Diet and genome health

Authors


We all start our life's journey at conception in our mother's womb as a single cell that contains the genetic code mainly in the nucleus but also a tiny but significant fraction within the mitochondria. The capacity of this cell to divide and develop into a normal embryo depends on the integrity of the genome contributed by the father and mother, nutritional cofactors required for DNA synthesis and repair and the absence/presence of environmental (chemicals/radiation) or lifestyle (alcohol/drugs) genotoxins within the placental blood supply. Successful replication of DNA with high fidelity is essential for normal development, successful reproduction and healthy ageing because a variety of genetic mutations (e.g. base damage, deletions of gene sequences, chromosome rearrangements or abnormal chromosome number) can lead to aberrant cellular phenotype, organ dysfunction, cancer and/or accelerated ageing.[1] This is particularly important because it is evident from prospective epidemiological studies that the risk for infertility, developmental defects, cancer, cardiovascular and other age-related degenerative diseases increases as the DNA damage burden in human populations rises.[1-5] The age-related burden of genome damage is, to a large extent, due to the cumulative effect of metabolic defects, poor dietary and lifestyle choices and environments that are toxic to the genome.[6] I shall focus solely on the nutritional requirements for DNA synthesis and repair to maintain genome integrity or so-called ‘genome health’ because it is now evident that strategies for disease prevention need to consider more carefully damage to DNA because it is the most fundamental pathology. Furthermore, there is a continuous need to accurately replicate cells and their genetic material throughout all life stages. The cells we have today are merely copies of ones we had a few days, weeks or months ago (depending on the turnover rate of each tissue) and the extent to which they are genetically good copies depends to a large extent on nutrition, which provides the cofactors and substrates essential for nucleotide synthesis, DNA replication and repair.

Over the past few decades, several powerful techniques have been developed to measure DNA damage caused by environmental and lifestyle genotoxins such as ionising radiation, pesticides, cigarette smoke, alcohol and its carcinogenic metabolite acetaldehyde. These same techniques, including others focussing on deletions to the telomere ends of chromosomes and mitochondrial DNA, are now being used to study the effects of nutritional deficiency or excess on genome integrity in humans.[7] In fact, one of the best validated techniques for studying the effects of nutrition on DNA damage induction or prevention was discovered several decades ago by haematologists and shown in the 1960s to be caused by deficiency of folate and/or vitamin B12.[8-10] This biomarker, originally described as the ‘Howell–Jolly body’, is known as a micronucleus, which is caused by chromosome fragmentation or defective chromosome separation during mitosis.[11] The chromosome fragments and malsegregated chromosomes are enveloped in their own nuclear membrane forming a small nucleus alongside the larger nucleus within a cell hence the term ‘micronucleus’. In the 1970s, it was also observed that children with protein calorie deficiency have significantly higher chromosome damage than well-nourished children providing a possible molecular genetic explanation for the developmental defects associated with this macronutrient deficiency condition.[12]

Specific nutrient deficiencies can affect different aspects of DNA metabolism. For example, folate deficiency causes defects in nucleotide synthesis, particularly thymidine synthesis, resulting in the accumulation of its precursor uridine and replacement of thymidine by uracil in DNA, which is highly mutagenic; this effect is further exacerbated by deficiency of vitamin B12 and/or B6, which are required to convert folate to a form necessary for thymidine synthesis[13] Furthermore, minerals such as magnesium and zinc are essential as cofactors for the activity of DNA polymerases involved in DNA replication and repair.[14, 15] Zinc is also critical as an integral part of the structure of the hOGG1 zinc finger protein involved in the repair of oxidised guanine one of the most common DNA lesions caused by oxidative stress.[16] Other mineral nutrients involved in the function of antioxidant enzymes, such as selenium, manganese and copper, also play an important role in preventing damage to the genome occurring in the first place.[14, 15] Another important aspect is the role of nutrition in supplying methyl donors such as folate, vitamin B12, choline and methionine for maintenance of the 5-methylcytosine epigenetic mark on DNA that determines genes expression.[13, 17] More recently, research in nutrient–nutrient interactive effects and nutrient–gene interactions has become a focus of personalised nutrition research to optimise nutritional requirements for DNA replication and repair.[18] The various roles and mechanisms of micronutrients in genome maintenance have been recently reviewed in detail in a special issue of Mutation Research.[19]

An important aspect that has emerged is the concept that dietary reference values (DRVs) should take into consideration scientific evidence on the effects of nutrients (micro- and macro-) on genome integrity because this is ultimately the most fundamental pathology in cells and organs.[20, 21] In addition, it is particularly important when determining not only the effects of deficiency but also excess because DNA damage can occur under both conditions and the optimal concentration window for genome stability can be either narrow or wide depending on the nutrient. A roadmap for defining DRVs for DNA damage prevention has been recently described based on using a combination of the best validated DNA damage biomarkers at the chromosomal, telomere and mitochondrial DNA level.[7] Using for example this approach, it was possible to show that DNA damage in lymphocytes in human adults is minimised when folate and vitamin B12 intake is >400μg/day and >2.0μg/day, respectively, to achieve a serum B12 concentration >300ρmol/L and homocysteine <7.5μmol/L.[13] Furthermore, because some of the DNA damage techniques used are also internationally accepted standards for studying the harmful effects of ionising radiation (e.g. lymphocyte cytokinesis-block micronucleus assay) it is possible to show that the DNA damaging effects of nutritional deficiency or excess within the physiological range can sometimes be as high as that induced by doses of radiation considered unsafe for the general population.[7]

Research on dietary patterns associated with reduced DNA damage has revealed important new knowledge. A comparison of DNA damage levels between healthy vegetarians and non-vegetarians showed no difference between groups except for a tendency for increased DNA damage in non-vegetarian middle-aged adults and in young vegetarian males who became vitamin B12 deficient.[22] More recently, evidence has also emerged for reduced oxidative DNA damage with nutritionally balanced caloric restriction diets and also with the Mediterranean diet as compared with the Western diet.[23-26] Results from a cross-sectional study showed that chromosomal DNA damage tends to be minimised for diets that are naturally rich in folate, vitamin B12, niacin, vitamin E, carotenoids and calcium.[27]

Finally, it is important to note that there is growing interest in translating this knowledge into practice via the Genome Health Clinic (GHC) concept as a component of integrative preventive and anti-ageing medicine.[7, 28] The GHC is based on diagnosis of DNA damage using the best validated DNA damage biomarkers, and their reference values to classify results, together with personalised nutritional and/or lifestyle intervention, based on the highest level of evidence available, to optimise genome integrity. When appropriate, consideration of genotype information may be useful to guide recommendations and/or data interpretation. Such GHC services are now becoming available in Australia and internationally (e.g. http://www.reach100.com.au/; http://www.telomehealth.com/). In addition DNA damage biomarkers are also important to use in other dietetic and clinical practices to verify that therapies used do not cause unintended harm at the genome level.

Ancillary