Vitamin K is an enzyme cofactor required for the carboxylation of vitamin K-dependent proteins, several of which have been implicated in diseases of aging. Inflammation is recognized as a crucial component of many chronic aging diseases, and evidence suggests vitamin K has an anti-inflammatory action that is independent of its role as an enzyme cofactor. Vitamin K-dependent proteins and inflammation have been implicated in cardiovascular disease and osteoarthritis, which are leading causes of disability and mortality in older adults. The purpose of this review is to summarize observational studies and randomized trials focused on vitamin K status and inflammation, cardiovascular disease, and osteoarthritis. Although mechanistic evidence suggests a protective role for vitamin K in these age-related conditions, the benefit of vitamin K supplementation is controversial because observational data are equivocal and the number of randomized trials is few.
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Booth SL. Roles for vitamin K beyond coagulation. Annu Rev Nutr. 2009;29:89–110. A review of emerging evidence suggesting physiological and biochemical functions of vitamin K beyond that as an enzyme cofactor for vitamin K dependent clotting proteins.
Booth SL, Suttie JW. Dietary intake and adequacy of vitamin K. J Nutr. 1998;128:785–8.
Shearer MJ, Fu X, Booth SL. Vitamin K nutrition, metabolism, and requirements: current concepts and future research. Adv Nutr. 2012;3:182–95.
Schurgers LJ, Vermeer C. Determination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations. Haemostasis. 2000;30:298–307.
Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL. Vitamin K contents of meat, dairy, and fast food in the U.S. diet. J Agric Food Chem. 2006;54:463–7.
Booth SL, vitamin K: food composition and dietary intakes. Food Nutr. Res. 2012; 56.
Booth SL, Al Rajabi A. Determinants of vitamin K status in humans. Vitam Horm. 2008;78:1–22.
Booth SL, Martini L, Peterson JW, Saltzman E, Dallal GE, Wood RJ. Dietary phylloquinone depletion and repletion in older women. J Nutr. 2003;133:2565–9.
Trumbo P, Yates AA, Schlicker S, Poos M. Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. J Am Diet Assoc. 2001;101:294–301.
Reumann S. Biosynthesis of vitamin K1 (phylloquinone) by plant peroxisomes and its integration into signaling molecule synthesis pathways. Subcell Biochem. 2013;69:213–29.
Shea MK, Booth SL, Massaro JM, Jacques PF, D’Agostino Sr RB, Dawson-Hughes B, et al. Vitamin K and vitamin D status: associations with inflammatory markers in the Framingham Offspring Study. Am J Epidemiol. 2008;167:313–20.
Suttie JW, Booth SL. Vitamin K. Adv Nutr. 2011;2:440–1.
Ohsaki Y, Shirakawa H, Hiwatashi K, Furukawa Y, Mizutani T, Komai M. Vitamin K suppresses lipopolysaccharide-induced inflammation in the rat. Biosci Biotechnol Biochem. 2006;70:926–32.
Ohsaki Y, Shirakawa H, Miura A, Giriwono PE, Sato S, Ohashi A, et al. Vitamin K suppresses the lipopolysaccharide-induced expression of inflammatory cytokines in cultured macrophage-like cells via the inhibition of the activation of nuclear factor kappaB through the repression of IKKalpha/beta phosphorylation. J Nutr Biochem. 2010;21:1120–6.
Reddi K, Henderson B, Meghji S, Wilson M, Poole S, Hopper C, et al. Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds. Cytokine. 1995;7:287–90.
Juanola-Falgarona M, Salas-Salvadó J, Estruch R, Portillo MP, Casas R, Miranda J, et al. Association between dietary phylloquinone intake and peripheral metabolic risk markers related to insulin resistance and diabetes in elderly subjects at high cardiovascular risk. Cardiovasc Diabetol. 2013;12:7.
Shea MK, Cushman M, Booth SL, Burke GL, Chen H, Kritchevsky SB. Associations between vitamin K status and haemostatic and inflammatory biomarkers in community-dwelling adults. The multi-ethnic study of atherosclerosis. Thromb Haemost. 2014;112:438–44.
Shea MK, O’Donnell CJ, Hoffmann U, Dallal GE, Dawson-Hughes B, Ordovas JM, et al. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr. 2009;89:1799–807.
