Topic of the Month

Micronutrients in human development – Part 2

August 1, 2013

Improved living conditions – arising as a result of better medical care and hygiene, and better nutrition – mean that a large majority of the population in the industrialized world is living longer than would have been possible just a few decades ago. However, living longer does not always equal a better quality of life. The aging process, an inevitable, gradual decline in the function of physical systems, cannot be stopped – but the rate of this decline can be influenced. The changes that accompany the aging process are more a consequence of our way of life than the length of time we have been alive. Many degenerative diseases are the outcome of physical damage caused by poor diet, too much alcohol and tobacco, and too little exercise. A healthy lifestyle which includes an adequate intake of micronutrients such as vitamins, minerals, trace elements and essential fatty acids can help maintain health well into old age.

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While many people take an increasing interest in maintaining and enhancing their physical and mental fitness in the second half of their lives, it is frequently ob-served that their micronutrient intake is inadequate, especially as they get older. This can be due to changes in eating habits and problems digesting certain food-stuffs (1). This inadequate intake can have negative effects on physical and mental performance and may accelerate the aging process and the onset of health problems like heart disease and stroke (as a consequence of atherosclerosis), infections, cancer and osteoporosis. A sufficient intake of micronutrients from the start of life can contribute to the prevention of age-related diseases by supporting the relevant organ systems or can delay their onset to an advanced age. Compensating for micronutrient deficits is important well into old age (2). See also Micronutrients in human development – Part 1

Micronutrients in the prevention of age-related changes to the

Cardiovascular system

Throughout life it is the job of the cardiovascular system to supply all the cells of the body with blood. This is a huge task that over time leads to signs of wear and tear. Gradually the tissue of the cardiac muscle undergoes transformation: the proportion of connective tissue increases, the muscle can no longer beat as strongly and physical fitness deteriorates. Moreover, the cells of the heart’s conduction system, which are needed to keep the heartbeat regular, are also partially replaced by connective tissue. This may lead to cardiac arrhythmias. From as early as the age of 30 the walls of the blood vessels start to change. The elasticity of the arteries is restricted due to more or less extensive atherosclerosis, and they begin to lose their ability to compensate for blood pressure changes by changing their diameter and wall tension. In many older people blood pressure is permanently raised, and changes to the blood vessels and the reduced strength of the heartbeat mean that the cardiac muscle is constantly undersupplied with oxygen and nutrients. Several diseases can develop as a consequence of these normal, age-related changes in the cardiovascular system. How long the heart and blood vessels can function properly depends on the interaction of individual genetic disposition and the presence of harmful external influences. Some risk factors are not susceptible to influence (e.g. age or sex); some can be treated with medication (e.g. hypertension or diabetes); and then there are those which each of us can influence directly through our lifestyle. Among the measures which serve to maintain heart and vascular health are – apart from regular physical exercise and the avoidance of stress and smoking – a balanced diet which among other things ensures a good supply of micronutrients.

Many micronutrients are involved in the elementary functions of the cardiovascular system, and an adequate intake throughout life is important for the maintenance of cardiovascular health. Since the risk of developing chronic cardiovascular disease increases with age, research into the possible preventive effects of micro-nutrients is of great interest. Studies investigating preventive actions are complex and their results are often ambiguous, because the development of cardiovascular diseases is influenced by numerous factors. The main causes of heart attack and stroke are hypertension and atherosclerosis, which in the long term lead to a hardening and narrowing of the arteries, restricting blood flow to organs such as the heart and brain. Experimental findings indicate that antioxidantmicronutrients in particular – such as vitamins E and C as well as the carotenoids beta-carotene and lycopene, and also selenium– can combat the atherosclerotic process. These antioxidants prevent low density lipoprotein (LDL) cholesterol particles being oxidized by free radicals. This is important because oxidized LDL cholesterol can be bound by macrophages, leading to the deposition of plaque on the artery walls via the formation of so-called “foam cells”. Consequently, antioxidant micronutrients could prevent the formation of plaque and thus furring of the arteries (3). Furthermore, these nutrients could limit inflammatory processes in the vessel wall, in which existing plaques rupture and can cause an even greater narrowing of the blood vessel or even complete occlusion. In addition, vitamin E seems to have the ability to prevent other features of atherosclerotic vessel wall remodeling: the vitamin counteracts the growth and proliferation of vascular smooth muscle cells, the adhesion of macrophages to the lining of the cell wall (endothelium) and the clumping together of platelets (thrombus formation), thereby promoting vascular health.

