How to keep fit during the summer holidays

• a greater endurance of “sporting” fatigue and an increased ability to “react” to acute stressful events, which are very different from routine daily stress. A faster post-workout recovery. To understand the effects mediated by this molecule, it is necessary to understand the endogenous biosynthetic pathway that leads to the formation of carnitine, noting that it has an important molecule as a precursor: S-Adenosyl-Methionine (SAM-e).

The latter is formed in the liver from simple methionine and ATP, which is degraded to transfer adenine to methionine in order to form SAM-e. A formed SAM-e molecule has “consumed” an ATP molecule for its synthesis. Understanding this is fundamental, since the SAM-e sparing process by carnitine administration can help explain the psychic and physical benefits that we already mentioned, as SAM-e is fundamental for the synthesis of numerous brain neurotransmitters.

Clinical studies have found an improvement in sports and in the intellectual performance, an aid for the memory, the immune system and for the maintenance of intellectual faculties, against depression, against chronic fatigue syndrome, etc. These studies also indicate that appreciable cognitive benefits occur after a few months of additional administration and highlight the neuroprotective role of ALC on the cholinergic system. Carnitine and ALC should not be used in people with bipolar disease (manic depression) and epilepsy, unless recommended by the attending physician.

Dosages

The average dosage is 500-1000 mg/day, although in the presence of slimming regimes and intense physical activity, it can reach 1500-2000 mg per day.

It is interesting to note that ALCAR in daily quantities equal to 2 g, in combination with alpha-lipoic acid, can potentially reduce the hypertension thanks to its antioxidant and pro-energetic action, as well as improve the insulin resistance and glucose tolerance in people with compromised heart health.

Effectiveness

Strength Resistant strength Mass Endurance Slimming Concentration Recovery

ACETYLCYSTEINE (NAC)

Description

N-acetylcysteine (NAC) is a precursor of L-cysteine, a non-essential but important sulfur amino acid for the hepatic metabolism and also for the metabolism of homocysteine and the antioxidant glutathione (GSH). In nature, it is found in plants of the Allium species, in particular in onion (Allium cepa, 45 mg NAC/kg). It is a donor molecule of thiol groups (the sulfhydryl-SH group) which, within the NAC molecule, directly eliminate reactive oxygen species (ROS) and modulate the redox state of NMDA and AMPA receptors (involved in transmission at the central nervous system level), and it also inhibits NF-κB (a transcription factor for inflammatory processes).

GSH, together with SOD (superoxide dismutase) and catalase, are the most potent organic endogenous antioxidant. The level of free radicals to which the cell is subjected is

indicated by the GHS/GSSG ratio (reduced glutathione/oxidized glutathione). It is known that in athletes, the administration of exogenous antioxidants must be evaluated very scrupulously. The free radicals produced during the training must be managed primarily by the cell’s endogenous antioxidant defenses. Nature has foreseen a hormetic adaptation of these defenses, which tend to improve the following sessions of physical activity with an intensive training (different from subject to subject). This happens, above all, if the correct recoveries are respected, which depend on the type of sport, intensity, duration, frequency, volume, etc. Muscle adaptation to exercise is also mediated by the hormetic stimulus of free radicals (increase in protein synthesis, mitochondrial biogenesis, recovery capacity), so much so that many studies suggest a worsening of the muscle adaptation and performance in subjects taking chronic and/or supraphysiological doses of antioxidants (typically vitamins C and E). With this in mind, encouraging the intake of thiols such as NAC could increase the body’s anti-radical defenses without creating an exogenous abatement by downregulating the hormetic stimulus given by the training. In addition, NAC stabilizes HIF (Hipoxia-Inducible Factor), which is responsible for activating the erythropoietin transcription gene (EPO), which increases its production. EPO is a protein hormone produced mainly in the kidneys which increases in situations of poor tissue oxygenation and stimulates the erythropoiesis by increasing the production of red blood cells, which act as oxygen transporters for the tissues.

