The Role of Vitamin K in Humans: Implication in Aging and Age-Associated Diseases
Abstract
:1. Introduction
2. Vitamin K in Bone Health
3. Vitamin K in the Prevention and Therapy of Vascular Calcification and Cardiovascular Diseases
4. The Effects of Vitamin K on Metabolic Disorders
5. The Effect of Vitamin K on Neurodegenerative Diseases
6. The Effect of Vitamin K on Cancer
7. Correlation between Vitamin K and Pulmonary Disease
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ACE-I | Angiotensin-converting enzyme inhibitor |
AD | Alzheimer’s disease |
AKT | Protein kinase B |
AMPK | Adenosine monophosphate-activated protein kinase |
Bcl-2 | B-cell lymphoma 2 |
BMC | Bone mineral content |
BMD | Bone mineral density |
CCC | Cholangiocellular carcinoma |
CHD | Coronary heart disease |
CKD | Chronic kidney disease |
CNS | Central nervous system |
cOC | Carboxylated osteocalcin |
CRP | C-reactive protein |
CV | Cardiovascular |
CVD | Cardiovascular disease |
dp-ucMGP | Dephosphorylated-uncarboxylated matrix Gla protein |
Gas6 | Growth arrest-specific protein 6 |
GGCX | Gamma-glutamyl carboxylase |
Gla | γ-carboxylated glutamic acid |
Glu | Glutamic acid |
GRP | Gla-rich protein |
HbA1c | Glycated hemoglobin |
HCC | Hepatocellular carcinoma |
HDL | High-density lipoprotein |
HIF-1α | Hypoxia-inducible factor-1α |
HOMA-IR | Homeostatic model assessment for insulin resistance |
HR | Hazard ratio |
IL | Interleukin |
JNK | C-Jun N-terminal kinase |
metS | Metabolic syndrome |
MGP | Matrix Gla protein |
MK | Menaquinone |
mTORC | Mammalian target of rapamycin complex |
NF-кB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
Nrf2 | Nuclear factor erythroid 2–related factor 2 |
OA | Osteoarthritis |
OC | Osteocalcin |
OR | Odds ratio |
OS | Oxidative stress |
PCOS | Polycystic ovary syndrome |
PD | Parkinson’s disease |
PI3K | Phosphatidylinositide-3-kinase |
PK | Phylloquinone |
RCT | Randomized controlled trial |
ROS | Reactive oxygen species |
SIRT | Sirtuin |
T2D | Type 2 diabetes |
TNF-α | Tumor necrosis factor-alpha |
tOC | Total osteocalcin |
UBIAD1 | UbiA prenyltransferase domain containing 1 |
ucMGP | Uncarboxylated matrix Gla protein |
ucOC | Undercarboxylated osteocalcin |
VC | Vascular calcification |
vitD | Vitamin D |
VK | Vitamin K |
VKAs | Vitamin K antagonists |
VKDP | Vitamin K-dependent protein |
ACE-I | angiotensin-converting enzyme inhibitor |
AD | Alzheimer’s disease |
AKT | protein kinase B |
AMPK | adenosine monophosphate-activated protein kinase |
Bcl-2 | B-cell lymphoma 2 |
BMC | bone mineral content |
BMD | bone mineral density |
CCC | cholangiocellular carcinoma |
CHD | coronary heart disease |
CKD | chronic kidney disease |
CNS | central nervous system |
