Phase 4 Pharmaceutical AgeForce R&D Div.

B-vitamins are a group of water-soluble vitamins that play important roles in cell metabolism. Despite structural differences, though, the B-vitamis work in concert for our health.

• Thiamin (B1) plays a central role in the generation of energy from carbohydrates. It is involved in RNA and DNA production, as well as nerve function. Its active form is a coenzyme called thiamin pyrophosphate (TPP), which takes part in the conversion of pyruvate to acetyl coenzyme A (CoA) in metabolism.

• Riboflavin (B2) is involved in the energy production for the electron transport chain, the citric acid cycle, as well as the catabolism of fatty acids (beta oxidation)

• Niacin (B3) is composed of two structures: nicotinic acid and nicotinamide. There are two co-enzyme forms of niacin: nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Both play an important role in energy transfer reactions in the metabolism of glucose, fat and alcohol.

• Pantothenic acid (B5) is involved in the oxidation of fatty acids and carbohydrates. Coenzyme A, which can be synthesised from pantothenic acid, is involved in the synthesis of amino acids, fatty acids, ketones, cholesterol, phospholipids, steroid hormones, neurotransmitters (such as acetylcholine), and antibodies.

• Pyridoxin (B6) or rather its active form pyridoxal 5'-phosphate (PLP) (depicted) serves as a cofactor in many enzyme reactions mainly in amino acid metabolism including biosynthesis of neurotransmitters.

• Biotin (B7) plays a key role in the metabolism of lipids, proteins and carbohydrates. It is a critical co-enzyme of four carboxylases: acetyl CoA carboxylase, which is involved in the synthesis of fatty acids from acetate; propionyl CoA carboxylase, involved in gluconeogenesis; β-methylcrotonyl CoA carboxylase, involved in the metabolism of leucin; and pyruvate CoA carboxylase, which is involved in the metabolism of energy, amino acids and cholesterol.

• Folic acid (B9) acts as a co-enzyme in the form of tetrahydrofolate (THF), which is involved in the transfer of single-carbon units in the metabolism of nucleic acids and amino acids. THF is involved in pyrimidine nucleotide synthesis, so is needed for normal cell division, especially during pregnancy and infancy, which are times of rapid growth. Folate also aids in erythropoiesis, the production of red blood cells.

• Cobalamine (B12) is involved in the cellular metabolism of carbohydrates, proteins and lipids. It is essential in the production of blood cells in bone marrow, and for nerve sheaths and proteins. Vitamin B12 functions as a co-enzyme in intermediary metabolism for the methionine synthase reaction with methylcobalamin, and the methylmalonyl CoA mutase reaction with adenosylcobalamin.

As the above list shows, all of the b-vitamins are of fundamental importance for our health. Yet while back in the days specifically niacin, biotin and other vitamins that have been scarce in the diet of the people living during the Industrial Revolution have been at the center of the attention, Folic acid (B7), pyridoxine (B6) and the various cobalamines (B12) have recently been the B-vitamins that got the most attention from scientists. No wonder, B6, B7 and B12 are after all of fundamental importance for normal brain and nervous system function.

B-Vitamins, Cognition and Brain Function

Like no other organ group, our brain and central nervous system depends critically on a sufficient supply of folate (folic acid), vitamin B12 (cobalamin) and B6 (pyridoxine). These B-vitamins are involved in a plethora of critical metabolic processes in the brain (Alpert. 1997; Bottiglieri 1996). As Eva Calvaresi and Janet Bryan (2014) point out in their review of the role of B-vitamins in cognition and aging:

• "Research to date indicates two interlinked neurochemical mechanisms by which folate, with Vitamins B12 or B6 as catalyzing cofactors, exerts an influence on cognitive performance and mood via its role in methylation in the CNS. It could be hypothesized that the B vitamins effect CNS function in two interrelated ways: a direct, and possibly acute influence via hypomethylation, and a more indirect, longer term influence on homocysteine levels resulting in structural changes in the." (Calvaresi. 2001)

In this context, specifically the so-called "hypomethylation hypothesis", which proposes that folate, B12, and B6 have direct effects on the functioning of the brain through their role in the one-carbon cycle, has gotten a lot of scientific attention. According to the hypomethylation hypothesis, a lack of folate can lead to a malfunction of the methylation cycle by inhibiting the synthesis of methionine and the powerful antioxidant SAMe. The subsequent malfunction of membrane phospholipids, DNA, the metabolism of neurotransmitters such as the monoamines dopamine, norepinephrine, and serotonin, as well as an impaired production of melatonin will then significantly impair the neurological and psychological function of the brain (Alpert. 1997; Bottiglieri. 1996; Bottiglieri. 1995; Fenech. 1998).