Properties

NAC is used as an antidote for paracetamol overdose in order to prevent acute liver failure. Another dated pharmacological use (from 1963) is that which sees it as a mucolytic (used as an aerosol or by mouth). In fact, it has also been used to combat the action of some substances that produce free radicals, such as carbon monoxide (CO) and some contrast fluids used in radiology. It is used both parenterally (intravenously) and by mouth. In the literature, in 2002, a single case of anaphylactic reaction from NAC was described at a dosage of 150 mg/kg in an asthmatic 40-year-old woman. When taken by mouth, however, side effects are very rare and the areas in which this molecule has been used vary from non-alcoholic steatohepatitis to COPD (chronic obstructive pulmonary disease), substance abuse, ovarian polycystosis, diabetic retinopathy, cataracts, for a total of 300 clinical studies. However, many studies focus on the preventive use of NAC in diseases such as Alzheimer’s disease, irritable bowel, obesity, insulin resistance, cardiovascular diseases, heavy metal toxicity, diabetic retinopathy etc. Some studies on invertebrates and mammals have also reported an increase in the lifespan, with a substantially antiaging effect (yet to be confirmed in humans).

Evidence

NAC has also attracted considerable attention as a sports supplement for reducing the muscle fatigue, improving athletic performance and promoting muscle recovery.

However, there is a great variability of results in sports studies, also due to very heterogeneous methodologies. Some studies have shown very significant increases (over 50%) in athletic performance, particularly in single workouts consisting of interval exercises, performed under the use of NAC. These results were found in particular in subjects who, characteristically, had an enormous production of free radicals during a single workout.

In a 1994 study, it was found that the use of NAC was particularly useful for inhibiting the muscle fatigue especially in long-lasting sports (endurance), probably for its effectiveness in countering free radicals and oxidative processes, which cause fatigue once they’re produced.

The main disputes regarding the use of NAC as a sports supplement are related to the dosages and the times of administration, which are not standardized. For example, the daily dose of NAC in the studies included by Rhodes and Brakhuis ranged from 1.2 to 20 g and the supplementation period varied from a few minutes to eight days before performing the exercises. In various studies, the heterogeneous effects of NAC reflect the fact that there is an optimal state of the redox balance in various tissues, which is, however, difficult to assess. In these conditions, an incorrect dosage of an antioxidant (too much or too little) can lead to a significant reduction in the performance. A 2018 study (Paschalis et al.) took into consideration three categories of athletes, 100 subjects divided according to their basic glutathione level (low, medium, high). These athletes were supplemented with NAC at a dose of 600 mg twice a day, for 30 days, and their redox balance and performance were assessed on the Windgate test (an exhaustion test that examines the subject’s anaerobic capacity). The group starting with a lower GSH level reported a significant improvement in both post-NAC redox balance and in the performance level during the Windgate test, while there was little improvement in the groups that had medium to high baseline GSH concentrations. Other studies on rugby players (Rodi et al., 2019) and volleyball players (de Jesus Pires de Moraes et al., 2018) have found that supplementation with NAC gave better results particularly in acute cases, after an intense training session. According to the meta-analysis by Rhodes and Brakhuis, NAC doses >5 g have a greater potential to cause side effects. Although these side effects are generally mild and limited to gastrointestinal disorders, they can hinder the athletic performance and therefore affect the purpose of the supplement itself. However, the evidence of these side effects is limited and in many studies included in the meta-analysis of Rhodes and Brakhuis, they were not reported despite the generous doses of NAC.

In one study, 1200 mg of NAC were administered to well-trained athletes for eight days and, in addition to an increase in glutathione, they also found an increase in EPO. In another study by Momeni et al. it has been shown that with a single dose of 600 mg of NAC, there was an EPO increase of 20-30% during the 24 hours following the administration. The single dose, of course, did not produce an increase in the red blood cell production, as verified by a measurement made two weeks after the experiment. Conversely, the dose of 1200 mg for eight days significantly raised glutathione levels (+33%), EPO (+26%) and hematocrit (+9%), confirming the validity of NAC as a supplement for aerobic sports.