cOC | carboxylated osteocalcin |
CRP | C-reactive protein |
CV | cardiovascular |
CVD | cardiovascular disease |
dp-ucMGP | dephosphorylated-uncarboxylated matrix Gla protein |
Gas6 | growth arrest-specific protein 6 |
GGCX | gamma-glutamyl carboxylase |
Gla | γ-carboxylated glutamic acid |
Glu | glutamic acid |
GRP | Gla-rich protein |
HbA1c | glycated hemoglobin |
HCC | hepatocellular carcinoma |
HDL | high-density lipoprotein |
HIF-1α | hypoxia-inducible factor-1α |
HOMA-IR | homeostatic model assessment for insulin resistance |
HR | hazard ratio |
IL | interleukin |
JNK | c-Jun N-terminal kinase |
metS | metabolic syndrome |
MGP | matrix Gla protein |
MK | menaquinone |
mTORC | mammalian target of rapamycin complex |
NF-кB | nuclear factor kappa-light-chain-enhancer of activated B cells |
Nrf2 | nuclear factor erythroid 2–related factor 2 |
OA | osteoarthritis |
OC | osteocalcin |
OR | odds ratio |
OS | oxidative stress |
PCOS | polycystic ovary syndrome |
PD | Parkinson’s disease |
PI3K | phosphatidylinositide-3-kinase |
PK | phylloquinone |
RCT | randomized controlled trial |
ROS | reactive oxygen species |
SIRT | sirtuin |
T2D | type 2 diabetes |
TNF-α | tumor necrosis factor-alpha |
tOC | total osteocalcin |
UBIAD1 | UbiA prenyltransferase domain containing 1 |
ucMGP | uncarboxylated matrix Gla protein |
ucOC | undercarboxylated osteocalcin |
VC | vascular calcification |
vitD | vitamin D |
VK | vitamin K |
VKAs | vitamin K antagonists |
VKDP | vitamin K–dependent protein |
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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) |
Author, Year, Country [Ref.] | Subjects (W:M) Age (Mean ± SD) | Design (Length) | Intervention Exposure | Findings |
---|---|---|---|---|
Shiraki et al. 2000 Japan [44] | 241 PMO 67.2 y | prospective 2 y | 45 mg/d MK-4 vs. control | ↓ ucOC (p < 0.0001) ↑ cOC (p = 0.0081) ↓ fracture risk (p = 0.0273) |
Iwamoto et al. 2001 Japan [48] | 72 PMO 65.3 y | prospective 2 y | 45 mg/d MK-4 + Ca vs. Ca | ↓ vertebral fractures (p < 0.0001) ↑ BMD (forearm) (p < 0.0001) |
Purwosunu et al. 2006 Indonesia [49] | 63 PMO 60.8 y | RCT 48 w | 45 mg/d MK-4 + Ca vs. Ca | ↓ ucOC (p ˂ 0.01) ↑ BMD (lumbar) (p < 0.05) |
Bolton-Smith et al. 2007 UK [45] | 244 healthy W 68.2 y | RCT 2 y | 200 μg/d VK1 + 10 μg/d vitD3 + Ca vs. placebo | ↓ ucOC (p < 0.001) ↑ BMD (ultradistal radius) (p < 0.01) |
Knapen et al. 2007 Netherlands [50] | 325 PMW 66.0 y | RCT 3 y | 45 mg/d MK-4 vs. placebo | ↑ BMC (p < 0.05) and bone strength (femoral neck) |
Booth et al. 2008 USA [51] | 452 (267:185) 68.4 y | RCT 3 y | 500 μg/d PK vs. control | ↓ ucOC (p ˂ 0.0001) |