Knapen M, Braam L, Drummen N, Bekers O, Hoeks APG, Vermeer C. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. Thromb Haemost. 2015;113:1135–44.
Shea MK, Booth SL, Miller ME, Burke GL, Chen H, Cushman M, et al. Association between circulating vitamin K1 and coronary calcium progression in community-dwelling adults: the multi-ethnic study of atherosclerosis. Am J Clin Nutr. 2013;98:197–208.
Dalmeijer GW, van der Schouw YT, Booth SL, de Jong PA, Beulens JWJ. Phylloquinone concentrations and the risk of vascular calcification in healthy women. Arterioscler Thromb Vasc Biol. 2014;34:1587–90.
Beulens JWJ, Bots ML, Atsma F, Bartelink M-LEL, Prokop M, Geleijnse JM, et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009;203:489–93.
Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MHJ, Van Der Meer IM, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004;134:3100–5.
Gast GCM, de Roos NM, Sluijs I, Bots ML, Beulens JWJ, Geleijnse JM, et al. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis. 2009;19:504–10.
Dalmeijer GW, van der Schouw YT, Magdeleyns E, Ahmed N, Vermeer C, Beulens JWJ. The effect of menaquinone-7 supplementation on circulating species of matrix Gla protein. Atherosclerosis. 2012;225:397–402.
Shea MK, O’Donnell CJ, Vermeer C, Magdeleyns EJP, Crosier MD, Gundberg CM, et al. Circulating uncarboxylated matrix Gla protein is associated with vitamin K nutritional status, but not coronary artery calcium, in older adults. J Nutr. 2011;141:1529–34.
Dalmeijer GW, van der Schouw YT, Vermeer C, Magdeleyns EJ, Schurgers LJ, Beulens JWJ. Circulating matrix Gla protein is associated with coronary artery calcification and vitamin K status in healthy women. J Nutr Biochem. 2013;24:624–8.
Dalmeijer GW, van der Schouw YT, Magdeleyns EJ, Vermeer C, Verschuren WMM, Boer JMA, et al. Matrix Gla protein species and risk of cardiovascular events in type 2 diabetic patients. Diabetes Care. 2013;36:3766–71.
Dalmeijer GW, van der Schouw YT, Magdeleyns EJ, Vermeer C, Verschuren WMM, Boer JMA, et al. Circulating desphospho-uncarboxylated matrix γ-carboxyglutamate protein and the risk of coronary heart disease and stroke. J Thromb Haemost. 2014;12:1028–34.
van den Heuvel EGHM, van Schoor NM, Lips P, Magdeleyns EJP, Deeg DJH, Vermeer C, et al. Circulating uncarboxylated matrix Gla protein, a marker of vitamin K status, as a risk factor of cardiovascular disease. Maturitas. 2014;77:137–41.
Vaccaro JA, Huffman FG. Phylloquinone (vitamin K1) intake and pulse pressure as a measure of arterial stiffness in older adults. J Nutr Gerontol Geriatr. 2013;32:244–57.
Mayer O, Seidlerová J, Wohlfahrt P, Filipovský J, Vaněk J, Cífková R, et al. Desphospho-uncarboxylated matrix Gla protein is associated with increased aortic stiffness in a general population. J Hum Hypertens. 2015. doi:10.1038/jhh.2015.55.
Pivin E, Ponte B, Pruijm M, Ackermann D, Guessous I, Ehret G, et al. Inactive matrix Gla-protein is associated with arterial stiffness in an adult population-based study. Hypertension. 2015;66:85–92.
Oka H, Akune T, Muraki S, En-yo Y, Yoshida M, Saika A, et al. Association of low dietary vitamin K intake with radiographic knee osteoarthritis in the Japanese elderly population: dietary survey in a population-based cohort of the ROAD study. J Orthop Sci. 2009;14:687–92.
Neogi T, Booth SL, Zhang YQ, Jacques PF, Terkeltaub R, Aliabadi P, et al. Low vitamin K status is associated with osteoarthritis in the hand and knee. Arthritis Rheum. 2006;54:1255–61.
Misra D, Booth SL, Tolstykh I, Felson DT, Nevitt MC, Lewis CE, et al. Vitamin K deficiency is associated with incident knee osteoarthritis. Am J Med. 2013;126:243–8.
