Wellspan Vitamins, Minerials, & More
Vitamin A
Vitamin A is a generic term that refers to fat-soluble compounds found as preformed vitamin A (retinol) in animal products and as provitamin A carotenoids in fruit and vegetables. The three active forms of vitamin A in the body are retinol, retinal, and retinoic acid.
Vitamin A is involved in regulating the growth and specialization (differentiation) of virtually all cells in the human body. Vitamin A has important roles in embryonic development, organ formation during fetal development, normal immune functions, and eye development and vision.
Vitamin A deficiency is a major cause of preventable blindness in the world. It is most prevalent among children and women of childbearing age. Vitamin A deficiency is associated with an increased susceptibility to infections, as well as to thyroid and skin disorders.
The recommended dietary allowance (RDA) is 700 micrograms of retinol activity equivalents (μg RAE)/day for women and 900 μg RAE/day for men.
Beef liver
Cod liver oil
Sweet potato
One whole sweet potato, baked in its skin, provides 1,403 mcg of vitamin A, which is 156% of the DV.
The vitamin A present in this root vegetable is in the form of beta carotene.
suggests that this compound may help protect against age-related macular degeneration (AMD).
also suggest that beta carotene may help protect against cancers, such as prostate cancer, but the results are mixed.
Carrots
Black-eyed peas
Spinach
Broccoli
Sweet red pepper
Mango
Cantaloupe
B Vitamins: B1-Thiamine, B6-Pyridoxine, and B12-Cobalamin
Carlos Alberto Calderón‐Ospina and Mauricio Orlando Nava‐Mesa 2
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Abstract
Background
Neurotropic B vitamins play crucial roles as coenzymes and beyond in the nervous system. Particularly vitamins B1 (thiamine), B6 (pyridoxine), and B12 (cobalamin) contribute essentially to the maintenance of a healthy nervous system. Their importance is highlighted by many neurological diseases related to deficiencies in one or more of these vitamins, but they can improve certain neurological conditions even without a (proven) deficiency.
Aim
This review focuses on the most important biochemical mechanisms, how they are linked with neurological functions, and what deficits arise from the malfunctioning of these pathways.
Discussion
We discussed the main role of B Vitamins in several functions in the peripheral and central nervous system (PNS and CNS) including cellular energetic processes, antioxidative and neuroprotective effects, and both myelin and neurotransmitter synthesis. We also provide an overview of possible biochemical synergies between thiamine, pyridoxine, and cobalamin and discuss by which major roles each of them may contribute to the synergy and how these functions are interrelated and complement each other.
Conclusion
Taking into account the current knowledge on the neurotropic vitamins B1, B6, and B12, we conclude that a biochemical synergy becomes apparent in many different pathways in the nervous system, particularly in the PNS as exemplified by their combined use in the treatment of peripheral neuropathy.
Keywords: B vitamins, biochemical action mechanism, neuropathy, pyridoxine, thiamine, vitamin B12
1. BACKGROUND
The eight B vitamins B1 (thiamine), B2 (riboflavin), B3 (niacin), B5 (pantothenic acid), B6 (pyridoxine), B7 (biotin), B9 (folate), and B12 (cobalamin) form a group of chemically very heterogeneous essential substances, which have a wide variety of functions in the human body. Even though they are biochemically not related, referring to them as a group makes sense because they often naturally occur in the same foods and share the feature of being water‐soluble. Mammals are not able to synthesize B vitamins on their own; therefore, they must take them up in sufficient quantities with their diet. Even though most of them are produced by plants, they can be ingested indirectly via animal‐derived food like meat, dairy, and eggs. Only vitamin B12 is not produced by plants but by bacteria that colonize the foregut of ruminants or the colon of humans and thus can only be found in animal products like liver, fish, eggs, or dairy products. However, the vitamin B12 produced by bacteria in the colon of humans is not available for uptake because adsorption only takes place further up in the ileal mucosa through an intrinsic factor‐mediated mechanism. All B vitamins play crucial roles as coenzymes for enzymatic reactions in different biological systems. Although those roles differ, they are closely interrelated and complement each other. To fulfill the coenzymatic function, the biologically active form of the respective vitamin (coenzyme) needs to bind to a corresponding protein (enzyme), thereby activating its enzyme function, so that the cellular processes can take place with the help of the newly formed holoenzyme complex. Some of the B vitamins not only contribute to important physiological functions in the whole human body but also possess neuro-specific functions. These commonly called “neurotropic” B vitamins play special and essential roles both in the central nervous system (CNS) and the peripheral nervous system (PNS). It is well known that the diet and thus the supply of nutrients strongly affect the normal functioning of CNS and PNS. In particular, vitamins B1, B6, and B12 are essential for maintaining the health of the nervous system. Interaction between pyridoxine and cobalamin in the methionine cycle, as well as their participation in the citric acid cycle with other B vitamins, including thiamine, suggests that these three vitamins are linked from a biochemical point of view. Indeed, a significant association between cognitive impairment and methionine‐homocysteine cycle dysfunction indicated by low levels of vitamins B6 and B12 has been found. Evidence suggests that a significant proportion of the population suffers from deficiencies and insufficiencies of one or more of these neurotropic B vitamins. The importance of B vitamins in the context of nerve function is highlighted by the numerous neurological diseases, such as Wernicke's encephalopathy, depression, beriberi, seizures, subacute combined degeneration of the spinal cord, or peripheral neuropathy (PN), that are related to a deficiency in one or more of these neurotropic B vitamins. However, the significance of these vitamins is also emphasized by the fact that they can improve certain neurological conditions even if no (definite) deficiency can be proven. Indeed, several reports indicate that the specific supplementation with the combination of vitamins B1, B6, and B12 interacts synergistically to improve neuropathy, motor control, nociceptive, and neuropathic pain. The present review aims to compile the most important biochemical pathways of the B vitamins, focusing on thiamine, pyridoxine, and cobalamin, and link them with neurological functions and symptoms related to deficiencies. We also provide an overview of possible biochemical synergies between these neurotropic vitamins and discuss major roles by which they may contribute to this synergy.
