Received: 15 September 2016; Accepted: 9 November 2016; Published: date
Abstract: The potential protective roles of folate and the metabolically related B-vitamins (vitamins B12, B6 and riboflavin) in diseases of ageing are of increasing research interest. The most common cause of folate and riboflavin deficiencies in older people is low dietary intake, whereas low B12 status is primarily associated with food-bound malabsorption, while sub-optimal vitamin B6 status is attributed to increased requirements in ageing. Observational evidence links low status of folate and the related B-vitamins (and/or elevated concentrations of homocysteine) with a higher risk of degenerative diseases including cardiovascular disease (CVD), cognitive dysfunction and osteoporosis. Deficient or low status of these B-vitamins alone or in combination with genetic polymorphisms, including the common MTHFR 677 C → T polymorphism,could contribute to greater disease risk in ageing by causing perturbations in one carbon metabolism. Moreover, interventions with the relevant B-vitamins to optimise status may have beneficial effects in preventing degenerative diseases. The precise mechanisms are unknown but many have been proposed involving the role of folate and the related B-vitamins as co-factors for one-carbon transfer reactions, which are fundamental for DNA and RNA biosynthesis and the maintenance of methylation reactions. This review will examine the evidence linking folate and related B-vitamins with health and disease in ageing, associated mechanisms and public health implications.
An estimated 900 million people are aged ≥65 years globally, equating with 8% of the world’s population, and by 2050, this is predicted to exceed two billion (16%) . Approximately one quarter of the total global burden of disease is in older people, with a higher prevalence in high income countries . Hypertension, the leading risk factor of cardiovascular disease (CVD) affects an estimated one billion people worldwide and CVD is the most common cause of death in older people . Globally, osteoporotic fractures affect over nine million older people annually , while 46.8 million older people are reported to have dementia worldwide . The prevalence of these diseases of ageing is expected to substantially increase as a result of the ever-increasing ageing population. In addition, these degenerative diseases cause multiple co-morbidities in older people which in turn has important societal and economic consequences. Maintaining good health in older age has therefore become a major public health priority. Poor nutrition is recognised as a modifiable risk factor in the development of degenerative diseases in ageing, and improved nutrition may prevent or delay the onset of adverse health outcomes as people age. In this context, the potential adverse effect of elevated homocysteine and/or the protective roles of folate and the metabolically related B-vitamins (B12 and B6), have received much attention.
This review will examine the emerging evidence linking folate and the metabolically related B-vitamins with ageing, the potential roles of these nutrients in preventing or delaying diseases of ageing and the associated mechanisms. The challenges and opportunities in achieving optimal B-vitamin status in older people will also be considered with particular emphasis on the role of food fortification.
2. Metabolic Role of B-Vitamins in One-Carbon Metabolism
Folate along with vitamins B12, B6 and riboflavin in their co-enzymatic forms are all essential in one-carbon metabolism (Figure 1), a network of reactions involving the transfer of one-carbon units. In the folate cycle, tetrahydrofolate obtains a carbon unit from serine in a vitamin B6 (plasma pyridoxal phosphate; PLP) dependent reaction forming 5,10-methylenetetrahydrofolate which is used for the synthesis of thymidine and purines or converted to 5-methyltetrahydrofolate. 5-methyltetrahydrofolate is the principal circulating form of folate, and this reaction is catalysed by methylenetetrahydrofolate reductase (MTHFR) using riboflavin (flavin adenine dinucleotide, FAD) as a co-factor. At this point, the folate cycle links with the methionine cycle, 5-methyltetrahydrofolate donates its methyl group to homocysteine for the formation of methionine in a reaction catalysed by methionine synthase which uses vitamin B12 (methylcobalamin) as a cofactor. Methionine is the precursor for S-adenosyl-methionine (SAM), the universal methyl donor for DNA and RNA, proteins and numerous central nervous system methylation reactions involving neurotransmitters, membrane phospholipid synthesis and myelin methylation [6,7]. SAM is converted to S-adenosylhomocysteine and then homocysteine which is either remethylated back to methionine or conversely metabolised in the transsulphuration pathway to form cysteine through another vitamin B6-dependent process . The metabolism of the B-vitamins is closely related; folate and vitamin B12 are both intrinsically linked via the enzyme methionine synthase . In vitamin B12 depletion, methionine synthase activity is reduced and the formation of tetrahydrofolate is blocked, with folate essentially becoming trapped as 5-methyltetrahydrofolate because the conversion by MTHFR is physiologically irreversible . There is also an important metabolic inter-relationship between vitamin B6 and riboflavin. The conversion of dietary vitamin B6 in tissues to its functional enzyme, pyridoxal 5′ phosphate (PLP), requires the enzyme pyridoxine phosphate oxidase (PPO), which is dependent on the riboflavin in its co-factor form, flavin mononucleotide (FMN).
Deficiencies in any of these B-vitamins can perturb the complex regulatory network maintaining one-carbon metabolism resulting in reduced methylation status within the relevant tissue, hyperhomocysteinemia, and/or increased misincorporation of uracil into DNA as a result of thymidylate synthesis being impaired owing to low 5,10-methylene-THF concentrations and thus uracil is inserted instead during DNA synthesis which in turn may contribute to adverse health outcomes in ageing [11,12]. In addition, genetic polymorphisms, including the common 677 C → T polymorphism in the gene encoding the folate-metabolising enzyme MTHFR, can interact adversely with sub-optimal status of one or more of the B-vitamins in one-carbon metabolism and thus contribute to a greater disease risk . The MTHFR 677TT genotype affects an estimated 10% of individuals worldwide (ranging from 3% to 32% depending on ethnicity)  and 12% in Ireland .