Over the last 25 years roles have been established for vitamin D receptor (VDR) in influencing cell proliferation and differentiation. For example, murine knock-out approaches have revealed a role for the VDR in controlling mammary gland growth and function. These actions appear widespread, as the enzymes responsible for 1α,25-dihydroxycholecalciferol generation and degradation, and the VDR itself, are all functionally present in a wide range of epithelial and haematopoietic cell types. These findings, combined with epidemiological and functional data, support the concept that local, autocrine and paracrine VDR signalling exerts control over cell-fate decisions in multiple cell types. Furthermore, the recent identification of bile acid lithocholic acid as a VDR ligand underscores the environmental sensing role for the VDR. In vitro and in vivo dissection of VDR signalling in cancers (e.g. breast, prostate and colon) supports a role for targeting the VDR in either chemoprevention or chemotherapy settings. As with other potential therapeutics, it has become clear that cancer cells display de novo and acquired genetic and epigenetic mechanisms of resistance to these actions. Consequently, a range of experimental and clinical options are being developed to bring about more targeted actions, overcome resistance and enhance the efficacy of VDR-centred therapeutics.

The prevalence of obesity, defined as a BMI of ≥30·0 kg/m2, has increased substantially over previous decades to about 20% in industrialized countries, and a further increase is expected in the future. Epidemiological studies have shown that obesity is a risk factor for: post-menopausal breast cancer; cancers of the endometrium, colon and kidney; malignant adenomas of the oesophagus. Obese subjects have an approximately 1·5–3·5-fold increased risk of developing these cancers compared with normal-weight subjects, and it has been estimated that between 15 and 45% of these cancers can be attributed to overweight (BMI 25·0–29·9 kg/m2) and obesity in Europe. More recent studies suggest that obesity may also increase the risk of other types of cancer, including pancreatic, hepatic and gallbladder cancer. The underlying mechanisms for the increased cancer risk as a result of obesity are unclear and may vary by cancer site and also depend on the distribution of body fat. Thus, abdominal obesity as defined by waist circumference or waist:hip ratio has been shown to be more strongly related to certain cancer types than obesity as defined by BMI. Possible mechanisms that relate obesity to cancer risk include insulin resistance and resultant chronic hyperinsulinaemia, increased production of insulin-like growth factors or increased bioavailability of steroid hormones. Recent research also suggests that adipose tissue-derived hormones and cytokines (adipokines), such as leptin, adiponectin and inflammatory markers, may reflect mechanisms linked to tumourigenesis.

It is becoming increasingly evident that (a) risk for developmental and degenerative disease increases with more DNA damage, which in turn is dependent on nutritional status, and (b) the optimal concentration of micronutrients for prevention of genome damage is also dependent on genetic polymorphisms that alter the function of genes involved directly or indirectly in the uptake and metabolism of micronutrients required for DNA repair and DNA replication. The development of dietary patterns, functional foods and supplements that are designed to improve genome-health maintenance in individuals with specific genetic backgrounds may provide an important contribution to an optimum health strategy based on the diagnosis and individualised nutritional prevention of genome damage, i.e. genome health clinics. The present review summarises some of the recent knowledge relating to micronutrients that are associated with chromosomal stability and provides some initial insights into the likely nutritional factors that may be expected to have an impact on the maintenance of telomeres. It is evident that developing effective strategies for defining nutrient doses and combinations or ‘nutriomes’ for genome-health maintenance at the individual level is essential for further progress in this research field.

