the mitochondrial activity, relieve the Warburg effect and increase catabolism

Lipoic acid and Methylene Blue have been shown to enhance the mitochondrial activity, relieve the Warburg effect and increase catabolism

Lipoic acid and Methylene Blue have been shown to enhance the mitochondrial activity, relieve the Warburg effect and increase catabolism

Methylene Blue, Chlorine dioxide and Lipoic acid may help reduce long-term Covid-19 effects by stimulating the catabolism

Methylene Blue, Chlorine dioxide and Lipoic acid may help reduce long-term Covid-19 effects by stimulating the catabolism

Methylene Blue, Chlorine dioxide and Lipoic acid may help reduce long-term Covid-19 effects by stimulating the catabolism

direct consequence of redox iMeBalance, itself a consequence of decreased energy yield by the mitochondria

direct consequence of redox iMeBalance, itself a consequence of decreased energy yield by the mitochondria

mitochondrial dysfunction and increased levels of lactate, which are important characteristics of metabolic shift and Warburg effect in many diseases

mitochondrial dysfunction and increased levels of lactate, which are important characteristics of metabolic shift and Warburg effect in many diseases

increased lactate dehydrogenase activity (LDH) was observed in COVID-19 patients

increased lactate dehydrogenase activity (LDH) was observed in COVID-19 patients

almost every disease presents an increased anabolism

almost every disease presents an increased anabolism

cell division is the most sophisticated way to release entropy

cell division is the most sophisticated way to release entropy

transition from catabolism to anabolism is driven by a redox shift

transition from catabolism to anabolism is driven by a redox shift

viral spike protein binds to ACE2 receptor of the host cell [22,23].

redox signaling plays an important role in regulating immune function and inflammation, and disruptions in this signaling can lead to excessive cytokine production and immune system activation

Aging is associated with a poor control of the redox balance

thiol/disulfide homeostasis

reduced extracellular environment in the elderly and the increased susceptibility to Covid-19 infection

reduced extracellular environment in the elderly and the increased susceptibility to Covid-19 infection

Redox signaling tightly modulates the inflammatory response and oxidative stress has been reported in acute Covid-19

People at high risk are the elderly, patients suffering from metabolic syndrome such as obesity, or those suffering from chronic diseases such as cancer or inflammation

COVID-19 patients with severe disease have higher levels of oxidative stress markers and lower antioxidant levels

oxidative stress can activate the NLRP3 inflammasome, which is a protein complex that plays a key role in the cytokine storm

inflammation leads to the formation of ROS and RNS, while redox iMeBalance results in cellular damage, which in turn triggers an inflammatory response

persistently elevated mtROS triggers endothelial dysfunction and inflammation, which results in a vicious loop involving ROS, inflammation, and mitochondrial dysfunction

Damaged mitochondria releasing ROS induce inflammation via the NLRP3 inflammasome

Damaged mitochondria releasing ROS induce inflammation via the NLRP3 inflammasome

reduced environment during the cytokine storm

IL-2 is highly up-regulated in Covid-19 patients [37], and IL-2 is known to significantly stimulate the generation of NO in patients

Nitric acid is also the key mediator of IL-2-induced hypotension and vascular leak syndrome

mitochondrial dysfunction has been linked to the pathogenesis of Covid-19

mitochondrial dysfunction triggered by SARS-CoV-2 leads to damage to the mitochondria

mitochondrial dysfunction triggered by SARS-CoV-2 leads to damage to the mitochondria

As catabolism is decreased, entropy is released through anabolism

Elevated levels of lactate, a characteristic of the Warburg effect, were also reported in the high-risk Covid-19

elevated levels of ventricular lactic acid consistent with oxidative stress

A decrease of ΔΨm is implicated in several inflammation-related diseases

decrease in ΔΨm in leucocytes from Covid-19 patients

vaccinated with RNA or DNA vaccines triggering the synthesis of the viral spike protein in human cells

viral reactivation in varicella-zoster virus [55] or hepatitis [56], coagulopathy and resulting stroke and myocarditis following both DNA-based vaccines [57] and RNA-based vaccines

Covid-19, mitochondrial impairment

characteristic of the Warburg effect is present in almost every disease and appears to be a central feature in most of the hallmarks of cancer

inflammation, mitochondrial dysfunction and increased lactate concentrations in the extracellular fluid

In Covid-19, like any inflammation, there is a metabolic rewiring where cells rely on glycolysis

As the mitochondria are impaired, the infected cell cannot catabolize efficiently. It will release lactic acid in the blood stream

Striking similarities are seen between cancer, Alzheimer's disease and Covid-19, all related to the Warburg effect

Cancer, inflammation, Alzheimer's, and Parkinson's diseases share a common peculiarity, the inability of the cell to export entropy outside the body in the harmless form of heat

MEB relieves the Warburg effect [87], improves memory [77], is active in the treatment of depressive episodes [79,80] and reduces the importance of ischemic strokes

MEB relieves the Warburg effect [87], improves memory [77], is active in the treatment of depressive episodes [79,80] and reduces the importance of ischemic strokes