Whilst the results of in vitro experiments and animal studies as well as some  observational studies indicate that a targeted supply of antioxidants could reduce the risk of atherosclerosis and its sequelae, including cardiac insufficiency, heart failure, heart attack and stroke (4, 5), other epidemiological and clinical studies gave contradictory results (6). A potentially preventive effect could be demonstrated for vitamin C in particular (7, 8). Epidemiological studies indicate that higher concentrations of beta-carotene in the blood could reduce the risk of atherosclerosis (9) and low serum levels could increase the risk of sudden cardiac death (10) and severe (congestive) heart failure (11). Other data show a protective effect of lycopene against stroke (12). There are also early indications that low blood levels of selenium could exacerbate cardiac insufficiency (13).

Studies suggest that raised levels of the amino acid homocysteine exacerbate atherosclerosis and have a damaging effect on the arteries similar to that caused by high LDL cholesterol levels. The B vitamin folate is known to lower homocysteine levels in the blood, especially in combination with vitamins B6 and B12. According to current studies, an increased intake of these B vitamins could provide protection primarily against stroke (14).

An adequate intake of vitamin D also appears to help maintain cardiovascular health. Since the skin’s ability to produce this vitamin from UV radiation diminishes with age and older population groups tend to get less exposure to sunlight, older people are particularly vulnerable to the risk of a suboptimal to insufficient intake of vitamin D (15). In vitro experiments highlight that vitamin D can improve the elasticity of vessel walls and therefore counteract high blood pressure. Studies increasingly indicate that low blood levels of vitamin D (under 30 ng/ml) could be associated with an increased risk of hypertension, coronary atherosclerosis, car-diac muscle weakness, heart attack and stroke (16-18). Conversely, raising levels of vitamin D by means of dietary supplements could be linked to a lower disease-related mortality rate in cardiovascular patients (19).

Magnesium, too, appears to positively affect vascular elasticity and hence blood pressure regulation. It was demonstrated that targeted administration of the mineral as adjunct therapy can enhance the effect of anti- hypertensive drugs (20). The results of a cohort study make it seem likely that a higher intake of magnesium could reduce the rate of death from cardiovascular disease (21). An adequate intake of iron, which is essential for the production and functioning of the red blood corpuscles, increases the supply of oxygen to the organs. Heart function depends on an adequate supply of iron, and heart failure is often linked to iron deficiency (with or without anemia) (22).

Study results increasingly indicate that the properties of the polyunsaturated essential fatty acids docosa-hexaenoic acid (DHA) and eicopentaenoic acid (EPA) boost cardiovascular health and could reduce the risk of disease. They may combat cardiac arrhythmias (a risk factor in sudden cardiac death), the formation of thromboses and the growth of atherosclerotic plaques; lower triglyceride levels; stem inflam-matory processes in the vessel walls and improve their function (23). To what extent omega-3 fatty acids can protect against the onset of cardiovascular diseases has not yet been sufficiently researched (24). A number of studies already indicate that a good supply of DHA and EPA from fish and fish oil supplements could be associated with a drop in (sudden) cardiac death and general mortality (25, 26).      

Nervous system

The main components of the autonomic nervous system, the sympathetic and parasympathetic nervous systems, are responsible for maintenance of blood pressure, blood sugar and temperature regulation as well as all other vital functions. With age, these functions become impaired. The underlying reasons for this progressive deterioration are believed to be degenerative processes that lead to a loss of nerve cells. External factors that, over time, can cause damage to the nerves also play a role here. A lack of physical activity and an unbalanced diet significantly influence the course of events. The brain, too, is affected by the aging process. In addition to a drop in the number of nerve cells – for example the astrocytes that are involved in the exchange of nutrients between neurons and blood at the blood-brain barrier – there is a also a fall in neurotransmitter concentrations, and connective tissue thickening of the meninges occurs. It is not yet clear to what extent these organic changes affect the function of the nervous system. The extent to which cognitive abilities (perception, thinking, recognizing and remembering) deteriorate in old age varies greatly from one person to another. Significant changes may include slower information processing and mobility, limited attention and altered sleep patterns. Clearly impaired brain function is, as a rule, caused by patholo-gical changes (e.g. restricted blood supply because of atherosclerosis, or loss of independence due to Alzheimer’s disease). If nerve cells in the brain die or do not function properly due to the aging process, disease or other influences, other areas of the brain can often take over their tasks to at least some extent. Hence the brain and nervous system remains a flexible, adaptable organ that can be trained and is able to learn well into old age, and therefore continues to require an adequate supply of micronutrients (27).