As mentioned, there is also evidence relating to pathologies that are characteristic of the elderly, such as in the prevention of neurovegetative pathologies, neuropathic pain, mild cognitive disorders and immune system disorders. However, some studies have considered administering hydrolyzed keratin as a thiol donor to build up GSH reserves, and both mouse and human studies have shown promising results. For humans, using hydrolyzed keratin dosages of 10-40 g per day have shown an increase in endogenous taurine (another sulfur metabolite that participates in the GSH cycle).

Dosages

Dosages are 600 mg once a day, preferably in the evening as an antioxidant and 1200 mg to improve the endurance. Other studies use dosages of 40-70 mg/kg of body weight.

Effectiveness

Strength Resistant strength Mass Endurance Slimming Concentration Recovery + ++ + +++ + – +++

AGMATINE

Description

Agmatine is a biogenic amine produced through the decarboxylation (elimination of a carboxyl group) of L-arginine, a non-essential basic amino acid in adults, produced in physiologically sufficient quantities through the urea cycle.

The main function of this amino acid is to represent the main precursor in the metabolism of nitric oxide.

Although agmatine can influence the metabolism of nitric oxide, it does not represent its metabolic precursor, which is carried out by L-arginine, but it represents an intermediate of “polyamines”, cell growth factors capable of stimulating the proliferation especially in fastgrowing cells such as cancer cells.

One of the possible agmantine metabolic pathways is represented by the formation of 4-guanide butyrate by the enzyme diamine oxidase (DAO), and by hydrolysis into urea and putrescine (polyamine) by the enzyme agmatinase1.

Although agmatine represents an intermediate in the synthesis of polyamines, it seems to have an inhibitory effect on the bioactivity of polyamines by reducing their intracellular quantity.

Like other biogenic amines (putrescine, tyramine, cadaverine, serotonin, histamine), agmatine can represent a by-product of bacterial fermentation, including that of the intestinal flora. In this regard, it seems that some bacteria are able to produce ATP and therefore energy, starting from substrates such as arginine and agmatine.

In the past, it was identified as “the substance capable of displacing clonidine”, a drug classified as a selective agonist of α2-adrenergic receptors, that acts predominantly as an antidepressant.

Agmatine accumulates in various parts of the body, although the highest levels are found in the stomach, small intestine and adrenal glands. Lower levels are found in smooth muscles, endothelial cells, heart, spleen and brain, where it is found particularly in areas where neuron terminals form excitatory synapses with pyramidal neurons.

Properties

Also known as 4-aminobutyl-guanidine, agmatine is stored in neurons at the level of synaptic vesicles (synaptosomes), from which it is released during the neuronal activity, and for this reason it is often considered a real neurotransmitter and neuromodulator.

Some research suggests that this amino acid may have potential in the treatment of neuropathic pain and in the context of drug addiction. These potentials work in synergy with the work done by painkillers such as morphine and other opiates, thus increasing pain tolerance. Studies conducted on guinea pigs have shown that taking agmatine sulfate significantly improves the insulin sensitivity, and it also promotes the release of anabolic hormones, such as the growth hormone-GH and the luteinizing hormone-LH, which stimulate the release of testosterone. Agmatine exerts its effects through various mechanisms; we will list the most interesting ones below: • it can inhibit the N-methyl-D-aspartate receptor (NMDA) of glutamate (a very important neurotransmitter involved in neuronal plasticity and long-term memory consolidation), which, if excessively excited, causes excitotoxicity with induced neuronal death. Agmatine, by inhibiting this receptor, appears to improve the cognitive abilities and memory, resulting in a significant neuroprotective effect; • it can act by activating the receptors of imidazolines, synthetic substances used as drugs in hypertensive states, or in the modulation of pain. A study has shown that the activation of

imidazoline receptors by agmatine significantly improves the insulin sensitivity by reducing blood sugar levels in diabetic rats; • agmatine is able to inhibit the calcium channels of some serotonin receptors, in particular the 5-HT1a type receptors with an antidepressant action; • agmatine, by inhibiting the nitric oxide synthase enzyme, helps regulate nitric oxide levels.