2. BIOCHEMICAL MODE OF ACTION AND ROLE IN THE NERVOUS SYSTEM
2.1. Vitamin B1 (thiamine)
Vitamin B1, also known as thiamine, has long been known to be associated with functions in the nervous system. The connections between thiamine deficiency and the development of fatal conditions such as beriberi, a syndrome compromising the PNS by polyneuritis and/or cardiovascular symptoms, and the neuropsychiatric Wernicke‐Korsakoff syndrome, characterized by encephalopathy and psychosis, were already recognized in the early to the mid‐20th century.
In general, thiamine is essential for many physiological functions and is, among other roles, involved in glucose metabolism, the maintenance of nerve membrane function, and the synthesis of myelin and several types of neurotransmitters (eg, acetylcholine, serotonin, and amino acids).
However, the most important function of thiamine is considered to be that it largely contributes to cellular energy metabolism and, as an essential cofactor in the conversion of carbohydrates, helps provide energy to nerve cells. This constant supply of energy is essential because nerve cells, especially in the brain, consume a great amount of energy to maintain their functions and, for example, prevent premature aging, but can hardly store high‐energy compounds themselves.7 To be more precise, one of the main activities of thiamine is to enable biochemical steps in the energy‐creating processes pentose phosphate pathway, glycolysis, and Krebs cycle (citric acid cycle). These processes supply the nerves with energy mainly in the form of adenosine triphosphate (ATP) or nicotinamide adenine dinucleotide phosphate (NADPH), which in turn are essential for numerous other cellular processes and reactions in nerves. By means of that, vitamin B1 is also indirectly needed for the energy‐consuming synthesis of nucleic acids, neurotransmitters, and myelin. Therefore, thiamine even contributes to nerve conduction velocity because it participates in the maintenance of myelin sheaths. Because the mentioned pathways not only produce energy but also provide reducing power, thiamine is thought to also have an antioxidative—thereby protective—effect on nerve cells.
In addition to its coenzymatic functions, thiamine is also believed to be directly involved in nerve stimulation in a non‐coenzymatic way due to its interference with the structure and function of cellular membranes and its ability to regulate ion channels. Furthermore, through its antioxidative properties, sufficient amounts of thiamine may even prevent cell damage resulting from hyperglycemia.
At the molecular level, after being taken up by the cells by a usually active process, free thiamine is initially phosphorylated to form biochemically active thiamine diphosphate (TDP), synonymously known as thiamine pyrophosphate (TPP). TPP acts as a coenzyme for thiamine‐using enzymes in three major pathways of glucose metabolism; that is, for transketolase (TK) in the pentose phosphate pathway, for pyruvate dehydrogenase (PDH) in the glycolysis, and alpha‐ketoglutarate dehydrogenase (AKD) in the Krebs cycle. Each of these enzymes can only fulfill its purpose as a holoenzyme made up of several constituents. Therefore, the addition of thiamine to the complex is crucial for the enzymes' functionality. The pentose phosphate pathway, which generates the sugar molecule ribose‐5‐phosphate and the energy source NADPH, uses the TPP‐activated TK in the cytosol to convert ribose‐5‐phosphate to glycerinaldehyde‐3‐phosphate. The substrates of the pentose phosphate pathway are then used for the synthesis of nucleic acids, complex sugar molecules, coenzymes, steroids, fatty acids, amino acids, neurotransmitters, and glutathione. Through its operation, TK also connects the pentose pathway with glycolysis.
Biochemical mechanism of action of vitamin B1 (thiamine). Modified and simplified illustration based on. TPP, thiamine pyrophosphate; TK, transketolase; PDH, pyruvate dehydrogenase; AKD, alpha‐ketoglutarate dehydrogenase; CoA, coenzyme A; GABA, gamma‐aminobutyric acid
In contrast, the TPP‐activated enzymes PDH and AKD hold special functions in glycolysis and the Krebs cycle, which in particular provide ATP for cell energy. Further, PDH induces the formation of acetyl coenzyme A (CoA), a precursor of the neurotransmitter acetylcholine, and helps produce myelin that is needed to enwrap the axons of nerve cells. AKD in the Krebs cycle, on the other hand, helps to maintain the levels of neurotransmitters (ie, glutamate, GABA, and aspartate) and also supports protein synthesis.
In the case of a vitamin B1 deficiency, activity levels of all three enzymes mentioned above are biochemically impaired; however, TK activity may be the most sensitive, and AKD activity one of the earliest changes. As vitamin B1 is essential for the production of energy (ATP and NADPH) and a normal function of nerve cells, its deficiency can cause neurons to die or become damaged. Thiamine deficiency affects both the CNS and the PNS and can manifest clinically in multifaceted ways. In general, neurological symptoms of thiamine deficiency include confusion, psychomotor retardation, lack of insight, impaired retentive memory and cognitive function, confabulation, ataxia, and the loss of vibration and position sense. If thiamine is not present in sufficient quantity for the CNS, sensitive areas of the brain such as the thalamus and the mamillary bodies (part of the hypothalamus) suffer damage. Wernicke's encephalopathy and Korsakoff's psychosis (often referred to as Wernicke‐Korsakoff syndrome) can certainly be considered the most serious CNS manifestations of thiamine deficiency. In Wernicke's encephalopathy, for instance, thiamine deficiency is thought to trigger apoptotic cell death due to N‐methyl‐D‐aspartate (NMDA) toxicity and thereby induce neurological symptoms. In the PNS, typical manifestations of thiamine deficiency include polyneuritis and paralysis, as occurs in dry beriberi. In the sensory system, it influences the tactile sensation, causes pain, changes the temperature sensitivity, and leads to the loss of vibratory sense. In the motor system, paralysis typically begins in the tips of the lower extremities and spreads progressively. It involves increased muscle weakness, affected tendon reflexes, and atrophy of the leg muscles. Thiamine deficiency nowadays hardly affects the general population in developed countries, but certain vulnerable populations are very often deficient or show suboptimal levels. For example, it is assumed that this applies to up to 80% of alcoholics, up to 98% of diabetics, and around one‐third of dialysis patients with altered mental status.