For the cells and tissue of the nervous system and brain, as for other organs, protection against oxidative damage is key. A long-term high level of free radicals has been linked to an accelerated loss of cognitive abilities. The organism combats nerve-cell damaging oxidative stress through the body’s own antioxidative defense system and via antioxidants consumed in the diet. Although currently available findings on the preventive effects of antioxidant micronutrients are based primarily on laboratory trials and animal studies, many researchers believe that a balanced diet containing plenty of vitamin C and Ebeta-carotene and antioxidants can go a long way to help protect the nervous system against oxidative damage (28). Thus raised blood levels of antioxidants such as beta-carotene and other carotenoids, for example, were mea-sured in numerous studies on older people with relatively good cognitive abilities (29). In addition to their antioxidative action some nutrients appear to be able to contribute to the maintenance of nervous system health by means of other functions. As a redox sensor and regulator of gene expression, vitamin E could promote signal transmission between the nerve cells (30) and vitamin C appears to function as a mediator for learning, particularly in stressful situations, and memory (31).

Data from epidemiological studies indicate that the B vitamins folate and vitamin B12 may have a preven-tive effect  against cognitive decline and dementia (32). People with high levels of homocysteine and low levels of B vitamins in the blood could be susceptible to accelerated loss of cognitive abilities and increased risk of developing dementia or Alzheimer‘s (33).
A precondition for the proper functioning of nervous system and brain is a sufficient supply of blood to the tissue and a good supply of oxygen to the cells. Vitamin Dmagnesium and the omega-3 fatty acids docosahexaenoic acid (DHA) and eicopentaenoic acid (EPA) contribute to this by supporting the maintenance of blood vessel health (15, 34). Iron plays a central role in oxygen transportation and hence boosts the activity of the brain in particular, with its enormous need for oxygen. In older people a lack of iron is often accompanied by depressive moods (35).  

Immune system

In many mature organs we find cells capable of division (so-called “adult stem cells”), which throughout life contribute to tissue renewal and can renew themselves repeatedly. The adult stem cells of the bone marrow, for instance, continuously produce white blood cells (such as lymphocytes) as well as red blood cells. The white blood cells are the defense cells of the body’s own specific immune system. It has long been known that blood stem cells function less well as we get older. Although stem cells are among the longest-living of all human cells, over time they suffer increasing DNA damage, and consequently they lose their ability to continuously renew themselves. The portion of blood stem cells responsible for renewing the immune system is particularly vulnerable and is lost at a particularly fast rate as we age due to DNA damage. Moreover, it is assumed that in old age errors of communication creep into the immune system: certain scavenger cells (granulocytes) appear to be increasingly resistant to activation by physiological messenger substances; they remain inactive for longer and thus increase the chances of infections spreading. These age-related changes mean that the immune system gradually becomes weaker and older people become more susceptible to infections. Older people are affected more often by infections of the respiratory tract (bronchitis and pneu-monia) and viral infections (shingles). Further, pathologically-altered body cells can no longer be as effec-tively recognized and destroyed, increasing the risk of cancer. An adequate supply of certain micronutrients can help combat a weakening of the immune system.

Studies into vitamins D and C, zinc and omega-3 fatty acids were able to show in the first instance a boost to the immune response to infections of the respiratory tract, which can rapidly become life-threatening in older people (e.g. in the case of pneumonia). Moreover, there are indications that vitamins D and E and omega-3 fatty acids may play a role in the prevention and treatment of rheumatic diseases (36).