Cheung et al. 2008 Canada [52] | 400 PMOa 59.1 y | RCT 2–4 y | 5 mg/d VK1 vs. placebo | ↓ fracture risk (p = 0.04) |
Hirao et al. 2008 Japan [53] | 44 PMW 68.4 y | prospective 1 y | 45 mg/d VK2 + 5 mg/d alendronate vs. 5 mg/d alendronate | ↓ ucOC (p = 0.014) ↓ ucOC:cOC (p = 0.007) ↑ BMD (femoral neck) (p = 0.03) |
Tsugawa et al. 2008 Japan [54] | 379 W 63.0 y | prospective 3 y | high VK1 vs. low VK1 | ↓ vertebral fracture risk (p < 0.001) |
Binkley et al. 2009 USA [46] | 381 PMW 62.5 y | RCT 1 y | 1 mg/d VK1 or 45 mg/d MK-4 vs. placebo | ↓ ucOC (p < 0.001) for both VK1 and MK-4 groups |
Yamauchi et al. 2010 Japan [55] | 221 healthy W 60.8 ± 9.5 y | cross-sectional | 260±85 μg/d VK | ↓ ucOC (p < 0.0001) ↑ BMD (lumbar) (p = 0.015) |
Je et al. 2011 Korea [56] | 78 PMW 67.8 y | RCT 6 mo | 45 mg/d MK-4 + vitD + Ca vs. vitD + Ca | ↓ ucOC (p = 0.008) ↑ BMD (lumbar) (p = 0.049) |
Kanellakis et al. 2012 Greece [57] | 173 PMW 62.0 y | RCT 12 mo | 100 μg PK or MK-7 + vitD + Ca vs. control | ↓ ucOC (p = 0.001) * ↑ BMD (lumbar) (p < 0.05) * |
Knapen et al. 2013 Netherlands [58] | 244 PMW 60.0 y | RCT 3 y | 180 μg/d MK-7 vs. placebo | ↓ ucOC (p < 0.001) ↑ BMD (lumbar spine, femoral neck), bone strength (p < 0.05) |
Jiang et al. 2014 China [59] | 213 PMW 64.4 y | RCT 1 y | 45 mg/d MK-4 + Ca vs. Ca | ↓ ucOC (p < 0.001) ↑ BMD (lumbar) (p < 0.001) |
Rønn et al. 2016 Denmark [47] | 148 PMOa 67.5 y | RCT 1 y | 375 µg/d MK-7 vs. placebo | ↓ ucOC (p < 0.05) ↓ ucOC:cOC (p < 0.05) ↑ bone structure (tibia) (p < 0.05) |
Bultynck et al. 2020 UK [60] | 62 (42:20) 80.0 ± 9.6 y | Prospective | ↑ serum VK | ↓ hip fracture risk |
Moore et al. 2020 UK [61] | 374 PMO 68.7 y | cross-sectional | ↑ serum VK1 | ↓ fracture risk (p = 0.04) |
Sim et al. 2020 Australia [62] | 30 (10:20) 61.8 ± 9.9 y | RCT 12 w | 136.7 μg/d VK | ↓ ucOC and ucOC:tOC (p ≤ 0.01) |
Author, Year, Country (Ref.) | Subjects (W:M) Age (Mean ± SD) | Design (Length) | Intervention Exposure | Findings |
---|---|---|---|---|
Geleijnse et al. 2004 Netherlands [90] | 4807 (2971:1836) 67.5 y | 7 y | Q1 ˂ 21.6 μg/d VK2 Q2 21.6–32.7μg/d VK2 Q3 ˃ 32.7 μg/d VK2 | ↓ CHD mortality: RR = 0.43 (95% CI: 0.24–0.77, p = 0.005) Q3 vs. Q1 ↓ AC: OR = 0.48 (95% CI: 0.32–0.71, p ˂ 0.001) Q3 vs. Q1 |
Gast et al. 2009 Netherlands [91] | 16,057 W 57.0 ± 6.0 y | Longitudinal 8.1 y | 211.7μg/d VK1 29.1μg/d VK2 | ↓ CHD risk for 10 μg VK2: HR = 0.91 (95% CI: 0.85–1.00, p = 0.04) |
Shea et al. 2009 USA [92] | 388 (235:153) 68 y | RCT 3 y | 500 μg/d VK1 vs. control | ↓progression of CAC |
Schurgers et al. 2010 France [93] | 107 (43:64) 67 ± 13 y | 18 mo | VK levels dp-ucMGP | ↓ VK levels ↑ dp-ucMGP levels with CKD stage |
Ueland et al. 2010 Norway [94] | 147 (66:81) 74.0 ± 10 y | 20 mo | VK levels dp-ucMGP | ↓ VK levels ↑ dp-ucMGP in symptomatic AS |