MEB has been shown to inhibit SARS-Cov-2 replication in vitro

MEB has been shown to inhibit SARS-Cov-2 replication in vitro

It has been shown that Covid-19-patients treated with MEB, have a significant reduction in hospital stay duration and mortality

MeB is an acceptor-donor molecule

MeB + can take a pair of electrons (of H atoms) and MeBH can release this pair easily, so that MeB is partially recycled like a catalyst

MeB acts as an electron bridge between a donor (FADH2, FMNH, NADH) and an acceptor (complex IV of ETC or oxygen itself)

As a coenzyme of pyruvate dehydrogenase (PDH), alpha-lipoic acid (ALA) initiates the formation of acetyl-CoA to feed the TCA cycle

ALA enhances the catabolism of carbon. cycle and therefore may reduce the Warburg effect and consequently, lactate production

Methylene Blue plays a similar role after the TCA cycle, by carrying electrons to complex IV of the electron transport chain

Drugs such as lipoic acid and MeB, which target the metabolism, decrease the redox shift by increasing catabolism

Reactive oxygen species (ROS) refer to a class of radical or non-radical oxygen-containing molecules that have high oxidative reactivity with lipids, proteins, and nucleic acids

a large measure of intracellular ROS comes from the leakage of mitochondrial electron transport chain (ETC)

Another major source of intracellular ROS is the intentional generation of superoxides by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase

there are other ROS-producing enzymes such as cyclooxygenases, lipoxygenases, xanthine oxidase, and cytochrome p450 enzymes, which are involved with specific metabolic processes

To counteract the toxic effects of molecular oxidation by ROS, cells are equipped with a battery of antioxidant enzymes such as superoxide dismutases, catalase, peroxiredoxins, sulfiredoxin, and aldehyde dehydrogenases

intracellular oxidative stress has been indicated to contribute to metabolic syndrome and related diseases, including T2D [72; 73], CVDs [74-76], neurodegenerative diseases [69; 77-80], and cancers

intracellular oxidative stress is highly associated with the development of neurodegenerative diseases [69] and brain aging

dietary obesity was found to induce NADPH oxidase-associated oxidative stress in rat brain

mitochondrial dysfunction in hypothalamic proopiomelanocortin (POMC) neurons causes central glucose sensing impairment

Endoplasmic reticulum (ER) is the cellular organelle responsible for protein synthesis, maturation, and trafficking to secretory pathways

unfolded protein response (UPR) machinery

ER stress has been associated to obesity, insulin resistance, T2D, CVDs, cancers, and neurodegenerative diseases

brain ER stress underlies neurodegenerative diseases

under environmental stress such as nutrient deprivation or hypoxia, autophagy is strongly induced to breakdown macromolecules into reusable amino acids and fatty acids for survival

intact autophagy function is required for the hypothalamus to properly control metabolic and energy homeostasis, while hypothalamic autophagy defect leads to the development of metabolic syndrome such as obesity and insulin resistance

prolonged oxidative stress or ER stress has been shown to impair autophagy function in disease milieu of cancer or aging

TLRs are an important class of membrane-bound pattern recognition receptors in classical innate immune defense

Most hypothalamic cell types including neurons and glia cells express TLRs

overnutrition constitutes an environmental stimulus that can activate TLR pathways to mediate the development of metabolic syndrome related disorders such as obesity, insulin resistance, T2D, and atherosclerotic CVDs

Isoforms TLR1, 2, 4, and 6 may be particularly pertinent to pathogenic signaling induced by lipid overnutrition

hypothalamic TLR4 and downstream inflammatory signaling are activated in response to central lipid excess via direct intra-brain lipid administration or HFD-feeding

overnutrition-induced metabolic derangements such as central leptin resistance, systemic insulin resistance, and weight gain

these evidences based on brain TLR signaling further support the notion that CNS is the primary site for overnutrition to cause the development of metabolic syndrome.

circulating cytokines can limitedly travel to the hypothalamus through the leaky blood-brain barrier around the mediobasal hypothalamus to activate hypothalamic cytokine receptors

significant evidences have been recently documented demonstrating the role of cytokine receptor pathways in the development of metabolic syndrome components

entral administration of TNF-α at low doses faithfully replicated the effects of central metabolic inflammation in enhancing eating, decreasing energy expenditure [158;159], and causing obesity-related hypertension

Resistin, an adipocyte-derived proinflammatory cytokine, has been found to promote hepatic insulin resistance through its central actions

both TLR pathways and cytokine receptor pathways are involved in central inflammatory mechanism of metabolic syndrome and related diseases.