Vitamin D supports the immune system by crucially influencing the function and activity of killer T cells
(T lymphocytes). The vitamin appears to be able to activate these cells and stimulate their division so that immune defense is strengthened. After contact with a pathogen the T lymphocytes form vitamin D pattern recognition receptors on the surface of the cell. Contact with vitamin D then leads to greater proliferation of the defense cells. If vitamin D is lacking, there is no activation reaction, the immune system is weakened and the organism more vulnerable to infections. As older people are already at greater risk of vitamin D deficiency, further weakening of their already diminished immune defenses can lead to a considerable rise in the frequency and severity of infections (e.g. colds and flu). Conversely, combating the deficiency through increased consumption of vitamin D can reduce the frequency of the incidence of respiratory tract infections (37). In the long term, vitamin D could contribute to the suppression and healing of inflammatory processes, for instance by boosting the production of anti-inflammatory proteins (cytokines) (15). The vitamin also appears to combat the impaired defense function of white blood cells associated with the aging process (38).

Vitamin A, too, seems to be able to boost the immune system via the activation of T lymphocytes (39). Moreover, vitamin E may have a positive influence on T lymphocyte function (40). The antiviral effect of vitamin C (particularly against influenza viruses) is mediated by the production of immuno-stimulating proteins (interferons) and seems to appear in very early stages of the infection (41). Older people suffering from infections or diabetes mellitus have a greater requirement of vitamin C, as do smokers.

 As precursors of mediator substances, the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosa-pentaenoic acid (EPA) influence specific and unspecific immune reactions. Thus several tissue hormones synthesized from omega fatty acids (icosanoids) boost the immune system. The icosanoid prostaglandin, for instance, can regulate the function of immune defense cells (monocytes and macrophages). EPA can de-crease the production of pro-inflammatory mediators (e.g. interleukins and tumor necrosis factors) and in this way positively influence inflammatory processes that occur more frequently in older people (42).

Adequate intakes of zinc and magnesium can also give a boost to the immune system. In several studies zinc was shown to reduce the rates of infection in older people (43). Other studies showed that magnesium can stimulate the immune system and suppress pro-inflammatory mediators (44). 

Musculoskeletal system

The extent of age-related changes that occur in elements of the musculoskeletal system – bones and joints, muscles and connective tissue – varies greatly from one person to another. Once bone mass has reached its maximum around the age of 30, it steadily declines over the rest of a person’s life, a process known as age-related osteoporosis. Remodeling of the external, compact part of the bone and the sponge-like interior causes bones to become increasingly brittle and risk of fractures to increase. Post-menopausal women are particularly at risk, because the reduction in estrogen production negatively influences the incidence of osteoporosis. The way older people live often accelerates the loss of bone density: on the one hand they do not consume sufficient calcium and vitamin D, and on the other they often do not get enough exercise. Constant pressure on the joints means that over time the protective layer of cartilage becomes thinner; it also loses its elasticity. As a consequence the joint loses mobility. The muscles, too, are subject to the aging process: they lose approximately 0.5% of their mass per year. The lost mass is usually replaced by fatty tissue, leading to a loss of muscle strength. Finally, the supporting connective tissue (tendons and ligaments) is also affected. It loses elasticity, increasingly restricting mobility.

There is good scientific evidence to support the importance of a sufficient intake of calcium and vitamin D in maintaining bone health. Vitamin D is needed on the one hand for the integration of calcium and phos-phate into the bone (mineralization) and on the other regulates the uptake of minerals from the intestine and their reabsorption from primary urine in the kidneys. In the case of vitamin D deficiency, calcium uptake from the intestine is inadequate. If levels of calcium in the blood fall, the mineral is released from the bone to ensure an adequate supply to the heart and muscles. For the skeleton this means that insufficient calcium is stored in new bone. An insufficient supply of vitamin D is widespread and can lead to bone softening (osteomalacia) in adults, which expresses itself as strong pain in the bones and muscles as well as muscle weakness, especially when standing or walking (15). Vitamin D deficiency leads not only to reduced bone density, but also causes the outer shell of the bone (bone cortex) to age prematurely, thus increasing the risk of fractures (45). Numerous randomized controlled studies were able to show that targeted consumption of vitamin D can reduce the incidence frequency of bone fractures, particularly of the hips. Vitamin D streng-thens not only the bones themselves, but also the surrounding muscles (46). Older people in particular can benefit from this, as they often have low levels of vitamin D and their risk of osteoporosis is considerably higher (47). Further, a healthy bone metabolism requires a lifelong sufficient supply ofphosphate, which together with calcium forms the main component of bone, and of magnesium and vitamin K, which con-tribute to bone mineralization (48).