Because vitamin B1 is largely involved in pathways that also create reducing power in cells, a deficiency will cause cells to be exposed to oxidative stress, which can lead to cell damage and cell death and contribute to further symptoms and comorbidities.
In summary, these examples clearly show how important thiamine is for the nervous system function due to its activating role for neuronal excitability and metabolism as well as antioxidative effects.
2.2. Vitamin B6 (pyridoxine)
Vitamin B6 (pyridoxine) has been discovered in 1934 and has so far been associated with over 140 coenzymatic functions. Although its role goes far beyond, it is particularly well known for its important function in the synthesis of neurotransmitters like dopamine from L‐DOPA, serotonin from 5‐HTP, and gamma‐aminobutyric acid (GABA) from glutamate. According to its function for the previously mentioned neurotransmitters (and others), pyridoxine affects the adrenergic, serotonergic, and glutamatergic systems. Pyridoxine can also be attributed to a neuroprotective role which appears to be mainly linked with its ability to regulate the glutamatergic system and thus GABA and glutamate levels. Since GABA serves as the major inhibitory neurotransmitter, it seems obvious that GABA deficiency can lead to serious consequences, such as seizures. Increased levels of the GABA precursor glutamate, an excitatory neurotransmitter, can be linked with seizures, whereas the application of GABA or pyridoxine can end seizure activity. In addition, pyridoxine administration even attenuates the excitotoxicity of the neurotoxin domoic acid. Beyond that, it has been shown that vitamin B6 is essential during gestation and postnatal brain development, probably also through the regulation of GABA levels. Rats exposed to vitamin B6 deficiency during this time showed significantly lower GABA levels and permanently damaged brains.
While only nonphosphorylated B6 vitamers can cross cell membranes, including the blood‐brain barrier, and can therefore be taken up by cells, vitamin B6 is intracellularly phosphorylated to form the active interconvertible 5′‐phosphate esters pyridoxine 5′‐phosphate (PNP), pyridoxal 5′‐phosphate (PLP; most important coenzyme variant), and pyridoxamine 5′‐phosphate (PMP). Beyond its essential role in neurotransmitter production, PLP also acts as a coenzyme in one‐carbon unit generation and homocysteine metabolism, supports carbohydrate and fat synthesis as well as breakdown, and helps release food‐bound energy that is needed for the metabolism of proteins and amino acids. Besides, PLP also serves as a cofactor in sphingolipid synthesis and is thereby important for myelin formation.
About neurotransmitter synthesis, PLP helps, for instance, catalyze the final production step of dopamine and serotonin, that is, the enzymatic decarboxylation of L‐DOPA to dopamine and of 5‐HTP to serotonin. In both pathways, the successful formation of the neurotransmitters depends on the action of aromatic L‐amino acid decarboxylase (AADC), which in turn essentially depends on PLP.
Biochemical mechanism of action of vitamin B6 (pyridoxine). A, Role of PLP on Dopamine and Serotonin Synthesis. B, Role of PLP and Vit. B12 on one‐carbon unit metabolism and Hcy metabolism. Role of B Vitamins in the interlinked methionine and citric acid cycles. Modified and simplified illustration based on. TH, tyrosine hydroxylase; AADC, aromatic L‐amino acid decarboxylase; PLP, pyridoxal 5′‐phosphate; 5‐HTP, 5‐hydroxytryptophan; THF, tetrahydrofolate; SHMT, serine‐hydroxymethyltransferase; FAD, flavin adenine dinucleotide; SAM, S‐adenosylmethionine; SAH, S‐adenosylhomocysteine; R, methyl group acceptor
In the one‐carbon unit metabolism, PLP‐activated serine‐hydroxymethyltransferase (SHMT) catalyzes the process in which one‐carbon units are generated from serine and activated through association with tetrahydrofolate (THF). This pathway forms 5,10‐methylene‐THF for nucleic acid synthesis and the methyl donor 5‐methyl‐THF, which is needed for protein synthesis and to methylate homocysteine (Hcy) to methionine in a process that also depends on vitamin B12 and folate. A great proportion of the formed methionine is converted to S‐adenosylmethionine (SAM), a universal donor of methyl groups needed for the synthesis of DNA, RNA, hormones, neurotransmitters, membrane lipids, proteins, and others. Being an intermediate compound of methionine metabolism, Hcy can be disposed of by two pathways. When methionine is in excess or cysteine is required, it will be disposed of via the intermediates cystathionine and cysteine to glutathione. In methionine deficiency, on the other hand, it is remethylated to methionine in the above‐described way.
The role of pyridoxine in the nervous system is demonstrated by its use in the treatment of pyridoxine dependency seizures—an inborn abnormality in infants with seizures not responding to common anticonvulsants. Due to its important function as a coenzyme in pathways responsible for the synthesis of neurotransmitters and myelin, vitamin B6 deficiency can severely impair the CNS and the PNS. Biochemically, in a partial deficiency of vitamin B6, some enzymes may be more affected than others, resulting in greater depletion of some neurotransmitters and thereby imbalances between the levels of different neurotransmitters. Neurological symptoms of deficiency generally range from impaired cognitive function, convulsive seizures, depression, and even premature aging of neurons (CNS effects) to carpal tunnel syndrome and PN with symptoms like paresthesia, burning and painful dysesthesias, and thermal sensations (PNS effects). Treating these conditions with pyridoxine is useful, even though the intake of extremely high doses over long periods can trigger sensory neuropathy. However, even in these circumstances, symptoms resolve after withdrawal and no permanent damage to the nervous system has so far been described. Like thiamine deficiency, vitamin B6 deficiency is also rare in the healthy general population in countries with high nutritional standards but frequently affects hemodialysis patients (over 80%), particularly if they are uremic. In addition, increased amounts of vitamin B6 are needed during pregnancy to ensure fetal brain development, and pyridoxine supplementation may even reduce nausea during early pregnancy.
In summary, pyridoxine strongly contributes to the proper functioning of the nervous system by facilitating neurotransmitter and myelin synthesis, and also controlling glutamate excitability and neuronal metabolism.