In quiescent state, NF-κB resides in the cytoplasm in an inactive form due to inhibitory binding by IκBα protein

IKKβ activation via receptor-mediated pathway, leading to IκBα phosphorylation and degradation and subsequent release of NF-κB activity

Research in the past decade has found that activation of IKKβ/NF-κB proinflammatory pathway in metabolic tissues is a prominent feature of various metabolic disorders related to overnutrition

it happens in metabolic tissues, it is mainly associated with overnutrition-induced metabolic derangements, and most importantly, it is relatively low-grade and chronic

this paradigm of IKKβ/NF-κB-mediated metabolic inflammation has been identified in the CNS – particularly the comprised hypothalamus, which primarily accounts for to the development of overnutrition-induced metabolic syndrome and related disorders such as obesity, insulin resistance, T2D, and obesity-related hypertension

evidences have pointed to intracellular oxidative stress and mitochondrial dysfunction as upstream events that mediate hypothalamic NF-κB activation in a receptor-independent manner under overnutrition

In the context of metabolic syndrome, oxidative stress-related NF-κB activation in metabolic tissues or vascular systems has been implicated in a broad range of metabolic syndrome-related diseases, such as diabetes, atherosclerosis, cardiac infarct, stroke, cancer, and aging

intracellular oxidative stress seems to be a likely pathogenic link that bridges overnutrition with NF-κB activation leading to central metabolic dysregulation

overnutrition is an environmental inducer for intracellular oxidative stress regardless of tissues involved

excessive nutrients, when transported into cells, directly increase mitochondrial oxidative workload, which causes increased production of ROS by mitochondrial ETC

oxidative stress has been shown to activate NF-κB pathway in neurons or glial cells in several types of metabolic syndrome-related neural diseases, such as stroke [185], neurodegenerative diseases [186-188], and brain aging

central nutrient excess (e.g., glucose or lipids) has been shown to activate NF-κB in the hypothalamus [34-37] to account for overnutrition-induced central metabolic dysregulations

overnutrition can present the cell with a metabolic overload that exceeds the physiological adaptive range of UPR, resulting in the development of ER stress and systemic metabolic disorders

chronic ER stress in peripheral metabolic tissues such as adipocytes, liver, muscle, and pancreatic cells is a salient feature of overnutrition-related diseases

recent literature supports a model that brain ER stress and NF-κB activation reciprocally promote each other in the development of central metabolic dysregulations

when intracellular stresses remain unresolved, prolonged autophagy upregulation progresses into autophagy defect

autophagy defect can induce NF-κB-mediated inflammation in association with the development of cancer or inflammatory diseases (e.g., Crohn's disease)

The connection between autophagy defect and proinflammatory activation of NF-κB pathway can also be inferred in metabolic syndrome, since both autophagy defect [126-133;200] and NF-κB activation [20-33] are implicated in the development of overnutrition-related metabolic diseases

Both TLR pathway and cytokine receptor pathways are closely related to IKKβ/NF-κB signaling in the central pathogenesis of metabolic syndrome

Overnutrition, especially in the form of HFD feeding, was shown to activate TLR4 signaling and downstream IKKβ/NF-κB pathway

TLR4 activation leads to MyD88-dependent NF-κB activation in early phase and MyD88-indepdnent MAPK/JNK pathway in late phase

these studies point to NF-κB as an immediate signaling effector for TLR4 activation in central inflammatory response

TLR4 activation has been shown to induce intracellular ER stress to indirectly cause metabolic inflammation in the hypothalamus

central TLR4-NF-κB pathway may represent one of the early receptor-mediated events in overnutrition-induced central inflammation.

cytokines and their receptors are both upstream activating components and downstream transcriptional targets of NF-κB activation

central administration of TNF-α at low dose can mimic the effect of obesity-related inflammatory milieu to activate IKKβ/NF-κB proinflammatory pathways, furthering the development of overeating, energy expenditure decrease, and weight gain

the physiological effects of IKKβ/NF-κB activation seem to be cell type-dependent, i.e., IKKβ/NF-κB activation in hypothalamic agouti-related protein (AGRP) neurons primarily leads to the development of energy imbalance and obesity [34]; while in hypothalamic POMC neurons, it primarily results in the development of hypertension and glucose intolerance

the hypothalamus, is the central regulator of energy and body weight balance [

testosterone therapy causes a shift in the skeletal muscle of CHF patients toward a higher concentration of type I muscle fibers

Testosterone replacement therapy has also been shown to improve the homeostatic model of insulin resistance and hemoglobin A1c in diabetics26,68–69 and to lower the BMI in obese patients.

Lower levels of endogenous testosterone have been associated with longer duration of the QTc interval

testosterone replacement has been shown to shorten the QTc interval

negative correlation has been demonstrated between endogenous testosterone levels and IMT of the carotid arteries, abdominal aorta, and thoracic aorta

These findings suggest that men with lower levels of endogenous testosterone may be at a higher risk of developing atherosclerosis.

Current guidelines from the Endocrine Society make no recommendations on whether patients with heart disease should be screened for hypogonadism and do not recommend supplementing patients with heart disease to improve survival.

The Massachusetts Male Aging Study also projects ≈481 000 new cases of hypogonadism annually in US men within the same age group

since 1993 prescriptions for testosterone, regardless of the formulation, have increased nearly 500%

Testosterone levels are lower in patients with chronic illnesses such as end‐stage renal disease, human immunodeficiency virus, chronic obstructive pulmonary disease, type 2 diabetes mellitus (T2DM), obesity, and several genetic conditions such as Klinefelter syndrome

A growing body of evidence suggests that men with lower levels of endogenous testosterone are more prone to develop CAD during their lifetimes

There are 2 major potential confounding factors that the older studies generally failed to account for. These factors are the subfraction of testosterone used to perform the analysis and the method used to account for subclinical CAD.

