Editorial: Vitamin D: from pathophysiology to clinical impact

Beyond its well-established role as a key factor in calcium and phosphate homeostasis and bone health maintenance, vitamin D has been recognized as a key determinant for many extraskeletal targets (1). Indeed, while the calcium ion itself is involved in a large number of cellular and metabolic pathways, vitamin D interacts (negatively or positively) with hundreds of genes, which greatly expands its spectrum of action (2). In particular, the numerous non-classical effects of vitamin D include the regulation of cellular proliferation, differentiation, apoptosis, and immunity (3). Accordingly, a variety of conditions, including but not limited to infections, diabetes, cardiovascular and neurodegenerative diseases and cancer, all of which are of public health concern, have been found to be related to reduced 25(OH)D levels (4). This fact is also important in light of the fact that hypovitaminosis D, which is generally considered to be present when 25(OH)D values—the most reliable serum biomarker of vitamin D status—are < 75 nmol/L (30 ng/ml), is prevalent worldwide, especially among the poor, dark-skinned individuals, children and the elderly along with obese subjects. Levels of 25(OH)D are affected by the environment (especially seasonal variation, geographical latitude, and sun exposure), to a lesser extent by diet (food and supplementation), and also by one's own genetic background (1).

The manuscripts included in this Research Topic contribute to the ongoing debate on the determinants of vitamin D status, the effects of inappropriate vitamin D levels on many extraskeletal conditions and overall and specific mortality, along with supplementation issues (Table 1). Because diet is only a minor source of vitamin D (few foods provide significant amounts of vitamin D), supplementation is an easy and low-cost strategy to restore adequate 25(OH)D levels and reduce the risk of adverse health outcomes, and one contribution to this Research Topic evidenced comparable efficacy of intermittent vs. cumulative vitamin D supplementation in improving 25(OH)D concentrations (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 an instrumental variable to assess the association with specific outcomes of interest (Table 1) (5).

It is true that at present it has not been definitively proven that vitamin D has an effective causal role in many human pathophysiological conditions or that low vitamin D is only an epiphenomenon, given the controversial aspects that remain to be resolved (e.g. limited sample sizes, differences in ethnicity, variations in vitamin D dosage, adopted reference limits for defining inadequate levels of vitamin D, and unmeasured confounding factors) and the underlying mechanisms by which vitamin D may affect so many biological processes that remain largely to be better understood. Nonetheless, given the widespread involvement of vitamin D in key biological processes, it seems biased to think of vitamin D only as a marker of disease. However, the question remains: how can the suboptimal global distribution of a single vitamin cause the risk of so many diseases? The triage theory, proposed by Ames in 2006, offers a mechanistic explanation for the relationship between chronic and even moderate deficiency of a micronutrient, such as vitamin D, and 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). Indeed, in the case of a reduced intake of micronutrients, this theory proposes that micronutrients may be shifted for short-term survival to maintain pathways critical for life, at the expense of other, less essential processes, but which insidiously increase the risk of developing chronic degenerative conditions in the long term. And why can one person's risk for a particular disease be higher than another's? Vitamin D is not the only micronutrient that matters; more than 30 vitamins and essential minerals/elements have been identified as critical factors in reducing the risk of onset and development of chronic degenerative diseases and in extending life expectancy and quality. In addition to vitamin D, other essential vitamins include A, B (e.g. B1, B2, B3, B6, B9, B12), C, E, K, and minerals/elements such 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 combination of micronutrients generates a profile that may mark the fate of the 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” and allow enormous savings in healthcare spending. In recent years, the complexity of the effects derived from the modulation of these dietary biomarkers and the discovery of possible further key determinants can be confronted 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 this field will allow us to identify critical pathways and biomarkers and to develop individualized patterns for dietary responses in a new approach that will be helpful to expand future beneficial and sustainable nutritional strategies to safeguard health and reduce the risk of disease, modulated to the real individual needs of each subject.

The wide variety of article types, methodologies, and designs of the studies included in this Research Topic evidences the interest and the potential impact of this topic on future healthcare and personalized preventive medicine, and it underlies the need for further efforts to expand our knowledge and overcome all the gaps and challenges that still exist in this research area.

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