Vitamin K health benefits have been recently widely shown to extend beyond blood homeostasis and implicated in chronic low-grade inflammatory diseases such as cardiovascular disease, osteoarthritis, dementia, cognitive impairment, mobility disability, and frailty. Novel and more efficient nutritional and therapeutic options are urgently needed to lower the burden and the associated health care costs of these age-related diseases. Naturally occurring vitamin K comprise the phylloquinone (vitamin K1), and a series of menaquinones broadly designated as vitamin K2 that differ in source, absorption rates, tissue distribution, bioavailability, and target activity. Although vitamin K1 and K2 sources are mainly dietary, consumer preference for diet supplements is growing, especially when derived from marine resources. The aim of this review is to update the reader regarding the specific contribution and effect of each K1 and K2 vitamers in human health, identify potential methods for its sustainable and cost-efficient production, and novel natural sources of vitamin K and formulations to improve absorption and bioavailability. This new information will contribute to foster the use of vitamin K as a health-promoting supplement, which meets the increasing consumer demand. Simultaneously, relevant information on the clinical context and direct health consequences of vitamin K deficiency focusing in aging and age-related diseases will be discussed.

Chronic kidney disease (CKD) is one of the most powerful predictors of premature cardiovascular disease (CVD), with heightened susceptibility to vascular intimal and medial calcification associated with a high cardiovascular mortality. Abnormal mineral metabolism of calcium (Ca) and phosphate (P) and underlying (dys)regulated hormonal control in CKD-mineral and bone disorder (MBD) is often accompanied by bone loss and increased vascular calcification (VC). While VC is known to be a multifactorial process and a major risk factor for CVD, the view of primary triggers and molecular mechanisms complexity has been shifting with novel scientific knowledge over the last years. In this review we highlight the importance of calcium-phosphate (CaP) mineral crystals in VC with an integrated view over the complexity of CKD, while discuss past and recent literature aiming to highlight novel horizons on this major health burden. Exacerbated VC in CKD patients might result from several interconnected mechanisms involving abnormal mineral metabolism, dysregulation of endogenous calcification inhibitors and inflammatory pathways, which function in a feedback loop driving disease progression and cardiovascular outcomes. We propose that novel approaches targeting simultaneously VC and inflammation might represent valuable new prognostic tools and targets for therapeutics and management of cardiovascular risk in the CKD population.

Vitamin K is a multifunctional micronutrient implicated in age-related diseases such as cardiovascular diseases, osteoarthritis and osteoporosis. Although vitamin K-dependent proteins (VKDPs) are described to have a crucial role in the pathogenesis of these diseases, novel roles have emerged for vitamin K, independently of its role in VKDPs carboxylation. Vitamin K has been shown to act as an anti-inflammatory by suppressing nuclear factor κB (NF-κB) signal transduction and to exert a protective effect against oxidative stress by blocking the generation of reactive oxygen species. Available clinical evidences indicate that a high vitamin K status can exert a protective role in the inflammatory and mineralization processes associated with the onset and progression of age-related diseases. Also, vitamin K involvement as a protective super-micronutrient in aging and ‘inflammaging’ is arising, highlighting its future use in clinical practice. In this review we summarize current knowledge regarding clinical data on vitamin K in skeletal and cardiovascular health, and discuss the potential of vitamin K supplementation as a health benefit. We describe the clinical evidence and explore molecular aspects of vitamin K protective role in aging and age-related diseases, and its involvement as a modulator in the interplay between pathological calcification and inflammation processes.

Chronic kidney disease (CKD) patients have a higher risk of developing early cardiovascular disease (CVD). Although vascular calcification (VC) is one of the strongest predictors of CVD risk, its diagnosis among the CKD population remains a serious clinical challenge. This is mainly due to the complexity of VC, which results from various interconnected pathological mechanisms occurring at early stages and at multiples sites, affecting the medial and intimal layers of the vascular tree. Here, we review the most used and recently developed imaging techniques, here referred to as imaging biomarkers, for VC detection and monitoring, while discussing their strengths and limitations considering the specificities of VC in a CKD context. Although imaging biomarkers have a crucial role in the diagnosis of VC, with important insights into CVD risk, circulating biomarkers represent an added value by reflecting the molecular dynamics and mechanisms involved in VC pathophysiological pathways, opening new avenues into the early detection and targeted interventions. We propose that a combined strategy using imaging and circulating biomarkers with a role in multiple VC molecular mechanisms, such as Fetuin-A, Matrix Gla protein, Gla-rich protein and calciprotein particles, should represent high prognostic value for management of CVD risk in the CKD population.

Introduction: Gla rich protein (GRP) is a vitamin K dependent protein, shown to function as an inhibitor of pathological calcification and as an anti-inflammatory agent, with potential therapeutic use for age-related diseases such as osteoarthritis (OA) [1,2]. OA is a leading cause of disability and morbidity in the older population and constitutes a major worldwide challenge for our health system. Presently, there are no drugs approved that can prevent, stop, or even restrain progression of OA. GRP has been shown to be able to lower inflammation and mineralisation processes in the articular tissue. Chitosan/tripolyphosphate (TPP) nanoparticles were selected for this study due to their biocompatibility, biodegradability and capacity to overcome the problem of low solubility of GRP in physiological conditions. This study aims to produce and characterise chitosan/TPP nanoparticles as GRP-delivery vehicles and test its anti-inflammatory potential in human macrophages. S23 ANNALS OF MEDICINEMaterials and methods: Nanoparticles of fluorescein-labelled chitosan/TPP with and without GRP (NG and NP, respectively) were prepared by ionic gelation [3]. Resulting NP and NG were characterised by dynamic light scattering, transmission electron microscopy (TEM) and flow cytometry. The anti-inflammatory activity of NP and NG was assessed in THP-1 cells differentiated to macrophages. Mac-THP-1 cells were pre-treated with both NP and NG, followed by LPS stimulation. Cell viability was assessed by the MTS cell proliferation assay, and levels of TNFa released to cell culture media were determined by ELISA. Results: The average size determined for NG was increased relatively to the NP, while flow cytometry and TEM analysis indicate the presence of GRP in NG, suggesting an effective incorporation of human recombinant GRP. Flow cytometry studies confirmed the cellular uptake of nanoparticles by macrophages. The GRP-loaded nanoparticles were able to reduce the production of TNFa in LPS-stimulated macrophages. Discussion and conclusions: The results confirm that chitosan/TPP nanoparticles are excellent drug delivery vehicles for GRP in macrophages and predict a wider therapeutic application in chronic inflammation-related diseases. GRP-containing nanoparticles will be further used in OA functional assays and the results will bring new knowledge on the role of GRP in the interplay between inflammation and mineralisation events associated with OA.