The biologically inactive form of testosterone is tightly bound to SHBG and is therefore unable to bind to androgen receptors

The biologically inactive fraction of testosterone comprises nearly 68% of the total testosterone in human serum

The biologically active subfraction of testosterone, also referred to as bioavailable testosterone, is either loosely bound to albumin or circulates freely in the blood, the latter referred to as free testosterone

It is estimated that ≈30% of total serum testosterone is bound to albumin, whereas the remaining 1% to 3% circulates as free testosterone

it can be argued that using the biologically active form of testosterone to evaluate the association with CAD will produce the most reliable results

English et al14 found statistically significant lower levels of bioavailable testosterone, free testosterone, and free androgen index in patients with catheterization‐proven CAD compared with controls with normal coronary arteries

patients with catheterization‐proven CAD had statistically significant lower levels of bioavailable testosterone

In conclusion, existing evidence suggests that men with CAD have lower levels of endogenous testosterone,13–18 and more specifically lower levels of bioavailable testosterone

low testosterone levels are associated with risk factors for CAD such as T2DM25–26 and obesity

In a meta‐analysis of these 7 population‐based studies, Araujo et al41 showed a trend toward increased cardiovascular mortality associated with lower levels of total testosterone, but statistical significance was not achieved (RR, 1.25

the authors showed that a decrease of 2.1 standard deviations in levels of total testosterone was associated with a 25% increase in the risk of cardiovascular mortality

the relative risk of all‐cause mortality in men with lower levels of total testosterone was calculated to be 1.35

higher risk of cardiovascular mortality is associated with lower levels of bioavailable testosterone

Existing evidence seems to suggest that lower levels of endogenous testosterone are associated with higher rates of all‐cause mortality and cardiovascular mortality

studies have shown that lower levels of endogenous bioavailable testosterone are associated with higher rates of all‐cause and cardiovascular mortality

It may be possible that using bioavailable testosterone to perform mortality analysis will yield more accurate results because it prevents the biologically inactive subfraction of testosterone from playing a potential confounding role in the analysis

The earliest published material on this matter dates to the late 1930s

the concept that testosterone replacement therapy improves angina has yet to be proven wrong

In more recent studies, 3 randomized, placebo‐controlled trials demonstrated that administration of testosterone improves myocardial ischemia in men with CAD

The improvement in myocardial ischemia was shown to occur in response to both acute and chronic testosterone therapy and seemed to be independent of whether an intravenous or transdermal formulation of testosterone was used.

testosterone had no effect on endothelial nitric oxide activity

There is growing evidence from in vivo animal models and in vitro models that testosterone induces coronary vasodilation by modulating the activity of ion channels, such as potassium and calcium channels, on the surface of vascular smooth muscle cells

Experimental studies suggest that the most likely mechanism of action for testosterone on vascular smooth muscle cells is via modulation of action of non‐ATP‐sensitive potassium ion channels, calcium‐activated potassium ion channels, voltage‐sensitive potassium ion channels, and finally L‐type calcium ion channels

Corona et al confirmed those results by demonstrating that not only total testosterone levels are lower among diabetics, but also the levels of free testosterone and SHBG are lower in diabetic patients

Laaksonen et al65 followed 702 Finnish men for 11 years and demonstrated that men in the lowest quartile of total testosterone, free testosterone, and SHBG were more likely to develop T2DM and metabolic syndrome.

Vikan et al followed 1454 Swedish men for 11 years and discovered that men in the highest quartile of total testosterone were significantly less likely to develop T2DM

authors demonstrated a statistically significant increase in the incidence of T2DM in subjects receiving gonadotropin‐releasing hormone antagonist therapy. In addition, a significant increase in the rate of myocardial infarction, stroke, sudden cardiac death, and development of cardiovascular disease was noted in patients receiving antiandrogen therapy.67

Several authors have demonstrated that the administration of testosterone in diabetic men improves the homeostatic model of insulin resistance, hemoglobin A1c, and fasting plasma glucose

Existing evidence strongly suggests that the levels of total and free testosterone are lower among diabetic patients compared with those in nondiabetics

insulin seems to be acting as a stimulant for the hypothalamus to secret gonadotropin‐releasing hormone, which consequently results in increased testosterone production. It can be argued that decreased stimulation of the hypothalamus in diabetics secondary to insulin deficiency could result in hypogonadotropic hypogonadism

BMI has been shown to be inversely associated with testosterone levels

This interaction may be a result of the promotion of lipolysis in abdominal adipose tissue by testosterone, which may in turn cause reduced abdominal adiposity. On the other hand, given that adipose tissue has a higher concentration of the enzyme aromatase, it could be that increased adipose tissue results in more testosterone being converted to estrogen, thereby causing hypogonadism. Third, increased abdominal obesity may cause reduced testosterone secretion by negatively affecting the hypothalamus‐pituitary‐testicular axis. Finally, testosterone may be the key factor in activating the enzyme 11‐hydroxysteroid dehydrogenase in adipose tissue, which transforms glucocorticoids into their inactive form.

increasing age may alter the association between testosterone and CRP. Another possible explanation for the association between testosterone level and CRP is central obesity and waist circumference

Bai et al have provided convincing evidence that testosterone might be able to shorten the QTc interval by augmenting the activity of slowly activating delayed rectifier potassium channels while simultaneously slowing the activity of L‐type calcium channels

consistent evidence that supplemental testosterone shortens the QTc interval.

