Computational modelling folate metabolism and DNA methylation: implications for understanding health and ageing

Dietary folates have a key role to play in health, as deficiencies in the intake of these B vitamins have been implicated in a wide variety of clinical conditions. The reason for this is folates function as single carbon donors in the synthesis of methio- nine and nucleotides. Moreover, folates have a vital role to play in the epigenetics of mammalian cells by supplying methyl groups for DNA methylation reactions. Intriguingly, a growing body of experimental evidence suggests that DNA methyla- tion status could be a central modulator of the ageing process. This has important health implications because the methyla- tion status of the human genome could be used to infer age-related disease risk. Thus, it is imperative we further our understanding of the processes which underpin DNA methylation and how these intersect with folate metabolism and age- ing. The biochemical and molecular mechanisms, which underpin these processes, are complex. However, computational modelling offers an ideal framework for handling this complexity. A number of computational models have been assembled over the years, but to date, no model has represented the full scope of the interaction between the folate cycle and the reactions, which governs the DNA methylation cycle. In this review, we will discuss several of the models, which have been developed to represent these systems. In addition, we will present a rationale for developing a combined model of folate metabolism and the DNA methylation cycle.