Despite this, it still seems to have vasodilatory and hypotensive effects; • there is an interesting study that demonstrates the improving effect on the integrity of the vascular endothelium, as a consequence of supplementation with agmatine sulfate in the presence of damage to the vascular endothelium induced by the intake of nicotine; • agmatine appears to improve the lipid profile, among other things, achieving a reduction in serum LDL cholesterol levels and an increase in HDL cholesterol levels. It should be noted that these improvements were observed only in conjunction with damage caused by the intake of nicotine; • agmatine is able to influence a number of metabolic functions, however the mechanism by which they occur is not yet fully understood. A study done on laboratory animals with obesity induced by a high-fat diet suggests that the intake of high doses of agmatine is able, over time, to significantly improve the metabolism of these subjects. Agmatine appears to lead to a better expression of the genes that regulate thermogenesis, to a better gluconeogenesis and higher systemic levels of carnitine and acetylcarnitine, therefore a better activation of the beta oxidation of fatty acids. These metabolic changes are associated with a weight reduction and a reduction in metabolic and hormonal alterations; • agmatine is known to inhibit nitric oxide synthase (NOS); this activity is carried out by modulating the inhibitory action, especially related to (inducible) iNOS which is its main objective, while the inhibitory action is mild on eNOS (endothelial). Remember that iNOS seems to contribute to an excess of nitric oxide production with harmful consequences, while eNOS appears to be protective through vasodilation; • some studies have highlighted an involvement of nitric oxide production in the aging process; Specifically, it seems that a dysregulation occurs with increases in the levels of NOS and a sharp decrease in agmatine levels in certain areas of the brain. This dysregulation seems to be the cause of age-related behavioral disorders. Injections of agmatine in elderly rats seem to restore the NOS activity by correcting these disorders.

Evidence

In the sports field, the use of agmatine is fairly recent, especially because even if there are no visible side effects, there is still a lack of data that would make it safe in the long term. The use of this polyamine as a supplement stems from a shared thought; since agmatine represents the product of arginine catabolism (true proponent of stimulation in the production of NO), a surplus of agmatine would slow down this conversion process regulated by “arginine decarboxylase”. At most, agmatine could be considered a modulator of NO and not a stimulator of its production.

However, even in sports, the use of agmatine cannot be limited to the sole vision of an “arginine saver”.

Some probable or potential effects resulting from the use of this polyamine are listed below: • it improves the insulin sensitivity and therefore the anabolic effect of this hormone in the post-exercise phase; • it stimulates the production of the growth hormone GH by the pituitary gland and therefore, it amplifies its anabolic effects; • not only does it relieve pain, but it also increases mental well-being by reducing the production of cortisol, which is released during intense physical exercise; this avoids muscle catabolism.

However, until there are further studies carried out on athletes in training, the possible ergogenic properties of agmatine cannot be confirmed.

Dosages

Agmatine, once absorbed after oral ingestion, is rapidly distributed in various tissues, also reaching the brain. In the systemic circulation agmatine appears to have a half-life of less than 10 minutes, however it remains in the brain for up to 12 hours. The passage through the cell membrane cannot take place in a passive way, but requires an active transporter; moreover, its absorption is shared with putrescine, which, if in high concentrations, can inhibit the absorption of agmatine. Even though there is insufficient research to determine an official recommended dose, dosages between 1300 and 2600 mg per day appear to be effective and well tolerated.

However, experience indicates that in order to have significant benefits, it is sometimes necessary to increase the dosage. Some studies indicate that dosages of 6 to 40 mg/kg of body weight are required to have benefits like increasing the mental concentration or an anxiolytic effect. Other studies indicate that the effects of agmatine are not dose-dependent and that it follows a “bell-shaped” trend. Taking it orally is recommended on an empty stomach or with a small non-protein meal, as agmatine competes with some carriers used by amino acids.

Effectiveness

Strength Resistant strength Mass Endurance Slimming Concentration Recovery

ALPHA-GLYCERILPHOSPHORYLCHOLINE

Description

Alpha-glycerylphosphorylcholine (α-GPC) is a precursor of the neurotransmitter acetylcholine and a natural metabolite of phospholipids derived from soy lecithin. It improves the memory abilities and all brain functions in general. α-GPC is indicated to strengthen the release of GHRH (Growth Hormone Releasing Hormone), which in turn stimulates the secretion of growth hormone (GH, Growth Hormone) in young and elderly individuals.

