Vitamin D: From Pathophysiology to Clinical Impact

Cristina Vassalle ^*

• Gabriele Monasterio Tuscany Foundation (CNR), Pisa, Italy

important also in view to the fact that hypovitaminosis D, generally considered for values of 25(OH)D-the most reliable serum biomarker of vitamin D status-less than 75 nmol/L (30 ng/mL), is prevalent worldwide, especially between poor people, dark individuals, children and elderly as well as obese subjects, whereas levels of 25(OH)D are affected by environment (especially seasonal variation, geographical latitude, and sun exposure), to a lesser extent by nutrition (diet and supplementation), and also by one's own genetic background (1).Manuscripts included in this special issue make a contribution to the ongoing debate discussing determinants of vitamin D status, the effects of inappropriate vitamin D levels on many extraskeletal conditions as well as on overall and specific mortality, and supplementation issues (see Table 1). In fact, as the diet is only a small vitamin D source (few foods provide significant amount of vitamin D), supplementation is one easy and low-cost strategy to restore adequate 25(OH)D levels and reduce the risk of adverse consequences for health, and one contribution of the special issue evidenced comparable efficacy of intermittent versus cumulative vitamin D supplementation in improving 25(OH)D concentration (Table 1). Moreover, the genetic causal association between some diseases and the circulating levels of vitamin D was investigated in some contributions through Mendelian randomization, a methodology that uses genetic variation as instrumental variables to assess the association with specific outcomes of interest (Table 1) (5).It is true that, at now, it has not yet been definitively proven the effective causal role of vitamin D in many human pathophysiological conditions or whether low vitamin D is only an epiphenomenon in view of the controversial aspects still to clear (e.g. limited sample sizes, differences in ethnicity, variations in vitamin D dosage, adopted reference limits to define inadequate levels of vitamin D, and unmeasured confounding factors) as well as the underlying mechanisms by which vitamin D may affect so many biological processes remain largely to be better understood. Nonetheless, given the widespread involvement of vitamin D in key biological processes, it seems prejudicial to think about vitamin D as only a marker of disease. However, a question arises: why can the suboptimal worldwide spread of a single vitamin cause a risk of so many diseases? The triage theory, proposed by Ames in 2006, gives a mechanistic explanation of the relationship between a chronic and also moderate shortage of a micronutrient, including vitamin D, with multiple chronic degenerative conditions related to aging, such as neurodegenerative and cardiometabolic diseases and cancer, in terms of a "triage" response to micronutrient undersupply (6). In fact, in case of a reduced intake of micronutrients, this theory proposed that micronutrients might be shifted for short-term survival to sustain pathways critical for life, at the expense of other processes less essential, but which increases the risk of developing chronic degenerative conditions in the long-term, in an insidious way.And why can the risk of a certain disease be higher for one individual than for another? Vitamin D is not the only micronutrient to matter; more than 30 vitamins and essential minerals/elements have been identified as critical factors to reduce the risk of the onset and development of chronic degenerative diseases, extending life expectancy and quality. Beyond vitamin D, other vitamins as A, B (e.g. B1, B2, B3, B6, B9, B12), C, E, K, and minerals/elements as calcium, chloride, iodine, iron, manganese, magnesium, phosphorus, potassium, selenium, sodium, and zinc; other key biomarkers may still be unknown or neglected (2). It is possible that the reduced micronutrient combination generates a profile that can mark the fate of development of a certain pathophysiological condition over another one. Accordingly, maintaining/restoring adequate levels of these factors could be a pillar of " personalized preventive medicine" as well as allow enormous savings in healthcare spending. In recent years, complexity of effects derived by the modulation of these nutrition biomarkers and the discovery of possible further key determinants may be faced with the development of large-scale technologies that allow the simultaneous acquisition of transcriptome, epigenome, proteome, and metabolome data that can be merged (e.g.omics data integration, network analysis, and machine learning). However, the challenge always remains great, requiring multiple skills and expertise in metabolism, nutrition, biochemistry and regulatory functions and collaboration between different professionals in basic and clinical areas. Moreover, translating research data into clinical applications and policy will not be simple; the achievement of this target will represent one of the biggest challenges of biological and medical research in the next few years. Nonetheless, the many recent advances and efforts in the field will allow us to identify critical pathways and biomarkers and develop individualized patterns for dietary responses in a new approach helpful to expand future beneficial and sustainable nutrition strategies to safeguard health and reduce the risk of diseases, modulated to the real individual need of each subject.The great difference of the article types, methodology, and design of the studies included in this special issue evidence the interest and the potential impact of this topic on future healthcare and personalized preventive medicine, also underlying the need for further efforts to expand our knowledge and overcome all gaps and challenges still existing in this research area.