2.3. Vitamin B12 (cobalamin)
The discovery of vitamin B12 (cobalamin) can be attributed to a disease that already attracted attention a long time ago and became known as pernicious anemia. Even though it first became famous for its role in hematopoiesis, cobalamin also plays an essential role as a coenzyme in many biochemical processes that maintain or restore the health of the nervous system. Thus, vitamin B12 is especially awarded a function in the DNA synthesis of myelin‐producing oligodendrocytes and the synthesis of myelin. The myelin sheath surrounds the axons of many nerves and serves as an electrical insulation, thereby facilitating fast conduction velocity. This important contribution to myelin formation and remyelination, significantly supports the regeneration of nerves after an injury. In addition to this major role, cobalamin is involved in Hcy metabolism, nerve metabolism (transmethylation processes), fatty acid and nucleic acid synthesis, energy production as well as cell maturation processes and even supports the maintenance of an intact gastrointestinal mucosa. Since the level of cobalamin also affects the amount of reduced glutathione with antioxidant functions in the erythrocytes and the liver, the lower availability of reduced glutathione in cobalamin deficiency may expose cells to increased oxidative stress.7
The pathway from nutritional vitamin B12 intake to cellular usability of the coenzyme forms is complex and involves several steps during which cobalamin (Cbl) is bound and transported through the intestine and the blood by different proteins such as haptocorrin, intrinsic factor, and transcobalamin II. The holotranscobalamin complex is finally absorbed by the target cell after binding to the transcobalamin receptor. Cbl naturally occurs in several forms differing only in their prosthetic groups, all of which are cleaved and metabolized to the coenzyme variants methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) after uptake. It is important to understand that all of these forms first have to be converted to the Cbl core structure before they are later newly assembled into the active coenzymes in the body. Therefore, direct intake of the coenzyme forms does not seem to be associated with advantages. Cbl forms in the mitochondria are changed in a complex enzymatical process into AdoCbl, which supports the enzyme methyl malonyl CoA mutase (MCM) and thereby helps catalyze the formation of succinyl CoA—an important intermediate of the Krebs cycle—from methyl malonyl CoA . Methyl malonyl CoA emerges when odd‐chain fatty acids, cholesterol, and ketogenic amino acids are metabolized. In contrast to the processes in the mitochondria, the equally complex enzymatical conversion of Cbl to MeCbl only occurs in the cytosol. Here, the enzyme methionine synthase (MS) requires MeCbl as a cofactor to methylate the amino acid Hcy to methionine, which is needed to sustain adequate synthesis of proteins, DNA, and neurotransmitters. If Cbl is deficient in the cell, plasma concentrations of methylmalonic acid—a functional marker of vitamin B12 deficiency—and Hcy will rise. Moreover, deficiency also leads, among other things, to defects in myelin synthesis and the incorporation of abnormal fatty acids into neuronal.
Biochemical mechanism of action of vitamin B12 (cobalamin). Modified and simplified illustration based on. HoloTC, holotranscobalamin; TC, transcobalamin; Cbl, cobalamin; MeCbl, methylcobalamin; MS, methionine synthase; SAH, S‐adenosylhomocysteine; SAM, S‐adenosylmethionine; AdoCbl, adenosylcobalamine; MCM, methylmalonyl CoA mutase; CoA, coenzyme A
Because vitamin B12 is involved in so many essential pathways, its deficiency is a tremendous health problem. However, symptoms strongly differ in severity and can manifest as mild conditions or life‐threatening disorders.57 Neurological deficiency disorders include but are not limited to subacute combined sclerosis of the spinal cord, polyneuritis, neuropathy, myelopathy, optic nerve atrophy, impaired cognitive function, and are mainly related to impaired neurotransmitter production, myelin lesions, or increased Hcy and methylmalonic acid levels. Neuronal demyelination is thought to be mainly caused when the universal methyl donor SAM is less available. SAM synthesis critically depends on vitamin B12 and has various important functions in the nervous system, including myelin as well as neurotransmitter synthesis. Demyelination generally affects both peripheral and central nerves but especially the long tracts of white matter in the posterior and lateral columns of the spinal cord, which contain sensory fibers for vibration and position sense. However, motor fibers can also become demyelinated. Affected persons may suffer from symptoms such as symmetric dysesthesia, disturbance of position sense, spastic paraparesis or tetraparesis, paresthesias, numbness in limbs, and difficulties in activities of daily living like writing or buttoning. Vitamin B12 deficiency appears to be particularly common in the elderly with estimates as high as 30‐40% and may often be due to malabsorption. In addition, vegetarians and particularly vegans often show suboptimal vitamin B12 levels but do not necessarily develop a clinical deficiency.
Overall, it can also be summarized for vitamin B12 that it is essential for the nervous system, particularly concerning myelin synthesis, nerve metabolism, and neuronal regeneration.
3. THE ROLE OF NEUROTROPIC B VITAMINS IN DIFFERENT REGIONS OF THE NERVOUS SYSTEM
As outlined in this review, neurotropic B vitamins play important roles both in the CNS and the PNS. While the biochemical mechanisms at the cellular level are identical in both systems, the phenotypic manifestations of deficiencies differ.
In the CNS (ie, the brain and the spinal cord), one of the most prominent roles of neurotropic B vitamins (particularly vitamins B6 and B12 as well as the herein not described B9) derives from their contribution to the folate and Hcy metabolism. Deficiencies in these vitamins are associated with increased Hcy levels, which are assumed to have neurotoxic effects. By promoting oxidative stress and neurodegeneration, increased Hcy may be a risk factor for dementia, cognitive decline, and Alzheimer's disease. In addition, dietary supplementation with B Vitamins may have beneficial effects in other neurological conditions such as anxiety, stress‐related disorders, and multiple sclerosis.