Schlieper et al. 2011 Serbia [95] | 188 (89:99) 58 ± 15 y | Follow-up, 1104 days | VK levels dp-ucMGP dp-cMGP | ↓ dp-cMGP ↑ CV: HR = 2.7 (95% CI: 1.2–6.2, p = 0.015) ↑ All-cause: HR = 2.16 (95% CI: 1.1–4.3, p = 0.027) |
Ueland et al. 2011 Norway [96] | 179 (39:140) 56 y | 2.9 y | VK levels dp-ucMGP | ↓ VK levels; ↑ dp-ucMGP ↑ heart failure: HR=5.62 (95% CI: 2.05–15.46, p = 0.001) |
Westenfeld et al. 2011 Germany [97] | 103 (48:55) ˃ 60.5 y | RCT 6 w | G1–45 µg/d MK-7 G2–135 µg/d MK-7 G3–360 µg/d MK-7 | ↓ dp-ucMGP by 77–93% G2 and G3 vs. control |
Dalmeijer et al. 2012 Netherlands [98] | 60 (36:24) 59.5 y | RCT 12 w | G1–180 μg/d MK-7 G2–360 μg/d MK-7 | ↓ dp-ucMGP by 31% G1 and 46% G2 vs. placebo |
van den Heuvel et al. 2013 Netherlands [99] | 577 (322:255) 59.9 ± 2.9 y | Follow-up 5.6 y | VK levels dp-ucMGP | ↓ VK levels; ↑ dp-ucMGP ↑ CVD: HR=2.69 (95% CI: 1.09–6.62, p = 0.032) |
Caluwé et al. 2014 Norway [100] | 165 (83:82) 70.8 y | RCT 8 w | 360, 720 or 1080 μg MK-7 thrice weekly | ↓ dp-ucMGP by 17–33–46% |
Liabeuf et al. 2014 France [101] | 198 (40:158) 64 ± 8 y | Cross-sectional | VK levels dp-ucMGP | ↓ VK levels; ↑ dp-ucMGP ↑ PAC: OR = 1.88 (95% CI: 1.14–3.11, p = 0.014) |
Cheung et al. 2015 USA [102] | 3401 (2245:1156) 61.9 y | Follow-up 13.3 y | ↑ VK daily intake | ↓ CVD mortality: HR = 0.78 (95% CI: 0.64–0.95, p = 0.016) |
Knapen et al. 2015 Norway [103] | 244 PMW 59.5 ± 3.3 y | RCT 3 y | 180 µg/d MK-7 vs. placebo | ↓ Stiffness Index β: −0.67 ± 2.78 vs. +0.15 ± 2.51, p = 0.018 ↓ cfPWV: −0.36 ± 1.48 m/s vs. +0.021 ± 1.22 m/s, p = 0.040 |
Kurnatowska et al. 2015 Poland [104] | 42 (20:22) 58 y | RCT 270 days | 90 μg/d MK-7 + 10 μg/d vitD vs. control | ↑ CAC ↓dp-ucMGP |
Asemi et al. 2016 Iran [105] | 66 (31:35) 65.5 y | RCT 12 w | 180 µg/d MK-7 + 10 µg/d vitD + 1 g/d Ca vs. placebo | ↓ levels of left CIMT (p = 0.02) ↓ insulin (−0.9 vs. +2.6, p = 0.01) ↓ HOMA-IR (−0.4 vs. +0.7, p = 0.01) |
Fulton et al. 2016 UK [106] | 80 (36:44) 77 ± 5 y | RCT 6 mo | 100 µg MK-7 vs. placebo | ↓dp-ucMGP (p < 0.001) |
Kurnatowska et al. 2016 Poland [107] | 38 (17:21) 58.6 y | RCT 9 mo | 90 μg/d MK-7 + 10 μg/d vitD vs. control | ↓dp-ucMGP by 10.7% |
Sardana et al. 2016 USA [108] | 66 (6:60) T2D 62 ± 2 y | Cross-sectional | VK levels dp-ucMGP | ↓ VK levels; ↑ dp-ucMGP ↑ cfPWV (β = 0.40, p = 0.011) |
Aoun et al. 2017 Lebanon [109] | 50 (20:30) 71.5 y | RCT 4 w | 360 μg/d MK-7 | ↓ dp-ucMGP by 86% |
Brandenburg et al. 2017 Germany [110] | 99 (18:81) 69.1 y | RCT 1 y | 2 mg/d VK1 vs. placebo | ↓ progression of AVC (10.0% vs. 22.0%) |
Shea et al. 2017 USA [111] | 1061 (615:446) 74 ± 5 y | Follow-up 12.1 y | VK1 levels dp-ucMGP | ↑ CVD risk in HBP patients (n = 489): HR = 2.94 (95% CI: 1.4–6.13, p ˂ 0.01) |