Shea MK, Kritchevsky SB, Hsu F-C, Nevitt M, Booth SL, Kwoh CK, et al. The association between vitamin K status and knee osteoarthritis features in older adults: the health, aging and body composition study. Osteoarthr Cart. 2015;23:370–8.
Misra D, Booth SL, Crosier MD, Ordovas JM, Felson DT, Neogi T. Matrix Gla protein polymorphism, but not concentrations, is associated with radiographic hand osteoarthritis. J Rheumatol. 2011;38:1960–5.
Shea MK, Booth SL. Vitamin K’s role in age-related bone loss: a critical review. In: Holick M, Nieves J, editors. Nutrition and bone health. New York: Springer Sciences; 2014. p. 471–86.
McCabe KM, Adams MA, Holden RM. Vitamin K status in chronic kidney disease. Nutrients. 2013;5:4390–8.
López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194–217.
Ershler WB. Interleukin-6: a cytokine for gerontologists. J Am Geriatr Soc. 1993;41:176–81.
Strandberg TE, Tilvis RS. C-reactive protein, cardiovascular risk factors, and mortality in a prospective study in the elderly. Arterioscler Thromb Vasc Biol. 2000;20:1057–60.
Bruunsgaard H, Andersen-Ranberg K, Jeune B, Pedersen AN, Skinhoj P, Pedersen BK. A high plasma concentration of TNF- is associated with dementia in centenarians. J Gerontol Ser A Biol Sci Med Sci. 1999;54:M357–64.
Greene MA, Loeser RF. Aging-related inflammation in osteoarthritis. Osteoarthr Cart. 2015;23:1966–71.
Shea MK, Booth SL. Concepts and controversies in evaluating vitamin k status in population-based studies. Nutrients. 2016;8(1):8. A recent review outlining the various methods to estimate vitamin K nutrition status in population and clinical studies.
Potischman N. Biologic and methodologic issues for nutritional biomarkers. J Nutr. 2003;133(Suppl):875S–80.
National Center for Health Statistics. Health, United States 2014: with special feature on adults aged (pp 55–64), 2015.
Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med. 2008;358:1336–45.
Thompson GR, Partridge J. Coronary calcification score: the coronary-risk impact factor. Lancet. 2004;363:557–9.
Vliegenthart R, Oudkerk M, Hofman A, Oei H-HS, van Dijck W, van Rooij FJA, et al. Coronary calcification improves cardiovascular risk prediction in the elderly. Circulation. 2005;112:572–7.
Budoff MJ, Hokanson JE, Nasir K, Shaw LJ, Kinney GL, Chow D, et al. Progression of coronary artery calcium predicts all-cause mortality. JACC Cardiovasc Imaging. 2010;3:1229–36.
Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386:78–81.
Berkner KL, Runge KW. The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis. J Thromb Haemost. 2004;2:2118–32. A review of vitamin K-dependent protein function and vitamin K nutriture in atherosclerosis.
Shea MK, Holden RM. Vitamin K status and vascular calcification: evidence from observational and clinical studies. Adv Nutr. 2012;3:158–65. A review summarizing the current evidence of vitamin K and vascular calcification in community based studies and clinic based studies focusing on patients with kidney disease.
Institute of Medicine. Dietary references intakes for vitamin K, arsenic, chromium, copper, iodine, iron, manganese, molybdenum, silicon, vanadium, and zinc. 2001.
Lamon-Fava S, Sadowski JA, Davidson KW, O’Brien ME, McNamara JR, Schaefer EJ. Plasma lipoproteins as carriers of phylloquinone (vitamin K1) in humans. Am J Clin Nutr. 1998;67:1226–31.
Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet. 2014;384:626–35.
Cranenburg ECM, VAN Spaendonck-Zwarts KY, Bonafe L, Mittaz Crettol L, Rödiger LA, Dikkers FG, et al. Circulating matrix γ-carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome. J Thromb Haemost. 2011;9:1225–35.
Theuwissen E, Cranenburg EC, Knapen MH, Magdeleyns EJ, Teunissen KJ, Schurgers LJ, et al. Low-dose menaquinone-7 supplementation improved extra-hepatic vitamin K status, but had no effect on thrombin generation in healthy subjects. Br J Nutr. 2012;108:1652–7.