Intima‐media thickness (IMT) of the carotid artery is considered a marker for preclinical atherosclerosis

Studies have shown that levels of endogenous testosterone are inversely associated with IMT of the carotid artery,126–128,32,129–130 as well as both the thoracic134 and the abdominal aorta

1 study has demonstrated that lower levels of free testosterone are associated with accelerated progression of carotid artery IMT

another study has reported that decreased levels of total and bioavailable testosterone are associated with progression of atherosclerosis in the abdominal aorta

These findings suggest that normal physiologic testosterone levels may help to protect men from the development of atherosclerosis

Czesla et al successfully demonstrated that the muscle specimens that were exposed to metenolone had a significant shift in their composition toward type I muscle fibers

Type I muscle fibers, also known as slow‐twitch or oxidative fibers, are associated with enhanced strength and physical capability

It has been shown that those with advanced CHF have a higher percentage of type II muscle fibers, based on muscle biopsy

Studies have shown that men with CHF suffer from reduced levels of total and free testosterone.137 It has also been shown that reduced testosterone levels in men with CHF portends a poor prognosis and is associated with increased CHF mortality.138 Reduced testosterone has also been shown to correlate negatively with exercise capacity in CHF patients.

Testosterone replacement therapy has been shown to significantly improve exercise capacity, without affecting LVEF

the results of the 3 meta‐analyses seem to indicate that testosterone replacement therapy does not cause an increase in the rate of adverse cardiovascular events

Data from 3 meta‐analyses seem to contradict the commonly held belief that testosterone administration may increase the risk of developing prostate cancer

One meta‐analysis reported an increase in all prostate‐related adverse events with testosterone administration.146 However, when each prostate‐related event, including prostate cancer and a rise in PSA, was analyzed separately, no differences were observed between the testosterone group and the placebo group

the existing data from the 3 meta‐analyses seem to indicate that testosterone replacement therapy does not increase the risk of adverse cardiovascular events

the authors correctly point out the weaknesses of their study which include retrospective study design and lack of randomization, small sample size at extremes of follow‐up, lack of outcome validation by chart review and poor generalizability of the results given that only male veterans with CAD were included in this study

the studies that failed to find an association between testosterone and CRP used an older population group

low testosterone may influence the severity of CAD by adversely affecting the mediators of the inflammatory response such as high‐sensitivity C‐reactive protein, interleukin‐6, and tumor necrosis factor–α

mice deficient for telomerase or for telomere binding proteins are characterized by accelerated age-related defects

In humans, short telomeres are considered good indicators of an individual’s health status and correlate with both genetic and environmental factors

Although recent findings strongly support the idea that short telomeres drive several age-related diseases 38 we cannot exclude the possibility that in some situations short telomeres may be a consequence of the disease itself.

the current view is that telomerase deficiency may contribute to the early steps of cancer development by fueling chromosomal instability, while subsequent activation of telomerase may be necessary to allow tumor growth and tumor progression towards more malignant states

telomerase activation can be an early event in cancer, it is not necessary for cancer initiation

telomerase can stimulate tumor progression by ensuring maintenance of telomeres above a critically short length, thus preventing induction of cellular senescence or apoptosis

Almost all human cancers present activation of telomerase as a hallmark, most likely as a mechanism to allow unlimited cell proliferation of tumor cells

recent evidence demonstrated that short telomeres alone could lead to genomic instability and cancer

Getting rid of telomerase can also be problematic; the lack of telomerase could lead to increased chromosomal instability, which in turn could be at the basis for cancer initiation when tumor suppressor barriers are bypassed

telomerase activation is a potential therapeutic strategy for the treatment of age-related diseases

telomerase activation in adult or old mice by means of a gene therapy strategy was shown to be sufficient to improve metabolic fitness, neuromuscular capacity, and prevent bone loss, as well as significantly increase both median and maximum longevity, without increased cancer incidence

These studies suggest that telomerase expression could be considered a feasible approach to reverse tissue dysfunction and extend healthy lifespan without increasing cancer incidence

humans almost completely lose telomerase activity from somatic tissues in the adulthood

a change of paradigm seems to be occurring in telomerase biology, with a switch from viewing telomerase as fueling cancer to reversing aging

Telomerase expression in a background of high levels of tumor suppressors or in aged organisms seems to prevent its expected pro-cancer activity and yet it still functions as an anti-aging factor

dietary supplementation of aged mice with the probiotic bacterium Lactobacillus reuteri makes them appear to be younger than their matched untreated sibling mice

These results indicate that gut microbiota induce modulation of local gastrointestinal immunity resulting in systemic effects on the immune system which activate metabolic pathways that restore tissue homeostasis and overall health

all these studies we consistently observed that young and aged mice consuming purified L. reuteri organisms had particularly large testes and a dominant male behavior.