The assay features of biochemical markers of bone turnover have markedly improved in the past few years. The most sensitive and specific markers of bone formation include serum bone alkaline phosphatase, total osteocalcin (including the intact molecule and the large N-mid fragment) and the procollagen type I N-terminal propeptide assay. Among the various markers of bone resorption, measurements of the urinary excretion of N- and C-terminal cross-linked telopeptides) and of serum C-terminal cross-linked telopeptides are the most sensitive and specific. Markers of bone turnover can be used to predict the rate of bone loss in post-menopausal women and can also be used to assess the risk of fractures. In osteoporosis-treatment studies (with alendronate, risedronate, raloxifene) markers of bone turnover appear even more strongly associated with fracture risk reduction than bone mineral density (BMD). These observations support the use of markers of bone turnover as surrogates for fracture risk reduction, perhaps even more so than BMD. Bone markers can also be used to monitor the efficacy of antiresorptive therapy such as hormone-replacement therapy, raloxifene and bisphosphonates in individual patients. Furthermore, they have also proved to be helpful in monitoring the response to nutritional interventions and have the advantage over BMD in that they provide information about mechanism of effect and changes are often observed much more rapidly.

Throughout the life cycle the skeleton requires optimum development and maintenance of its integrity to prevent fracture. Bones break because the loads placed on them exceed the ability of the bone to absorb the energy involved. It is now estimated that one in three women and one in twelve men aged >55 years will suffer from osteoporosis in their lifetime and at a cost in the UK of >£1·7×109 per year. The pathogenesis of osteoporosis is multifactorial. Both the development of peak bone mass and the rate of bone loss are determined by key endogenous and exogenous factors. Ca supplements appear to be effective in reducing bone loss in women late post menopause (>5 years post menopause), particularly in those with low habitual Ca intake (<400 mg/d). In women early post menopause (<5 years post menopause) who are not vitamin D deficient, Ca supplementation has little effect on bone mineral density. However, supplementation with vitamin D and Ca has been shown to reduce fracture rates in the institutionalised elderly, but there remains controversy as to whether supplementation is effective in reducing fracture in free-living populations. Re-defining vitamin D requirements in the UK is needed since there is evidence of extensive hypovitaminosis D in the UK. Low vitamin D status is associated with an increased risk of falling and a variety of other health outcomes and is an area that requires urgent attention. The role of other micronutrients on bone remains to be fully defined, although there are promising data in the literature for a clear link between vitamin K nutrition and skeletal integrity, including fracture reduction.

Outlined are two main current research concerns relating to skeletal disorders in poultry: (a) osteoporosis in egg-laying hens; (b) leg problems caused by rapid bone growth in broiler chickens. Surveys indicate that 30% of caged laying hens suffer at least one lifetime fracture (a severe welfare issue). Modern hybrids produce one egg per d for 50 weeks. For this period ‘normal’ bone turnover ceases; only medullary bone (MB) is formed, a woven bone type of limited structural value. MB is resorbed for eggshell formation alongside structural bone, leading to increased fracture risk. Avian osteoporosis is reduced by activity and genetic selection but nutrition is also important. Fluoride and vitamin K are beneficial but the timing of nutritional intervention is important. Ca, inorganic P and vitamin D must be adequate and the form of Ca is critical. Limestone fed as particulates benefits skeletal and eggshell quality. In hens fed particulate limestone compared with flour-fed hens the tibiotarsus breaking strength and radiographic density are increased at 56 weeks of age (P<0·01 and P<0·001 respectively) and the number of tartrate-resistant acid phosphatase-positive stained active osteoclasts (mean number per microscopic field) is decreased (P<0·001). In broiler (meat) chickens selection for rapid growth from approximately 50 g to 3 kg in 42 d has inadvertently produced skeletal disorders such as tibial dyschondroplasia, rickets and associated valgus–varus deformities leading to lameness. The beneficial skeletal effects during growth of increased dietary n-3 PUFA:n-6 PUFA (utilising salmon oil) have been demonstrated. Experiments simulating daylight UVB levels have produced beneficial skeletal effects in Ca- and vitamin D-deficient chicks.