Puzantian et al. 2018 USA [112] | 137 (8:129) 59.6 y | VK levels dp-ucMGP | ↓ VK levels; ↑ dp-ucMGP ↑ cfPWV (β = 0.21; p = 0.019) | |
Dal Canto et al. 2020 Netherlands [113] | 601 (303:298) 70 ± 6 y | Follow-up 7 and 17 y | ↓ VK levels ↓ vitD levels | ↑ LVMI: β = 5.9 g/m2.7 (95% CI: 1.8–10.0 g/2.7) ↑ All-cause mortality: HR = 1.64 (95% CI: 1.12–2.39, p = 0.011) |
Roumeliotis et al. 2020 Greece [114] | 66 (31:35) diabetic CKD 68.5 ± 8.6 y | Follow-up 7 y | VK levels dp-ucMGP | ↓ VK levels; ↑ dp-ucMGP ↑ CVD mortality: HR = 2.82 (95% CI: 1.07–7.49, p = 0.037) |
Shea et al. 2020 USA [115] | 3891 (2154:1737) 65 ± 11 y | Follow-up 13 y | ↓ VK1 levels | ↑ CVD risk: HR = 1.12 (95% CI, 0.94–1.33) ↑ All-cause mortality |
Wessinger et al. 2020 USA [116] | 60 (11:49) chronic stroke 61.7 ± 7.2 y | Cross-sectional | VK dietary intake | Among stroke survivors, 82% reported consuming below the Dietary Reference Intake for VK |
Author, Year, Country [Ref.] | Subjects (W:M) Age (Mean ± SD) | Design (Length) | Intervention Investigations | Findings |
---|---|---|---|---|
Im et al. 2008 South Korea [129] | 339 PMW T2D 57.2 y | Biochemical and hormonal parameters for (1) NG; (2) IGF; (3) T2D groups | ↓ OC in (3) vs. (1) (p < 0.005) OC levels—inversely correlated with FG (r = −0.195, p < 0.001), HbA1c (r = −0.219, p < 0.001), FI (r = −0.131, p < 0.016), HOMA-IR (r = −0.163, p < 0.003) | |
Yoshida et al. 2008 USA [130] | 355 (213:142) 68 y | RCT 36 mo | 500 μg/d PK vs. control | ↓ HOMA-IR (p-adjusted < 0.01) and ↓ plasma insulin (p-adjusted < 0.04)—only for men ↓% ucOC (p < 0.001) for both men and women |
Kanazawa et al. 2009 Japan [131] | 329 (149:179) 65.8 y | Biochemical and hormonal parameters | Negative correlation between OC and FG and HbA1c (for all: p < 0.05),% fat, baPWV and IMT in men (p < 0.05) Positive correlation between OC and total adiponectin in PMF (p < 0.001) | |
Kindblom et al. 2009 Sweden [132] | 1010 M 857 non-T2D 153 T2D 75.3 ± 3.2 y | MrOS Sweden study | Biochemical and hormonal parameters | ↓ OC in T2D (−21.7%, p < 0.001) vs. non-T2D Plasma OC—inversely correlated with BMI, fat mass, and plasma glucose (p < 0.001) |
Shea et al. 2009 USA [133] | 348 (206:142) non-T2D 68 y | Cross sectional 3 y | OC levels (tOC, ucOC, cOC) and HOMA-IR | ↑ cOC and tOC were associated with ↓ HOMA-IR (p = 0.006 and p = 0.02, respectively) |
Bao et al. 2011 China [134] | 181 M 76 non-metS 105 metS 64.9 ± 10.7 y | Biochemical and hormonal parameters | ↓ OC in MetS vs. non-MetS (p < 0.001); OC was independently associated with metS (OR = 0.060, 95% CI: 0.005–0.651) | |