Against that background it is not surprising that Fioravanti et al. (1997) are not the only researchers who report that the provision of folate vitamin B6, or vitamin B12 will have significant beneficial effects on the cognitive performance of subjects with low dietary intakes of this group of important "B(rain)-vitamins" (see Figure 2).

For quite some time now, scientists have been speculating that even the debilitating cognitive decline in Alzheimer's patients could be caused or at least related to a lack of certain B-vitamins. Experimental evidence to support this hypothesis is still scarce, but one of the latest overviews of the research presents cites roughly three dozen of epidemiological studies, which confirm that Alzheimer's patients have lower folate, vitamin B12, B6, and B1 (thiamine) levels than age-matched healthy peers (Mohajeri. 2014). It is thus likely that a sufficient supply of these important vitamins will at least lower your risk of developing Alzheimer's disease and similar neurological pathologies.

An inadequate intake of B-vitamins is not the problem for most of us

In this context, it is important to remark that that the same review ny Mohajeri et al. (2014) also indicates that the majority of elderly US citizens consume more than adequate amounts of these vitamins from dietary and supplemental sources. The fact that still so many of our parents and grandparents have low or insufficient serum and cellular B12, B6 and folate levels can thus hardly be the consequence of a mere lack of dietary intake and/or oral supplement use. Rather than that, the low levels of folate, B6 and, most prominently, the ever-increasing number of older individuals with low levels of vitamin B12 (cobalamine) is a result of an age-induced decrease in digestive function.

Andrs et al. report in their 2004 review of the literature (Andrs. 2004) that food-cobalamin malabsorption syndrome is by far the most frequent reason of cobalamine deficiency.

More specifically, this means that ,ore than 60% of the cases of cobalamine deficiency are a consequence of the low bioavailbility of orally consumed vitamin B12 from foods and supplements. Against that backround it is not astonishing that specialized medical practitioners have stopped giving their vitamin B12 deficient patients oral B12 preparations and resort to injectable B12 formulas, nasal sprays or transdermals, instead.

Stage of cobalamin metabolism	Cause of cobalamin deficiency
Intake solely through food	Strict vegetarianism without vitamin supplementation
Digestion brings into play haptocorrin, gastric secretions (HCl and pepsin), intrinsic factor, pancreatic and biliary secretions, enterohepatic cycle	Gastrectomy; pernicious anemia (Biermers disease); food cobalamin malabsorption; gastric bypass surgery
Absorption brings into play intrinsic factor and cubilin	Ileal resection; malabsorption; pernicious anemia; Imerslund syndrome
Transport by transcobalamins	Congenital deficiency in transcobalamin II
Intracellular metabolism based on various intracellular enzymes	Congenital deficiency in variousintracellular enzymes

Table 1: Various factors can trigger vitamin B12 deficiency: An insufficient dietary intake (as in vegans), vitamin malabsorption and/or an insufficient / incomplete metabolism of the vitamin precursors in the diet (Andrs. 2004).

And in fact, several recent studies appear to confirm that vitamin B12 injections, nasal sprays (Rozgony. 2010) and transdermal patches (Yang. 2011; Madhaiyan. 2013; Salimi. 2013) are alternative ways to administer vitamin B12 that promise greater success than conventional oral cyano- or methylcobalamine preparations (Stabler. 2013).

Better patched than sorry - The transdermal advantage

The AgeForce vitamin B complex patch offers a safe, highly effective alternative to vitamin B12 pills and capsules that is particularly valuable for older people, men and women with digestive disorders, gastric bypass patients, vegans and other groups that are at high risk of vitamin B12 deficiency.

Despite the fact that the benefits are probably most striking for vitamin B12, cobolamine (B12) is by far the only B-vitamin from the B-complex with higher transdermal vs. oral bioavailability. For men and women with increased B12 requirements like athletes (Manore. 2000), people who are trying to lose weight on an energy reduced diet and men and women who are following an otherwise restrictive or one-sided diet will benefit from the advanced bioavailability of the full-spectrum of B-vitamins in the AgeForce B-Vitamin patch.

The patch will provide a steady supply of all nine B-vitamins that will be available to all cells of your body without having to take the detour via your digestive tract, through the liver and into the circulation. By ensuring a continuous supply of optimal amount of all B-vitamins the AgeForce B-vitamin patch will thus help you to avoid the following B-vitamin deficiency symptoms:

• Abnormal blood sugar, depression, fatigue, low, adrenals, nausea, vomiting, gastrointestinal disorders, which are common side effects of low thiamine (B1) deficiency

• Abnormal light sensitivity, cracks / inflammation of lips,tongue, corners of mouth, dizziness, insomnia, which are common side effects of riboflavin (B2) deficiency

• Nausea, vomiting, loss of appetite, fatigue, swollen red tongue, and dermatitis, which are commonly reported side effects of low niacin / nicotinamide (B3) levels