As oestrogen deficiency is the main cause in the pathogenesis of osteoporosis hormone-replacement therapy remains the mainstay for prevention. However, prophylaxis by hormone-replacement therapy is limited. Phyto-oestrogens, which are weakly-oestrogenic compounds present in plants, deserve particular mention because emerging data support the suggestion that they may prevent bone loss associated with the menopause. In the past few years extensive research using animal models has provided convincing data to indicate a significant improvement in bone mass or other end points following feeding with soyabean. Moreover, observational studies relate the lower incidence of osteoporosis among women in the Eastern world to a diet rich in phyto-oestrogens. However, it is not valid to extrapolate to the Western situation. The varied clinical trials that have been published suggest that isoflavones reduce bone loss in women in the early period post menopause, but a definitive result requires more investigations of the effect of phyto-oestrogens on bone health that have substantial sample size and are of long duration. In addition, the clinical efficacy of soya foods in preventing osteopenia depends on their intestinal metabolism. Thus, phyto-oestrogens are a source for putative innovative dietary health intervention for post-menopausal women. However, more data are necessary, particularly in relation to their effect on the risk of fracture.

Osteoporosis is a major public health problem, and as life expectancy and the world's population continue to increase will become even more important. Thus, there is an urgent need to develop and implement nutritional approaches and policies for the prevention and treatment of osteoporosis. Patients with some chronic inflammatory diseases appear to be more likely to develop osteopenia, and in some cases earlier in life, which is of particular concern as the incidence of inflammatory diseases in the Western world is increasing. While the cause of bone loss in patients with inflammatory disease is multifactorial, nutrition may have a role. Many of these patients may have one or more nutritional deficiencies, which can lead to altered rates of bone metabolism. On the other hand, some nutritional factors may attenuate the inflammatory process itself, and thus may indirectly benefit bone metabolism and bone health in patients with inflammatory disease. The present review will consider these issues, particularly in the context of inflammatory bowel disease, coeliac diease and atherosclerosis.

CVD is a common killer in both the Western world and the developing world. It is a multifactorial disease that is influenced by many environmental and genetic factors. Although public health advice to date has been principally in the form of prescribed population-based recommendations, this approach has been surprisingly unsuccessful in reducing CVD risk. This outcome may be explained, in part, by the extreme variability in response to dietary manipulations between individuals and interactions between diet and an individual's genetic background, which are defined by the term ‘nutrigenetics’. The shift towards personalised nutritional advice is a very attractive proposition. In principle an individual could be genotyped and given dietary advice specifically tailored to their genetic make-up. Evidence-based research into interactions between fixed genetic variants, nutrient intake and biomarkers of CVD risk is increasing, but still limited. The present paper will review the evidence for interactions between dietary fat and three common polymorphisms in the apoE, apoAI and PPARγ genes. Increased knowledge of how these and other genes influence dietary response should increase the understanding of personalised nutrition. While targeted dietary advice may have considerable potential for reducing CVD risk, the ethical issues associated with its routine use need careful consideration.

The involvement of free radicals and reactive oxygen and nitrogen species in the pathology of inflammatory and degenerative disease has been widely accepted, although the centrality of these species to the outcome of these diseases is still a matter for debate. In the case of CVD, and particularly the development of the atherosclerotic plaque, the oxidation of LDL is of particular importance and appears to explain many of the events that occur during the life history of the plaque. The corollary of this situation is that antioxidants must be a benign force to protect the population from the modern scourge of heart disease. In fact, recent evidence from intervention studies with large doses of the antioxidant vitamins and other antioxidants in foods has been very disappointing. Here, the background for the belief that antioxidants ought to be beneficial is examined and an attempt made to explain why the results of these intervention studies have been unsuccessful. It is agreed that a diet rich in fruit and vegetables is protective for both CVD and cancer, but the explanation for this effect may not necessarily lie with the presence of antioxidants.