Also in the PNS, neurotropic B vitamins contribute to the maintenance of optimal nerve functioning. Deficiencies can result in the development of disorders of the peripheral nerves, for example, peripheral neuropathies. Evidence suggests that these vitamins also play a role in the regeneration of injured nerves, as shown in several animal studies. In addition, studies in humans have shown that treatment with neurotropic B vitamins effectively relieved symptoms of neuropathy in different patient groups. Patients with such conditions may even benefit from pharmacological B vitamin doses if no clear diagnosis of deficiency can be established or only suboptimal B vitamin levels (“marginal deficiency”) are detected. This assumption is supported by a recent perspective, a non‐interventional study of Hakim et al, in which patients with PN of different etiology were treated with high‐dose B vitamins (B1, B6, and B12) for 90 days without prior determination of B vitamin levels; all groups benefited significantly from the treatment and felt progressive relief of different symptoms such as pain, burning, paresthesia, and numbness. However, the benefit of neurotropic B vitamins in patients with neuropathy should in the future also be confirmed by randomized controlled trials.
4. SYNERGISTIC EFFECT OF THE COMBINATION OF NEUROTROPIC B VITAMINS B1, B6, AND B12 WITH EMPHASIS ON THE PNS
It needs to be stressed that vitamins B1, B6, and B12 most likely hold synergistic biochemical roles in the nervous system, that is, neither of them can replace one of the others. Table 11 provides an overview of the major implications of overlapping biochemical pathways important for the nervous system, pointing to a synergistic effect as a logical consequence of these overlaps. Because PN of different etiologies is believed to be a multifactorial process involving different factors like oxidative stress and demyelination, the hypothesis of synergy becomes even more likely. We postulate that the synergistic function of neurotropic B vitamins in the PNS may be primarily due to the prominent functions of each vitamin. While we assume that vitamin B1 is mainly needed as an antioxidant in this context, vitamin B6 may be primarily involved in a neuroprotective and vitamin B12 in a myelin‐regenerating role. However, the idea of synergistic effects between B vitamins has already been discussed by other authors. Nevertheless, clinical studies that support the hypothesis are needed and should directly compare the combination of the neurotropic B vitamins B1, B6, and B12 with the individual vitamins in humans suffering from PN. In contrast, results from animal studies suggest the correctness of the hypothesis. Thus, evidence for the practical synergistic action in the PNS was impressively demonstrated by Jolivalt et al, who showed that none of the individual B vitamins (B1, B6, and B12) was as effective in alleviating neuropathic pain and restoring nerve function in rats with experimentally induced diabetic neuropathy as the combination of the three when comparing high‐dose administration.
Table 1
5. FINAL REMARKS AND CONCLUSION
As highlighted here, the neurotropic vitamins B1, B6, and B12 have different neuro-specific functions in the nervous system. They are all important for the maintenance of normal neurological functions due to different biochemical modes of action, especially as coenzymes but also beyond, and can effectively be used in combination for the treatment of PN in humans. However, the exact mechanisms of action of these B vitamins in PN are still not clarified in detail and require further research.
In summary, vitamin B1 is particularly needed as a cofactor in glucose metabolism and thereby indirectly supports the synthesis of nucleic acids, neurotransmitters, myelin, etc by providing energy for these processes. In addition, it is assumed to contribute to antioxidative mechanisms. Vitamin B6, most importantly, functions as a coenzyme in the synthesis of neurotransmitters needed for synaptic transmission (eg, dopamine, serotonin, GABA) and holds a neuroprotective role based on its importance for the glutamatergic system. Concerning neuropathy, the main role of vitamin B12 is attributed to the synthesis of myelin, which allows for the regeneration of peripheral nerves.
Taking into account the current knowledge on the neurotropic vitamins B1, B6, and B12, we conclude that they form a biochemical synergy in many different pathways in the nervous system, particularly in the PNS as exemplified by their combined use in the treatment of PN. It is important to start considering B vitamins in future clinical studies as a therapeutic and neuroprotective approach for both peripheral neuropathies and several brain disorders.
We’ve all heard the legend of the fountain of youth—a mythical spring that grants long life and youthful vitality. Unfortunately, no such fountain has been discovered.
But the good news for longevity is nutrients can help combat the aging process.
B12
Vitamin B12 is an essential nutrient, important in nerve and blood cell health, and most people obtain enough of it in food. Those with B12 deficiency, or an inability to absorb it, can use supplements.
B12 has a number of benefits for overall health in older adults:
Better energy levels
Reduction in fatigue
Prevention of memory loss
Reduction in the risk of dementia and Alzheimer's
Improved mood and reduced depression and anxiety levels
Vitamin C
Vitamin C is a powerful ingredient in many anti-ageing products. Some studies show that it can reduce the appearance of wrinkles when you use it for at least 12 weeks. A healthy diet that's high in this nutrient might help, too. Research suggests that people who eat more vitamin C have fewer wrinkles.
People who consume moderately high levels of Vitamin C have reduced death rates, most notably from heart disease, the leading cause of death in the United States, according to a new UCLA study. Vitamin C supplements have been touted as an aid to good health and longevity.
Vitamin C is already known to play an important role in bone health, but may also help us maintain strong muscles. This vitamin is only found in vegetables, potatoes, and fruits.
People who don’t consume enough of these in their diet are at risk of vitamin C deficiency, which may cause weakness, tiredness and fragile bones. In extreme cases, it may lead to scurvy. But before this occurs, insufficient dietary vitamin C intake may have other effects on health, including our muscles.
Around two-thirds of our body’s total vitamin C is found in skeletal muscle. It’s used for making carnitine, a crucial substance that provides energy for muscles to function, and collagen, which is an essential structural component of muscle.
In addition, vitamin C is a strong antioxidant that can help to counteract free radical molecules, which increase when we age. Unopposed, these free radicals can contribute to the destruction of muscle cells.
Vitamin D Lowers Risk of Autoimmune Disease
In a new study, investigators from Brigham and Women’s Hospital found the people who took vitamin D, or vitamin D and omega-3 fatty acids, had a significantly lower rate of autoimmune diseases — such as rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, and psoriasis — than people who took a placebo.
With their findings published Wednesday in BMJ, the team had tested this in the large-scale vitamin D and omega-3 trial (VITAL), a randomized study which followed participants for approximately five years. Investigators found the people who took vitamin D, or vitamin D and omega-3 fatty acids had a significantly lower rate of AD than people who took a placebo.