Alfadda et al. 2013 Saudi Arabia [135] | 203 T2D ± MetS 52.5 ± 9.6 y | Cross-sectional | Biochemical and hormonal parameters | ↓ tOC (p = 0.01) and ucOC (p = 0.03) in metS vs. non-metS. Positive correlation between ucOC and HDL-C (p = 0.023). Negative correlation between tOC and HbA1c (p = 0.01) and serum TGs (p = 0.049. |
Confraveux et al. 2014 France [136] | 798 M 65.3 ± 7 y | MINOS study | Biochemical and hormonal parameters | Negative correlation between OC and glycemia (p < 0.0001) |
Shea et al. 2017 USA [137] | 401 (237:164) 69 ± 6 y | RCT 3 y | 500 μg/d PK (+Ca and vitD) vs. control (Ca and vitD) | ↓ ucOC (p < 0.001) |
Knapen et al. 2018 Netherlands [138] | 214 PMW 60 y | RCT 3 y | 180 µg/d MK-7 vs. placebo | ↑ cOC (p < 0.0001) ↓ ucOC (p < 0.0001) |
Dumitru et al. 2019 Romania [139] | 146 PMW T2D 62.1 y | Cross sectional 30 mo | Biochemical and hormonal parameters in T2D group vs. control | ↓ tOC (p < 0.05) in T2D group Negative correlation between tOC and HbA1c, BMI, TGs (for all: p < 0.05), and HDL-C (p = 0.001) |
Guney et al. 2019 Turkey [140] | 191 PMW metS 56 y | cross-sectional | Biochemical and hormonal parameters in metS group vs. control | ↓ OC (p < 0.001) in metS group Positive correlation between vitD and OC (r = 0.198; p = 0.008) Negative correlation between OC and hs-CRP (p = 0.003), HOMA-IR (p = 0.048), and HbA1c (p = 0.001) |
Aguayo-Ruiz et al. 2020 Mexico [141] | 40 (24:16) T2D 56 y | RCT 3 mo | (1) 100 µg/d K2 (2) 100 µg/d K2+vit D3 (3) vit D3 | (1): ↓ glycemia (p = 0.002) ↑ cOC (p < 0.041) (2): ↓ glycemia (p = 0.002) |
Jeannin et al. 2020 France [142] | 198 (40:158) T2D 64 ± 8.4 y | Cohort | NDS, dp-ucMGP in plasma | ↑ peripheral NDS (15.7%) correlated with dp-ucMGP (r = 0.51, p < 0.0001) |
Sakak et al. 2020 Iran [143] | 68 (42:26) T2D 57.6 y | RCT 12 w | 360 μg MK-7 vs. placebo | ↓ FPG (p-adjusted = 0.031) ↓ HbA1c (p-adjusted = 0.004) ↓ HOMA-IR (p = 0.019) vs. baseline |
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Popa, D.-S.; Bigman, G.; Rusu, M.E. The Role of Vitamin K in Humans: Implication in Aging and Age-Associated Diseases. Antioxidants 2021, 10, 566. https://doi.org/10.3390/antiox10040566
Popa D-S, Bigman G, Rusu ME. The Role of Vitamin K in Humans: Implication in Aging and Age-Associated Diseases. Antioxidants. 2021; 10(4):566. https://doi.org/10.3390/antiox10040566
Chicago/Turabian StylePopa, Daniela-Saveta, Galya Bigman, and Marius Emil Rusu. 2021. "The Role of Vitamin K in Humans: Implication in Aging and Age-Associated Diseases" Antioxidants 10, no. 4: 566. https://doi.org/10.3390/antiox10040566
APA StylePopa, D. -S., Bigman, G., & Rusu, M. E. (2021). The Role of Vitamin K in Humans: Implication in Aging and Age-Associated Diseases. Antioxidants, 10(4), 566. https://doi.org/10.3390/antiox10040566