Morphological and immunocytochemical studies have elucidated the complex processes involved in atherogenesis. The notion of plaque instability has emerged from this work and underscored the importance of inflammation in determining clinical complications associated with atherosclerosis, such as acute coronary syndrome. Cells of the immune system have been detected within atherosclerotic lesions and auto-antibodies directed against modified LDL and heat-shock proteins have been identified in the blood of individuals with atherosclerosis. The use of risk ‘engines’, e.g. the Framingham coronary risk score, has facilitated the identification of individuals at high risk, but the constituent classical risk factors used in these algorithms do not adequately differentiate individuals at moderate risk. As age is a major component of the equations used in these algorithms they are not particularly useful in young adults, and their applicability to non-Caucasian populations has been questioned. Biomarkers of early disease and plaque instability have therefore both been sought. Although some of these markers have been shown individually to be associated with a significant hazard ratio, no substantial improvement in discrimination has been demonstrated when they are incorporated into a risk ‘engine’. The latter has generally been assessed by receiver operator characteristic curve analysis, although this approach has been criticised. Other modalities, including imaging and functional assessments of vascular function, are now being developed for clinical use.

There is considerable interest in plasma homocysteine (tHcy) as a CVD risk factor. Although the secondary prevention trials published to date have been inconclusive in confirming a benefit of tHcy-lowering treatment with B-vitamins on CVD events generally, such studies are widely recognised to have been insufficiently powered to detect a significant effect for the predicted magnitude of association between tHcy and heart disease risk, and therefore cannot be interpreted as evidence that no relationship exists. In fact, a recent meta-analysis of clinical trials has confirmed that folic acid supplementation reduces the risk of stroke, particularly in individuals without a history of stroke. Evidence supporting a causal relationship between elevated tHcy and heart disease also comes from genetic studies. The most important genetic determinant of tHcy in the general population is the common C677T variant in methylenetetrahydrofolate reductase (MTHFR) that results in higher tHcy. Individuals with the homozygous mutant (TT) genotype have a significantly higher (14–21%) risk of heart disease. Plasma tHcy is very responsive to intervention with the B-vitamins required for its metabolism, in particular folic acid, and to a lesser extent vitamins B12 and B6. Thus, although primarily aimed at reducing neural-tube defects, folic acid fortification may have an important role in the primary prevention of CVD via tHcy lowering. Besides folate, riboflavin is required as a cofactor for MTHFR and enhanced riboflavin status results in a marked lowering in tHcy specifically in individuals with the TT genotype, presumably by neutralising the variant form of the enzyme. About 10% of the UK and Irish populations have the TT genotype. In the present paper the potential role of folate and related B-vitamins in the primary prevention of CVD and the implications for nutrition policy are explored.

Emerging evidence suggests that dietary-derived flavonoids have the potential to improve human memory and neuro-cognitive performance via their ability to protect vulnerable neurons, enhance existing neuronal function and stimulate neuronal regeneration. Long-term potentiation (LTP) is widely considered to be one of the major mechanisms underlying memory acquisition, consolidation and storage in the brain and is known to be controlled at the molecular level by the activation of a number of neuronal signalling pathways. These pathways include the phosphatidylinositol-3 kinase/protein kinase B/Akt (Akt), protein kinase C, protein kinase A, Ca–calmodulin kinase and mitogen-activated protein kinase pathways. Growing evidence suggests that flavonoids exert effects on LTP, and consequently memory and cognitive performance, through their interactions with these signalling pathways. Of particular interest is the ability of flavonoids to activate the extracellular signal-regulated kinase and the Akt signalling pathways leading to the activation of the cAMP-response element-binding protein, a transcription factor responsible for increasing the expression of a number of neurotrophins important in LTP and long-term memory. One such neurotrophin is brain-derived neurotrophic factor, which is known to be crucial in controlling synapse growth, in promoting an increase in dendritic spine density and in enhancing synaptic receptor density. The present review explores the potential of flavonoids and their metabolite forms to promote memory and learning through their interactions with neuronal signalling pathways pivotal in controlling LTP and memory in human subjects.