Tsao CW, Pencina KM, Massaro JM, Benjamin EJ, Levy D, Vasan RS, et al. Cross-sectional relations of arterial stiffness, pressure pulsatility, wave reflection, and arterial calcification. Arterioscler Thromb Vasc Biol. 2014;34:2495–500.
Blaha MJ, Budoff MJ, Rivera JJ, Katz R, O’Leary DH, Polak JF, et al. Relationship of carotid distensibility and thoracic aorta calcification: multi-ethnic study of atherosclerosis (MESA). Hypertension. 2009;54:1408–15.
Sekikawa A, Shin C, Curb JD, Barinas-Mitchell E, Masaki K, El-Saed A, et al. Aortic stiffness and calcification in men in a population-based international study. Atherosclerosis. 2012;222:473–7.
Assmann G, Cullen P, Evers T, Petzinna D, Schulte H. Importance of arterial pulse pressure as a predictor of coronary heart disease risk in PROCAM. Eur Heart J. 2005;26:2120–6.
Mitchell GF, Hwang S-J, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, et al. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation. 2010;121:505–11.
Mitchell GF, Parise H, Benjamin EJ, Larson MG, Keyes MJ, Vita JA, et al. Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study. Hypertension. 2004;43:1239–45.
Rees K, Guraewal S, Wong YL, Majanbu DL, Mavrodaris A, Stranges S, et al. Is vitamin K consumption associated with cardio-metabolic disorders? A systematic review. Maturitas. 2010;67:121–8.
Westerterp KR, Goris AHC. Validity of the assessment of dietary intake: problems of misreporting. Curr Opin Clin Nutr Metab Care. 2002;5:489–93.
Hartley L, Clar C, Ghannam O, Flowers N, Stranges S, Rees K. Vitamin K for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2015;9:CD011148.
Wallin R, Schurgers LJ, Loeser RF. Biosynthesis of the vitamin K-dependent matrix Gla protein (MGP) in chondrocytes: a fetuin-MGP protein complex is assembled in vesicles shed from normal but not from osteoarthritic chondrocytes. Osteoarthr Cart. 2010;18:1096–103.
Loeser RF, Varnum BC, Carlson CS, Goldring MB, Liu ET, Sadiev S, et al. Human chondrocyte expression of growth-arrest-specific gene 6 and the tyrosine kinase receptor Axl: potential role in autocrine signaling in cartilage. Arthritis Rheum. 1997;40:1455–65.
Ohno S, Tanaka N, Ueki M, Honda K, Tanimoto K, Yoneno K, et al. Mechanical regulation of terminal chondrocyte differentiation via RGD-CAP/beta ig-h3 induced by TGF-beta. Connect Tissue Res. 2005;46:227–34.
Viegas CSB, Cavaco S, Neves PL, Ferreira A, João A, Williamson MK, et al. Gla-rich protein is a novel vitamin K-dependent protein present in serum that accumulates at sites of pathological calcifications. Am J Pathol. 2009;175:2288–98.
Rafael MS, Cavaco S, Viegas CSB, Santos S, Ramos A, Willems BAG, et al. Insights into the association of Gla-rich protein and osteoarthritis, novel splice variants and γ-carboxylation status. Mol Nutr Food Res. 2014. doi:10.1002/mnfr.201300941.
Neogi T, Felson DT, Sarno R, Booth SL. Vitamin K in hand osteoarthritis: results from a randomised clinical trial. Ann Rheum Dis. 2008;67:1570–3.
All authors have read and approved the final manuscript. This study is supported by the National Institute of Arthritis Musculoskeletal and Skin Diseases (K01AR063167) and US Department of Agriculture, Agricultural Research Service under Cooperative Agreement No. 58-1950-7-707. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the US Department of Agriculture.
Conflict of Interest
Stephanie G. Harshman and M. Kyla Shea declare that they have no conflict of interest.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
This article is part of the Topical Collection on Nutrition and Aging
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Harshman, S.G., Shea, M.K. The Role of Vitamin K in Chronic Aging Diseases: Inflammation, Cardiovascular Disease, and Osteoarthritis. Curr Nutr Rep 5, 90–98 (2016). https://doi.org/10.1007/s13668-016-0162-x
- Cardiovascular disease
- Older adults
- Vitamin K