“It is exciting to have these new and positive results for nontoxic vitamins and supplements preventing potentially highly morbid diseases,” said senior author Karen Costenbader of the Brigham’s Division of Rheumatology, Inflammation and Immunity. “This is the first direct evidence we have that daily supplementation may reduce AD incidence, and what looks like more pronounced effect after two years of supplementation for vitamin D. We look forward to honing and expanding our findings and encourage professional societies to consider these results and emerging data when developing future guidelines for the prevention of autoimmune diseases in midlife and older adults.”
“Now, when my patients, colleagues, or friends ask me which vitamins or supplements I’d recommend they take to reduce risk of autoimmune disease, I have new evidence-based recommendations for women age 55 years and older and men 50 years and older,” said Costenbader. “I suggest vitamin D 2000 IU a day and marine omega-3 fatty acids (fish oil), 1000 mg a day — the doses used in VITAL.”
VITAL is a randomized, double-blind, placebo-controlled research study of 25,871 men (age 50 and older) and women (age 55 and older) across the U.S., conducted to investigate whether taking daily dietary supplements of vitamin D3 (2000 IU) or omega-3 fatty acids (Omacor fish oil, 1 gram) could reduce the risk for developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses. Participants were randomized to receive either vitamin D with an omega-3 fatty acid supplement; vitamin D with a placebo; omega-3 fatty acid with a placebo; or placebo only. Prior to the launch of VITAL, investigators determined that they would also look at rates of AD among participants, as part of an ancillary study.
“Given the benefits of vitamin D and omega-3s for reducing inflammation, we were particularly interested in whether they could protect against autoimmune diseases,” said JoAnn Manson, co-author and director of the parent VITAL trial at the Brigham.
Participants answered questionnaires about new diagnoses of diseases, including rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and inflammatory bowel disease, with space to write in all other new onset ADs. Trained physicians reviewed patients’ medical records to confirm reported diagnoses.
“Autoimmune diseases are common in older adults and negatively affect health and life expectancy. Until now, we have had no proven way of preventing them, and now, for the first time, we do,” said first author, Jill Hahn, a postdoctoral fellow at the Brigham. “It would be exciting if we could go on to verify the same preventive effects in younger individuals.”
Among patients who were randomized to receive vitamin D, 123 participants in the treatment group and 155 in the placebo group were diagnosed with confirmed AD (22 percent reduction). Among those in the fatty acid arm, confirmed AD occurred in 130 participants in the treatment group and 148 in the placebo group. Supplementation with omega-3 fatty acids alone did not significantly lower incidence of AD, but the study did find evidence of an increased effect after longer duration of supplementation.
The VITAL study included a large and diverse sample of participants, but all participants were older and results may not be generalizable to younger individuals who experience AD earlier in life. The trial also only tested one dose and one formulation of each supplement. The researchers note that longer follow-up may be more informative to assess whether the effects are long-lasting.
This study was funded by the National Institutes of Health grants R01 AR059086, U01 CA138962, R01 CA138962.
Vitamin E
Vitamin E refers to a family of several compounds that possess a similar chemical structure comprising a chromanol ring with a 16-carbon side chain. The degree of saturation of the side chain, and positions and nature of methyl groups designate the compounds as tocopherols or tocotrienols. Vitamin E compounds have antioxidant properties due to a hydroxyl group on the chromanol ring. Recently, it has been suggested that vitamin E may also regulate signal transduction and gene expression. We previously reported that lifelong dietary vitamin E (alpha-tocopherol) supplementation significantly increased median lifespan in C57BL/6 mice by 15%. This lifespan extension appeared to be independent of any antioxidant effect. Employing a transcriptional approach, we suggest that this increase in lifespan may reflect an anti-cancer effect via induction of the P21 signalling pathway, since cancer is the major cause of death in small rodents. We suggest that the role of this pathway in life span extension following supplementation of vitamin E now requires further investigation.
Selenium regulates thyroid hormones and works together with Vitamin E to reduce free radicals generated in the cell.
Selenium, similar to vitamin E, helps in cellular functions by protecting cell membranes, proteins, and DNA from oxidation consequently keeping inflammation in check.
Alpha-linolenic Acid
Alpha-linolenic acid is thought to decrease the risk of heart disease by helping to maintain normal heart rhythm and pumping. It might also reduce blood clots.
Alpha-linolenic acid (ALA) is an essential omega-3 fatty acid found in walnuts, flaxseed oil, soy, sunflower oil. It is necessary for normal human growth and development.
Alpha-linolenic acid is thought to decrease the risk of heart disease by helping to maintain normal heart rhythm and pumping. It might also reduce blood clots.
Alpha-linolenic acid is most commonly used for diseases of the heart and blood vessels, such as hardening of the arteries, heart disease, and high blood pressure. It is also used for other conditions, but there is no good scientific evidence to support most of these uses.
Oats excellent for fiber are also a source of healthy omega-3 fatty acids, containing a total of 0.17 grams for every cup. It contains significant amounts of alpha linoleic acid. Also a good source of omega-6 fatty acids, every cup of oats contain a total of 3.8 grams of omega-6.
Walnuts are a great anti-aging food because of the amount of omega-3s in just a handful. These omega-3 fatty acids are real longevity tools. They fight off heart disease by improving your cholesterol. 2 Make walnuts part of your day, every day.
Leaner bodies, less heart disease and diabetes risk in people with higher levels of linoleic acid
Alpha-lipoic acid and NAD, Reclaim the Energy
Speaking of cellular energy, lipoic acid is a crucial nutrient for “cellular energy maintenance,” aka keeping your mitochondria pumping and your cells chugging along—all while avoiding the speedbumps caused by cellular stress.
The thing is, there are two forms of lipoic acid: R and S. For simplicity’s sake, we’ll just say that it is the R form of lipoic acid that is biologically active in your body—it’s the better of the two for fighting off those pesky free-radicals. A special R-Lipoic Acid formula achieves much higher blood levels of lipoic acid than traditional supplements—which is why it’s one of our most popular anti-aging products.