• Insomnia, joint pains, gouty arthritis, edema,kidney stones, abd burning feet, which can occur in men and women with low panthotenic acid (B5) levels

• Mental disorders, seborrheic dermatitis, PMS, dizziness, insomnia, irritability, kidney stones, abnormal electroencephalogram (EEG), anemia, convulsions, edema (water retention), hypothyroidism, and migraine-headaches which have all been associated with a lack of pyridoxine (B6)

• Skin disorders, hair loss, brittle nails, anemia, seborrheic dermatitis in infants, depression, fatigue, nausea, loss of appetite, muscular pains increased total cholesterol levels, and hypoglycemia which have been reported in patients with biotin (B7) deficiency

• Hemolytic and megaloblasticanemia, low energy, abnormal fetal development (neural tube defect), higher homocysteine levels / vascular degeneration, mental disorders, confusion, forgetfulness, insomnia, irritability, depression, cervical dysplasia, higher risk to develop some cancers, and high blood pressure which have been reported to be consequences of low folate (B9) levels

• Pernicious anemia, numbness and tingling in hands and feet / nerve damage, shortness of breath, severe fatigue, birth defects, dementia, confusion, poor memory, depression, reduced white blood cell and platelet formation, loss of appetite, weight loss, sore tongue, headaches, and nausea as they have been observed in patients with low vitamin B12 levels

That's quite an number of benefits for a single patch, right? You are right, but if you consider the number of vital nutrients the AgeForce B-vitamin patch contains, it's not really surprising that its benefits range from "A" as in "anemia (low red blood cell count) prevention" over "B" as in "blood sugar and pressure abnormalities" and "C" as in "cancer preventionto "Z" as in "zits", which can be all over your face as a result of B-vitamin deficiencies as well.

References:

Alpert, Jonathan E., and Maurizio Fava. "Nutrition and depression: the role of folate." Nutrition Reviews 55.5 (1997): 145-149.

Andrs, Emmanuel, et al. "Vitamin B12 (cobalamin) deficiency in elderly patients." Canadian Medical Association Journal 171.3 (2004): 251-259.

Bottiglieri, T. E. O. D. O. R. O., RICHARD F. Crellin, and EDWARD H. Reynolds. "Folate and neuropsychiatry." Folate in health and disease 1995 (1995): 435-462.

Bottiglieri, Teodoro. "Folate, vitamin B12, and neuropsychiatric disorders." Nutrition reviews 54.12 (1996): 382-390.

Calvaresi, Eva, and Janet Bryan. "B Vitamins, Cognition, and Aging A Review." The Journals of Gerontology Series B: Psychological Sciences and Social Sciences 56.6 (2001): P327-P339.

Fenech, Michael, Clare Aitken, and Josephine Rinaldi. "Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults." Carcinogenesis 19.7 (1998): 1163-1171.

Fioravanti, M., et al. "Low folate levels in the cognitive decline of elderly patients and the efficacy of folate as a treatment for improving memory deficits." Archives of gerontology and geriatrics 26.1 (1997): 1-13.

Herrmann, Markus, et al. "Altered vitamin B12 status in recreational endurance athletes." International journal of sport nutrition and exercise metabolism 15.4 (2005): 433-441.

Madhaiyan, Kalaipriya, et al. "Vitamin B< sub> 12 loaded polycaprolactone nanofibers: A novel transdermal route for the water soluble energy supplement delivery." International journal of pharmaceutics 444.1 (2013): 70-76.

Manore, Melinda M. "Effect of physical activity on thiamine, riboflavin, and vitamin B-6 requirements." The American journal of clinical nutrition 72.2 (2000): 598s-606s.

Mohajeri, M. Hasan, Barbara Troesch, and Peter Weber. "Inadequate supply of vitamins and DHA in the elderly: implications for brain aging and Alzheimers type dementia." Nutrition (2014).

Rozgony, Nancy R., et al. "Vitamin B12 Deficiency is Linked with Long-Term Use of Proton Pump Inhibitors in Institutionalized Older Adults: Could a Cyanocobalamin Nasal Spray be Beneficial?." Journal of Nutrition for the Elderly 29.1 (2010): 87-99.

Salimi, Anayatollah, Behzad Sharif Makhmal Zadeh, and Eskandar Moghimipour. "Preparation and Characterization of Cyanocobalamin (Vit B12) Microemulsion Properties and Structure for Topical and Transdermal Application." Iranian journal of basic medical sciences 16.7 (2013): 865.

Stabler, Sally P. "Vitamin B12 deficiency." New England Journal of Medicine 368.2 (2013): 149-160.

Yang, Ye, Haripriya Kalluri, and Ajay K. Banga. "Effects of Chemical and Physical Enhancement Techniques on Transdermal Delivery of Cyanocobalamin (Vitamin B12) In Vitro." Pharmaceutics 3.3 (2011): 474-484.