Encyclopedia
Vitamin K is a vital cofactor in activating several proteins, which act against age-related syndromes. Thus, vitamin K can carboxylate osteocalcin (a protein capable of transporting and fixing calcium in bone), activate matrix Gla protein (an inhibitor of vascular calcification and cardiovascular events) and carboxylate Gas6 protein (involved in brain physiology and a cognitive decline and neurodegenerative disease inhibitor). By improving insulin sensitivity, vitamin K lowers diabetes risk. It also exerts antiproliferative, proapoptotic, autophagic effects and has been associated with a reduced risk of cancer. Recent research shows that protein S, another vitamin K-dependent protein, can prevent the cytokine storm observed in COVID-19 cases. The reduced activation of protein S due to the pneumonia-induced vitamin K depletion was correlated with higher thrombogenicity and possibly fatal outcomes in COVID-19 patients.
- vitamin K
- phylloquinone
- menaquinone
- menadione
- osteocalcin
- matrix Gla protein
- bone health
- COVID-19
- osteoporosis
- vascular calcification
1. Introduction
Aging is a multifactorial process that gradually deteriorates the physiological functions of various organs, including the brain, musculoskeletal, cardiovascular, metabolic, and immune system leading to numerous pathological conditions with high rates of morbidity and mortality. Oxidative stress (OS) and chronic inflammation are fundamental pathophysiological mechanisms in the aging progression [1][2][3].
As human life expectancy is rising, age-related diseases will increase as well. Recent studies validated the importance of modifiable lifestyle factors, diet included, in the attenuation of pathological changes in mature adults [4]. Healthy fats, vitamins, minerals, polyphenolics, with antioxidant and anti-inflammatory activity, can increase the quality of life and influence the aging process, and among these factors, vitamin K (VK) has an important part [5].
VK is known for its role in synthesizing some blood-clotting proteins (K for koagulation in German). VK represents a fat-soluble family of compounds with a common chemical structure, a 2-methyl-1,4-naphthoquinone ring and a variable aliphatic side-chain. The variable aliphatic chain differentiates two isoforms: vitamin K1 (VK1) or phylloquinone (PK) and vitamin K2 (VK2), usually designated as menaquinone (MK). MK exists in multiple structures, which are distinguished by the number of isoprenyl units and saturation in the side-chain (MK-n, where n is the number of isoprenyl units) [6]. These acronyms were used interchangeably throughout this article. The most common subtypes in humans are the short-chain MK-4, which is the only MK produced by systemic conversion of phylloquinone to menaquinone, and MK-7 through MK-10, which are synthesized by bacteria. VK3 (menadione), without side-chain and classified as a pro-vitamin, is a synthetic form of this vitamin (Figure 1).
Figure 1. Vitamin K chemical structures. Vitamins K1 (VK1), K2 (VK2), and K3 (VK3) share the naphthoquinone ring; VK1 has a phytyl side-chain; VK2 has a side-chain with a varying number of isoprenyl units; VK3 has no side-chain.
Dark green leafy vegetables are the main sources for dietary PK (e.g., collards, turnip, broccoli, spinach, kale), 70–700 μg/100 g, as well as several fruits (e.g., dried prunes, kiwifruit, avocado, blueberries, blackberries, grapes), 15–70 μg/100 g, and some nuts (pine nuts, cashews, pistachios), 10–75 μg/100 g [7][8]. In contrast, the main sources of VK2 are fermented foods, cheeses, eggs, and meats (Table 1) [9][10].
Table 1.
| Food Category | Food Source | VK2 * |
|---|
| Fermented foods | Natto Sauerkraut |
850–1000 (90% MK-7, 8% MK-8) 5.5 (31% MK-6, 23% MK-9, 17% MK-5 and -8) |
| Hard cheeses | 50–80 (15–67% MK-9, 6–22% MK-4, 6–22% MK-8) | |
| Soft cheeses | 30–60 (20–70% MK-9, 6–20% MK-4, 6–20% MK-8) | |
| Eggs | Yolk | 15–30 (MK-4) |
| Meats | Pork, beef, chicken | 1.4–10 (MK-4) |
*—μg/100 g food sample; MK-n—menaquinone.