What about if you’re not just trying to proactively keep your energy levels up—you’re enmeshed in a bitter fight with general fatigue…the kind that you need to have more than a few decades under your belt to be familiar with. This is not the time to turn to your coffee cup—the effects of caffeine are short-lived and may not be all that good for you in the long run. Instead, turn to nicotinamide riboside, an alternative form of vitamin B3 that fights general fatigue, promotes longevity and supports youthful energy production at the cellular level.
There’s a coenzyme in every cell called nicotinamide adenine dinucleotide (or NAD+). It also helps create ATP, the compound that your body uses for cellular energy (and production of which declines over time). So if you’ve ever felt like you don’t have the energy you used to, you’re probably right!
Curcumin, Comfortable Movement
Inhibiting inflammation to support whole-body health is important—especially as you get older. You want to encourage a healthy inflammatory response…like when you were younger.
Curcumin is a compound found in extracts of the spice turmeric that is famous for its health properties. The main reason for curcumin’s reputation is its ability to inhibit inflammatory factors to support joint and vital organ health. Healthy joints are more comfortable and allow for better mobility as you age—and why you want to keep your vital organs healthy is pretty self-explanatory.
CoQ10, for Vital Organs
Odds are you’ve heard of CoQ10—an antioxidant produced naturally by your body. Unfortunately, levels of CoQ10 decline with age. And this is a problem, because CoQ10 is a vital component for the biological process that turns nutrients from the food you eat into ATP, the main compound that your cells use for energy.
While commonly (and correctly) associated with heart health, CoQ10’s status as a cellular-energy helper means it is crucial for all of the high-energy organs in your body (think brain, liver and kidneys). But once again, which CoQ10 supplement to take comes down to absorption…or this nutrient’s troubling lack thereof.
Traditional CoQ10 supplements are made with ubiquinone, an already-oxidized form of CoQ10 that is difficult for your body to absorb. Ubiquinol is different. This unoxidized form of CoQ10 absorbs up to seven times better than standard ubiquinone…which means your heart and energy-demanding cells get more of it.
A word on absorption: getting CoQ10 into your cells is the other challenge. Choose an ubiquinol supplement augmented with shilajit, a mineral-like compound that promotes cellular CoQ10 absorption by stabilizing it in its ubiquinol form. And if you’re really getting up there in years, consider one with PQQ as well—this nutrient encourages the growth of new mitochondria (to help maintain healthy metabolic function).
L-Ergothionine, Cellular Level Health
When we say “stay healthy”, we tend to think about our heart, mind and joints. But all of your body’s moving and non-moving parts have one thing in common: they’re made up of cells. And cells can age just like the rest of you. To prevent this from happening too quickly, your body is rife with a special amino acid called L-ergothionine. We can’t make it ourselves, so we must get it from the foods we eat (white button mushrooms are packed with L-ergothionine, for instance).
Here’s the interesting part: we all have highly specialized mechanisms for getting L-ergothionine into our cells. If this special amino acid wasn’t vital to our vitals, that pathway simply wouldn’t be there. Scientists think that ergothionine is so important because it helps fight oxidation at the cellular level. Oxidative stress is one of the key underlying factors of normal aging—and egothionine levels decrease as you age.
Lithium, Brain and Telomeres Health
Lithium is a trace mineral that has been used for decades at high doses for healthy mood support. At lower doses, however, lithium has a different benefit: brain health. Your brain naturally produces certain proteins, some of which can accumulate and affect brain health as you age.
Lithium has the ability to encourage your mind’s natural biological processes for clearing those proteins, making way for healthy brain function. What’s more, emerging evidence points to lithium as a longevity nutrient in its own right—and it has to do with your DNA.
Each of your chromosomes is tipped by a protective cap called a telomere. Every time your DNA replicates itself, however, those telomeres get ever-so-slightly shorter. This process is considered to be a major hallmark of aging. When they get too short, they can’t fulfill their primary function—protecting your delicate DNA—as effectively.
Research has observed that some people on long-term, high-dose lithium regimens have longer-than-expected telomeres—which could lead to longer lifespans. In fact, one study also found that lower doses of lithium found in tap water were associated with longer lifespan. Speak to a healthcare professional and decide the dose of lithium that is right for your needs!
References
Campisi, Judith et al. “Cellular senescence: when bad things happen to good cells.” Nature Reviews Molecular Cell Biology, September 2007, https://www.nature.com/articles/nrm2233
Higdon, Jane, Ph.D. “Lipoic Acid.” Oregon State University, 2002, https://lpi.oregonstate.edu/mic/dietary-factors/lipoic-acid
Kaeberlein, Matt. “How healthy is the healthspan concept?” GeroScience, August 2018, https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6136295/
Mehmel, Mario et al. “Nicotinamide Riboside— The Current State of Research and Therapeutic Uses.” Nutrients, June 2020, https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7352172/
Squassina, Alessio et al. “Leukocyte telomere length positively correlates with duration of lithium treatment in bipolar disorder patients.” Eur Neuropsychopharmacol, April 2016, https://pubmed.ncbi.nlm.nih.gov/27084304/
Ratini, Melinda, DO, MS. “Coenzyme Q10: CoQ10.” WebMD, April 2021, https://www.webmd.com/diet/supplement-guide-coenzymeq10-coq10#1
“Curcumin.” PubChem, https://pubchem.ncbi.nlm.nih.gov/compound/Curcumin
Magnesium
Magnesium treatment improved mitochondrial ATP synthesis, and thus greater ATP availability, which is necessary for cellular energy supply and survival. Consistently, magnesium treatment improved mice longevity and reduced vascular calcification.
Most people don’t get nearly enough magnesium from their diet.
In the U.S., approximately 65% of all adults have below optimal intake of magnesium.11,12 That number gets even higher in older age, with more than 80% of people over 71 consuming inadequate amounts of magnesium.
Over time, this leads to magnesium deficiency, which contributes to many chronic conditions including cardiovascular disease and age-related loss of cognitive function.
Magnesium is a critically important mineral required for the function of hundreds of enzymes in the human body, making it essential for nearly 80% of our metabolic reactions.
In the brain, magnesium is needed for the proper functioning of synapses involved in complex tasks such as learning and memory.