The testes of probiotic-fed aged mice were rescued from both seminiferous tubule atrophy and interstitial Leydig cell area reduction typical of the normal aging process. Preservation of testicular architecture despite advanced age or high-fat diet coincided with remarkably high levels of circulating testosterone. The beneficial effects of probiotic consumption were recapitulated by the depletion of the pro-inflammatory cytokine Il-17.

feeding of L. reuteri consistently increased the gonadal weights, consumption of a non-pathogenic strain of Escherichia coli (E. coli) K12 organisms did not affect testicular weight

mice with dietary L. reuteri supplements were rescued from diet-induced obesity and had normal body weight and lean physique

Despite the comparable numbers of ST profiles, we determined that testes from L. reuteri-treated mice had increased ST cross-sectioned profiles

the probiotic organism induced prominent Leydig cell accumulations in the interstitial tissue between the ST's

The probiotic-associated increase of interstitial Leydig cell areas was sustained with advancing age at 7 (CD vs CD+LR, P = 0.0025; CD+E.coli vs CD+LR, P = 0.0251) and 12 months

mice eating L. reuteri had profoundly increased levels of circulating testosterone regardless of the type of diet they consumed

blocking pro-inflammatory Il-17 signaling entirely recapitulates the beneficial effects of probiotics

previous studies we found that dietary probiotics counteract obesity [19] and age-related integumentary pathology [18] at least in part by down-regulating systemic pro-inflammatory IL-17A-dependent signaling

Testes histomorphometry and serum androgen concentration data were both suggestive of a probiotic-associated up-regulation of spermatogenesis in mice

Lactobacillus reuteri we discovered that aging male animals had larger testes compared to their age-matched controls

xamined testes of probiotic microbe-fed mice and found that they had less testicular atrophy coinciding with higher levels of circulating testosterone compared to their age-matched controls

Similar testicular health benefits were produced using systemic depletion of the pro-inflammatory cytokine Il-17 alone, implicating a chronic inflammatory pathway in hypogonadism

One specific aspect of this paradigm is reciprocal activities of pro-inflammatory Th-17 and anti-inflammatory Treg cells

Feeding of L. reuteri organisms was previously shown to up-regulate IL-10 levels and reduce levels of IL-17 [19] serving to lower systemic inflammation

insufficient levels of IL-10 may increase the risk for autoimmunity, obesity, and other inflammatory disease syndromes

Westernized diets are also low in vitamin D, a nutrient that when present normally works together with IL-10 to protect against inflammatory disorders

Physiological feedback loops apparently exist between microbes, host hormones, and immunity

The hormone testosterone has been shown to act directly through androgen receptors on CD4+ cells to increase IL-10 expression

studies in both humans and rodents suggest that hypogonadism is due to age-related lesions in testes rather than irregular LH metabolism

We postulate that probiotic gut microbes function symbiotically with their mammalian hosts to impart immune homeostasis to maintain systemic and testicular health [34]–[35] despite suboptimal dietary conditions.

Dietary factors and diet-induced obesity were previously shown to increase risk for age-associated male hypogonadism, reduced spermatogenesis, and low testosterone production in both humans and mice [2]–[4], [8]–[11], [14]–[17], phenotypic features that in this study were inhibited by oral probiotic therapy absent milk sugars, extra protein, or vitamin D supplied in yogurt.

Similar beneficial effects of probiotic microbes on testosterone levels and sperm indices were reported in male mice that had been simultaneously supplemented with selenium

L. reuteri-associated prevention of age- and diet-related testicular atrophy correlates with increased numbers and size of Leydig cells

the initial changes of testicular atrophy begin to occur in mice from the age of 6 moths onwards [7] and indicates that the trophic effect of L. reuteri on Leydig cells is a key event which precedes and prevents age-related changes in the testes of mice. This effect is reminiscent of earlier studies describing Leydig cell hyperplasia and/or hypertrophy in the mouse and the rat testis that were achievable by the administration of gonadotropins, including human chorionic gonadotropin, FSH and LH

Researchers tried to examine whether serum total or free testosterone would be a better/more reliable choice when studying the effect of testosterone. The results were mixed. Some reported significant associations of both serum total and free testosterone level with clinical parameters25, whereas others reported that only serum free testosterone26 or only serum total testosterone6 showed significant associations.

−0.124 nmol/L/year in serum total testosterone

In experimental studies, androgen receptor knockout mice developed significant insulin resistance rapidly

In mouse models, testosterone promoted differentiation of pluripotent stem cells to the myogenic lineage

testosterone decreased insulin resistance by enhancing catecholamine induced lipolysis in vitro, and reducing lipoprotein lipase activity and triglyceride uptake in human abdominal tissue in vivo

by promoting lipolysis and myogenesis, testosterone might lead to improved insulin resistance

testosterone regulated skeletal muscle genes involved in glucose metabolism that led to decreased systemic insulin resistance

In the liver, hepatic androgen receptor signaling inhibited development of insulin resistance in mice

independent and inverse association of testosterone with hepatic steatosis shown in a cross-sectional study carried out in humans

In short, androgen improves insulin resistance by changing body composition and reducing body fat.