Properties

The stimulation of acetylcholine and the consequent natural release of growth hormone are the result of the stimulation of neurotransmitters on the cholinergic system, however other modulations and biochemical-related systems may also be involved. α-GPC, in particular,

increases the synthesis and release of an important neurotransmitter called acetylcholine,

which allows the growth hormone levels to increase even after physical exercises.

Recent studies have also suggested that α-GPC may be an effective ergogenic aid.

Evidence

A recent study examined the GH release in endurance athletes after supplementation with α-GPC. In athletes supplemented with α-GPC, GH levels rose 68% more than those who took the placebo. In particular, the peak strength on the bench press in the athletes who had used the α-GPC was 14% higher than the controls.

Similar results were found in another study involving both young and elderly men. In younger subjects (30-34 years), α-GPC showed a 40% increase in the GH release compared to non-α-GPC group. In older subjects (80-82 years) taking α-GPC increased the GH secretion up to 140% more than in non-α-GPC.

The researchers suggest that α-GPC could amplify GHRH-induced GH release through two mechanisms. According to the first hypothesis, supplementation with α-GPC would lead to an increase in brain levels of acetylcholine, which, in turn, would increase the pituitary sensitivity and amplify the release of GH. The second hypothesized mechanism foresees that the increase of the growth hormone secretion is determined by the increase in the fluidity and permeability of the pituitary membranes, i.e. by a greater ease of signal transmission.

Lena Marcus et al., In 2017, designed a study to evaluate the effectiveness of two doses of α-GPC compared to placebo and caffeine for increasing the jumping performance, the isometric strength and the psychomotor function.

Forty-eight healthy college-age males volunteered for the study and underwent baseline jumping assessment, mid-thigh isometric pull (IMTP), upper body isometric strength test (UBIST), and psychomotor alertness (PVT). Following this evaluation, participants were randomly assigned to groups taking 500 mg of α-GPC, 250 mg of α-GPC, 200 mg of caffeine or placebo daily. Blood samples were collected 1 hour and 2 hours after the initial dose to quantify the free choline and the thyroid stimulating hormone.

Serum TSH was found to be significantly depressed in the 500 mg α-GPC group compared to other treatments (p <0.04). Group differences were observed for maximum speed and mechanical power on jumping (p <0.05) and the 250 mg α-GPC group demonstrated the greatest improvements in outcome. In conclusion, on the basis of these tests, α-GPC could be considered an efficient ergogenic supplement.

Another interesting aspect concerns the mitochondria. It has been hypothesized that α-glycerylphosphorylcholine (α-GPC) can influence the mitochondrial respiratory activity and, in this way, it can exert protective effects on the tissues. Rat liver mitochondria were examined with high-resolution respirometry to analyze the effects of α-GPC on the electron transport chain in normal oxygen conditions and in the absence of oxygen. The activities of reduced glutathione (GSH) and oxidized glutathione (GSSG), tissue myeloperoxidase, xanthine oxidoreductase and NADPH oxidase were measured.

The formation of tissue malondialdehyde and nitrite/nitrate was evaluated, together with the production of superoxide and hydrogen peroxide in the blood. It was observed that, following the cell damage and the oxidative stress, the administration of α-GPC reduced the inflammatory activation and also the inflammatory markers. In conclusion, α-GPC, by preserving the respiration of the mitochondrial complex, reduced the biochemical signs of oxidative stress. This suggests that α-GPC is a compound that also targets mitochondria and that it is able to indirectly suppress the activity of the main intracellular proximity enzymes.

Dosages

The normal use of α-GPC, in quantities ranging from 100 to 1000 mg per day, contributed to a significant improvement in the endogenous secretion of GH and to the stimulation of the enzymatic synthesis of phosphatidylcholine, especially in nerve and muscle cells. Small doses of 150-400 mg also appear to be effective.

Effectiveness

Strength Resistant strength Mass Endurance Slimming Concentration Recovery