A large majority of the population suffers from inadequate magnesium intake. Because most magnesium supplements are poorly absorbed and do not enter the brain in sufficient quantities, fixing this problem has been difficult.
Scallops, cooked
100 grams
8
44
Prunes, dried
100 grams
10
41
Potato, baked
1 medium
39
Rice, brown and wild
100 grams
1/2 cup
37
Salmon, cooked
100 grams
1/3 fillet
37
Pollock, cooked
100 grams
1 large fillet
37
Soy milk
1 cup
36
Lentils, cooked
100 grams
1/2 cup
36
Oysters, steamed
100 grams
3 pacific oysters or 8 eastern oysters
36
Rockfish, cooked
100 grams
2/3 fillet
33
Kale
100 grams
5 cups
33
Bulgur, cooked
100 grams
1/2 cup
32
Bananas
1 medium
31.9
Yogurt, plain
1 cup
29.4
Halibut, cooked
100 grams
1/3 fillet
28
Broccoli, raw
100 grams
1 cup
21
Omega 3
According to the National Institutes of Health (NIH)
Omega-3 is one of the two main types of polyunsaturated fatty acids. These acids, which contribute to forming cell membranes, are considered “essential” since the body cannot make them on its own.
The NIH says that omega-3s “provide energy for the body and are used to form eicosanoids,” which affect the body’s cardiovascular, pulmonary, immune, and endocrine systems.
There are three primary types of omega-3 fatty acids: alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid (DHA). People commonly take DHA supplements during pregnancy, as they can help with fetal development.
Aside from supplements, some sources of omega-3s include:
flaxseed oil
soybeans
canola oil
certain fish, including salmon, tuna, and sardines
chia seeds
Quercetin, fisetin and theaflavins from black tea each have their individual benefits, but we are enamored with the longevity benefits of these nutrients when they’re combined. Why? The answer is senescent cells. These old cells get to a point where they no longer function as optimally as younger cells—and can rain on the parades of nearby cells that are still going strong—a natural phenomenon called “cellular senescence”.
Theaflavin compounds from black tea as well as quercetin and fisetin are particularly good at helping your body clear senescent cells, so your body can function like it did when it was younger. The best part: if you combine these senolytics (senolytics are nutrients that help remove senescent cells to promote levels of youthful cells) you only have to take it once a week!
There’s a compound found in red grapes called resveratrol. It helps fight oxidizing free radicals that can affect everything from your skin to your heart at the cellular level.
More importantly, resveratrol is adept at getting your body to mimic the health-benefits of a calorie-restricted diet. These difficult-to-maintain dietary regimens have shown results in supporting lifespan…and a resveratrol supplement can help you achieve similar results, without counting calories from now until your last breath.
Taurine
What is taurine?
Taurine is a nonproteinogenic (it is not incorporated into proteins during translation) sulfur-containing beta-amino acid that is omnipresent in the body and is particularly abundant in electrically excitable tissues such as the heart, retina, brain, and skeletal muscle.
A small amount of taurine is produced in the liver from the metabolism of cysteine (which is derived from the essential amino acid methionine). Taurine can also be obtained directly from certain foods like beef and dark meat poultry, but most abundantly from shellfish such as scallops and mussels.
Taurine is considered a conditionally essential nutrient.
Zinc
Zinc plays a key role in more than 300 enzymes and it is involved in cell communication, proliferation, differentiation and survival. Zinc plays also a role in regulating the immune system with implications in pathologies where zinc deficiency and inflammation are observed.
Ageing and a low life expectancy are caused, at least partly, by oxidative stress. A team of researchers led by Prof. Dr. Ivana Ivanovi-Burmazovi from the Chair of Bioinorganic Chemistry at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), together with researchers from the USA, have discovered that zinc can activate an organic molecule, helping to protect against oxidative stress.
Zinc is a trace mineral we need in order to remain healthy. FAU researchers working together with Prof. Dr. Christian Goldsmith from Auburn University, Alabama, USA, have discovered that zinc can protect against the superoxide responsible for oxidative stress when taken together with a component found in foodstuffs such as wine, coffee, tea and chocolate. This component is a hydroquinone group found in polyphenols, in other words the plant substances responsible for smell and taste. Zinc activates the hydroquinone groups, producing natural protection against superoxide, a by-product of human cell respiration which damages the body's own biomolecules, for example proteins or lipids, as well as the human genome. Superoxide is thought to have a role to play in the ageing process and a number of illnesses such as inflammation, cancer or neurodegenerative diseases.
New metal complex against superoxide
Hydroquinone alone is not capable of breaking down superoxide. If zinc and hydroquinone combine, however, a metal complex is created which imitates a superoxide dismutase enzyme (SOD). These enzymes protect the body from the degradation processes caused by oxidation and have an antioxidative effect. In this way, the superoxide can be metabolised and damage to the organism prevented; oxidative stress is avoided.
Chocolate, coffee, tea, with added zinc
For the first time, the function of this enzyme has been copied without reverting to redox-active transition metals such as manganese, iron, copper or nickel. Whilst the metals could also have an antioxidative effect, any positive effects are quickly outweighed by the fact that if too much is taken they can even cause oxidative stress to increase. Zinc is much less toxic than the transition metals mentioned above, making it possible for new medication or supplements to be created with considerably fewer side-effects. It would also be plausible to add zinc to food which contains hydroquinone naturally to boost the consumer's health. 'It is certainly possible that wine, coffee, tea or chocolate may well become be available in future with added zinc. However, any alcohol content whatsoever would destroy the positive effects of this combination,' emphasises Ivana Ivanovi-Burmazovi.
Story Source:
Materials provided by University of Erlangen-Nuremberg. Note: Content may be edited for style and length.
Journal Reference:
Meghan B. Ward, Andreas Scheitler, Meng Yu, Laura Senft, Annika S. Zillmann, John D. Gorden, Dean D. Schwartz, Ivana Ivanović-Burmazović, Christian R. Goldsmith. Superoxide dismutase activity enabled by a redox-active ligand rather than metal. Nature Chemistry, 2018; DOI: 10.1038/s41557-018-0137-1