Although a low serum testosterone level could contribute to the development of obesity and type 2 diabetes through changes in body composition, obesity might also alter the metabolism of testosterone

In obese men, the peripheral conversion from testosterone to estrogen could attenuate the amplitude of luteinizing hormone pulses and centrally inhibit testosterone production

leptin, an adipokine, has been shown to be inversely correlated with serum testosterone level in men

Leydig cells expressed leptin receptors and leptin has been shown to inhibit testosterone secretion, suggesting a role of obesity and leptin in the pathogenesis of low testosterone

Baltimore Longitudinal Study of Aging (BLSA) cohort made up of 3,565 middle-class, mostly Caucasian men from the USA, the incidence of low serum total testosterone increased from approximately 20% of men aged over 60 years, 30% over 70 years, to 50% over 80 years-of-age

30–44% sex hormone binding globulin (SHBG)-bound testosterone and 54–68% albumin-bound testosterone

As the binding of testosterone to albumin is non-specific and therefore not tight, the sum of free and albumin-bound testosterone is named bioavailable testosterone, which reflects the hormone available at the cellular level

Serum total testosterone is composed of 0.5–3.0% of free testosterone unbound to plasma proteins

alterations in SHBG concentration might affect total serum testosterone level without altering free or bioavailable testosterone

listed in Table​T

A significant, independent and longitudinal effect of age on testosterone has been observed with an average change of −0.124 nmol/L/year in serum total testosterone28. The same trend has been shown in Europe and Australia

Asian men residing in HK and Japan, but not those living in the USA, had 20% higher serum total testosterone than in Caucasians living in the USA, as shown in a large multinational observational prospective cohort of the Osteoporotic Fractures in Men Study

subjects with chronic diseases consistently had a 10–15% lower level compared with age-matched healthy subjects

In Caucasians, the mean serum total testosterone level for men in large epidemiological studies has been reported to range from 15.1 to 16.6 nmol/L

Asians, higher values, ranging from 18.1 to 19.1 nmol/L, were seen in Korea and Japan

Chinese middle-aged men reported a similar mean serum testosterone level of 17.1 nmol/L in 179 men who had a family history of type 2 diabetes and 17.8 nmol/L in 128 men who had no family history of type 2 diabetes

The reduction of total testosterone was 0.4% per year in both groups

HK involving a cohort of 1,489 community-dwelling men with a mean age of 72 years, a mean serum total testosterone of 19.0 nmol/L was reported

pro-inflammatory factors, such as tumor necrosis factor-α in the testes, could locally inhibit testosterone biosynthesis in Leydig cells47, and testosterone treatment in men was shown to reduce the level of tumor necrosis factor-α

In Asians, a genetic deletion polymorphism of uridine diphosphate-glucuronosyltransferase UGT2B17 was associated with reduced androgen glucuronidation. This resulted in higher level of active androgen in Asians as compared to Caucasians, as Caucasians' androgen would be glucuronidated into inactive forms faster.

Compared with Caucasians, the frequency of this deletion polymorphism of UGT2B17 was 22-fold higher in Asian subjects

Other researchers have suggested that environmental, but not genetic, factors influenced serum total testosterone

The basal and ligand-induced activity of the AR is inversely associated with the length of the CAG repeat chain

In the European Male Aging Study, increased estrogen/androgen ratio in association with longer AR CAG repeat was observed

a smaller number of AR CAG repeat had been shown to be associated with benign prostate hypertrophy and faster prostate growth during testosterone treatment

In India, men with CAG ≤19 had increased risk of prostate cancer

the odds of having a short CAG repeat (≤17) were substantially higher in patients with lymph node-positive prostate cancer than in those with lymph node-negative disease or in the general population

assessing the polymorphism at the AR level could be a potential tool towards individualized assessment and treatment of hypogonadism.

In elderly men, there was reduced testicular response to gonadotropins with suppressed and altered pulsatility of the hypothalamic pulse generator

a significant, independent and longitudinal effect of age on serum total testosterone level had been observed

A significant graded inverse association between serum testosterone level and insulin levels independent of age has also been reported in Caucasian men

Low testosterone is commonly associated with a high prevalence of MES

most studies showed that changes in serum testosterone level led to changes in body composition, insulin resistance and the presence of MES, the reverse might also be possible

MES predicted a 2.6-fold increased risk of development of low serum testosterone level independent of age, smoking and other potential confounders

Other prospective studies have shown that development of MES accelerated the age-related decline in serum testosterone level

In men with type 2 diabetes, changes in serum testosterone level over time correlated inversely with changes in insulin resistance

weight loss by either diet control or bariatric surgery led to a substantial increase in total testosterone, especially in morbidly obese men, and the rise in serum testosterone level was proportional to the amount of weight lost