2. Relationship between Vitamin K and Age-Associated Diseases
The latest scientific evidence indicated that VK has a significant role in mitigating aging and preventing age-related diseases and has the potential to improve the efficacy of some medical treatments among adults over the age of 50 years. The novel role of VK on aging and age-associated diseases is mainly due to its antioxidant and anti-inflammatory effects. It focused on the most prevalent age-related diseases, including osteoporosis and bone fractures, neurodegenerative diseases, VC, CVD, and cancer, as well as metabolic disorders, mainly T2D and obesity. In addition, we presented the most recent findings on the association between VK and COVID-19 and its potential effect on reducing fatal outcomes in such cases. Specifically, the scientific data showed that VK has an integral role in bone metabolism through the carboxylation of OC, which is an important protein capable of transporting and depositing calcium in bone. MK-4 was revealed to be a more effective antiosteoporotic agent than VK1, with increased pro-osteoblastic and anti-osteoclastogenic actions achieved by inhibiting the NF-кB pathway. VitD improves OC carboxylation and, along with VK and magnesium supplementations, can be a better strategy for reducing bone fractures, a highly public health concern among the elderly. In addition, it is concluded that VK supplement could be a safe approach for reducing CVD morbidity and mortality. By activating matrix Gla protein, VK keeps calcium from accumulating in the walls of blood vessels, thus making VK a potential treatment for patients at risk for either VC or CVD. Furthermore, VK may reduce the risk for metabolic disorders, such as T2D, by improving insulin sensitivity and anti-inflammatory activity, as well as obesity, through a lipid-lowering effect. It also showed the influence VK has on age-related neurodegenerative diseases, such as AD and PD. VK is involved in the brain’s physiology and can reduce its cognitive decline by carboxylation of Gas6 protein, a VKDP that could defend against neuronal apoptosis induced by OS and Aβ. The anticancer potential of VK was summarized by several in vitro and epidemiological studies. There are multiple mechanisms where the potential anticancer agent of VK can react, including the modulation of various transcription factors, which induced antiproliferative, proapoptotic, and autophagic effects, which were found to be associated with a reduced risk of cancer. The latest evidence on VK and pulmonary disease stem from the fact that VK can activate protein S, which was recently shown to prevent the generation of inflammatory cytokines and cytokine storms detected in COVID-19 cases. Low levels of protein S, due to pneumonia-induced VK depletion, were correlated with higher thrombogenicity and possibly fatal outcomes in COVID-19 patients.
Consuming a healthy diet is vital throughout the aging process to maintain and promote wellbeing. The aging population may be at risk for many suboptimal nutrient intakes, including VK, which have been shown to be associated with adverse health outcomes highly prevalent in this age group. Thus, the intake of VK-rich diets or VK supplements could prevent age-related diseases and/or support the effectiveness of medical treatments. However, more studies are needed to formulate the exactly recommended intakes of VK, including VK1, MK-4, and MK-7, due to their distinct bioavailability and biological activities. Higher values of VK intakes are needed, especially among the elderly and people who have comorbidities conditions that are most likely to be VK deficient.
References
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- Bjørklund, G.; Chirumbolo, S. Role of oxidative stress and antioxidants in daily nutrition and human health. Nutrition 2017, 33, 311–321.
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- Rusu, M.E.; Gheldiu, A.-M.; Mocan, A.; Vlase, L.; Popa, D.-S. Anti-aging potential of tree nuts with a focus on phytochemical composition, molecular mechanisms and thermal stability of major bioactive compounds. Food Funct. 2018, 9, 2554–2575.
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- Braasch-Turi, M.; Crans, D.C. Synthesis of Naphthoquinone Derivatives: Menaquinones, Lipoquinones and Other Vitamin K Derivatives. Molecules 2020, 25, 4477.
- Schurgers, L.; Vermeer, C. Determination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations. Haemostasis 2000, 30, 298–307.
- Turck, D.; Bresson, J.-L.; Burlingame, B.; Dean, T.; Fairweather-Tait, S.; Heinonen, M.; Hirsch-Ernst, K.I.; Mangelsdorf, I.; McArdle, H.; Naska, A.; et al. Dietary reference values for vitamin K. EFSA J. 2017, 15, e04780.
- Elder, S.J.; Haytowitz, D.B.; Howe, J.; Peterson, J.W.; Booth, S.L. Vitamin K Contents of Meat, Dairy, and Fast Food in the U.S. Diet. J. Agric. Food Chem. 2006, 54, 463–467.
- Melse-Boonstra, A. Bioavailability of Micronutrients from Nutrient-Dense Whole Foods: Zooming in on Dairy, Vegetables, and Fruits. Front. Nutr. 2020, 7, 101.