To date, published clinical trials are small, of short duration and often used pharmacological, not physiological, doses of testosterone

In the population-based Osteoporotic Fractures in Men Study cohort from Sweden, men in the highest quartile of serum testosterone level had the lowest risk of cardiovascular events compared with men in the other three quartiles (hazard ratio [HR] 0.70

low serum total testosterone was associated with a significant fourfold higher risk of cardiovascular events when comparing men from the lowest testosterone tertile with those in the highest tertile

Shores et al. were the first to report that low serum testosterone level, including both serum total and free testosterone, was associated with increased mortality

low serum total testosterone predicted increased risk of cardiovascular mortality with a HR of 1.38

low serum total testosterone increased all-cause (HR 1.35, 95% CI 1.13–1.62, P < 0.001) and cardiovascular mortality (HR 1.25

European Association for the Study of Diabetes 2013 suggested there was an inverse relationship between serum testosterone level and acute myocardial infarction

Diabetic men in the highest quartile of serum total testosterone had a significantly reduced risk of acute MI when compared with those in the lower quartiles

serum total testosterone level in the middle two quartiles at baseline predicted reduced incidence of death compared with having the highest and lowest levels

T may slow development of or progression of atherosclerosis by modulating effects on insulin resistance, inflammation, endothelial function, preclinical atherosclerosis or the vasculature.

these cross-sectional and longitudinal studies support a relationship between low circulating T with CIMT and higher E2 with its progression

lower levels of T are biomarkers for aortic vascular disease

circulating free T was negatively associated with the presence of AAA

luteinizing hormone (LH) was positively associated.

low levels of total or bioavailable T were associated with aortic atherosclerosis manifested as calcified deposits detected by radiography

Men with total or free T in the lowest quartile had increased adjusted ORs for PAD defined as ABI <0.90, as did men with free E2 in the highest quartile of values

The apparent association of SHBG with intermittent claudication reflects the correlation of total T with SHBG, while the contribution of E2 to risk of PAD remains unclear

men with total T in the lowest quartile of values (<11.7 nmol l−1 ) experienced an increased incidence of stroke or transient ischemic attack

lower total T with increased incidence of CVD events

cohort studies in mostly older men have supported the association of lower androgen levels with higher mortality

lower total or free T levels were associated with mortality in older men, but with discordant results for cause-specific mortality and for associations of E2

several large studies identifying lower endogenous levels of total or free T as independent predictors of all-cause or CVD-related deaths in middle-aged and older men

T exhibits anti-inflammatory effects, enhances flow-mediated brachial artery reactivity, and reduces arterial stiffness

Short-term T therapy had a beneficial effect on exercise-induced myocardial ischemia in middle-aged men with coronary artery disease or chronic stable angina, [95],[96],[97] and reduced angina frequency in older men with diabetes and coronary artery disease

T therapy resulted in an increase in treadmill test duration and time to ST segment depression

there are interventional studies supporting a protective effect of exogenous T against myocardial ischemia in men with coronary artery disease

employ conservative doses

Observational studies indicate that lower levels of endogenous T in older men are associated with the presence of carotid atherosclerosis, aortic and peripheral vascular disease, and incidence of CVD events and mortality

Interventional studies have shown beneficial effects of exogenous T on vascular function and on exercise-induced myocardial ischemia in men with coronary artery disease

The CHALICE cohort of 404 individuals aged 50 years had an average vitamin C intake of ~110 mg/day, which should provide adequate plasma concentrations [14]. Despite this, a significant proportion of the participants had inadequate plasma vitamin C status

inadequate plasma vitamin C concentrations (i.e., <50 µmol/L)

adequate plasma levels (i.e., >50 µmol/L)

Higher plasma vitamin C status was associated with lower weight, BMI and waist circumference

plasma vitamin C was negatively associated with blood triglycerides, HbA1c and insulin, and positively associated with HDL levels.

No correlation was found between plasma vitamin C and the two indicators of heart health; blood pressure and cardiovascular risk score.

2.4% of 50-year-olds were deficient in vitamin C (i.e., <11 µmol/L)

hypovitaminosis C (i.e., <23 µmol/L)

A high proportion (63%) of our participants had inadequate plasma vitamin C concentrations (i.e., <50 µmol/L)

The association of low vitamin C with obesity in this study replicates results in the literature [35,40,41,42,43,44], and it is apparent that individuals with higher weight require higher intakes of vitamin C to reach adequate vitamin C status

higher plasma vitamin C status is associated with lower circulating levels of blood triglycerides, insulin and HbA1c

A role for vitamin C in the prevention or management of diabetes and/or metabolic syndrome has been suggested

In this study, we also demonstrate lower levels of mild cognitive impairment in those with high vitamin C status

The odds of mild cognitive impairment were twice as high for those below 23 μmol/L plasma vitamin C concentration.

Vitamin C is present at very high concentrations in the brain

animal models have shown that the brain is the last organ to be depleted of the vitamin during prolonged deficiency

A recent animal study has shown that moderate vitamin C deficiency may play a role in accelerating amyloid plaque accumulation in Alzheimer’s disease