Micronutrients are also essential for the maintenance of joint health. Vitamin C is important for the forma-tion of cartilage, the tissue in the joints between the bones (49). Moreover, increased intake of vitamin C has been associated with a reduced risk of gout (an inflammatory disease of the joints) and a substantial fall in blood levels of uric acid, a substance which can exacerbate gout (50). Low blood levels of vitamin B6 appear to promote pro-inflammatory processes which can accelerate the development of joint diseases (51). A lack of vitamin D, which is generally associated with bone health, also appears to be linked to degeneration of cartilage (arthrosis) and the incidence of rheumatoid joint diseases (arthritis) (52, 53).
 
Many clinical studies showed that increased consumption of omega-3 fatty acids in patients with rheuma-toid arthritis or joint pain could bring about a significant reduction in the intensity of pain, the duration of morning stiffness and the number of joints that were painful or sensitive, as well as a reduction in the anal-gesic medication used (54-56). The effect was attributed to the anti-inflammatory effects of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in particular. 

References

  1. Marian M. and Sacks G. Micronutrients and older adults. Nutr Clin Pract. 2009; 24(2):179-195.
  2. Park S. et al. Vitamin and mineral supplements: barriers and challenges for older adults. J Nutr Elder. 2008; 27(3-4):297-317.
  3. Ozkanlar S. and Akcay F. Antioxidant vitamins in atherosclerosis: animal experiments and clinical studies. Adv Clin Exp Med. 2012; 21(1):115-123.
  4. McKeag N. A. et al. The Role of Micronutrients in Heart Failure. Journal of the Academy of Nutrition and Dietetics.2012; 112(6):873-886.
  5. Rautiainen S. et al. Total antioxidant capacity of diet and risk of heart failure: a population-based prospective cohort of women. Am J Med. 2013; 126(6):494-500.
  6. Kubota Y. et al. Dietary intakes of antioxidant vitamins and mortality from cardiovascular disease: the Japan Collaborative Cohort Study (JACC) study. Stroke. 2011; 42(6):1665-1672.
  7. Frei B. et al. Authors' perspective: What is the optimum intake of vitamin C in humans? Crit Rev Food Sci Nutr.2012; 52(9):815-829.
  8. Wannamethee S. G. et al. Plasma Vitamin C But Not Vitamin E Is Associated with Reduced Risk of Heart Failure in Older Men. Circ Heart Fail. Published online May 2013.
  9. Karppi J. et al. Serum Carotenoids Reduce Progression of Early Atherosclerosis in the Carotid Artery Wall among Eastern Finnish Men. PLoS One. 2013; 8(5):e64107.
  10. Karppi J. et al. Serum beta-carotene and the risk of sudden cardiac death in men: a population-based follow-up study. Atherosclerosis. 2013; 226(1):172-177.
  11. Karppi J. et al.  Serum beta-carotene concentrations and the risk of congestive heart failure in men:
    A population-based study. Int J Cardiol. 2013; pii: S0167-5273(12).
  12. Karppi J. et al. Serum lycopene decreases the risk of stroke in men: a population-based follow-up study. Neurology. 2012; 79(15):1540-1547.
  13. Kosar F. et al. Trace element status (Se, Zn, Cu) in heart failure. Anadolu Kardiyol Derg. 2006; 6(3):
    216-220.
  14. Yang H. T. et al. Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials. Eur J Intern Med. 2012; 23(8):745-754.
  15. Boucher B. J. The Problems of Vitamin D Insufficiency in Older People. Aging Dis. 2012; 3(4):313-329.
  16. Brøndum-Jacobsen P. et al. 25-hydroxyvitamin D and symptomatic ischemic stroke: an original study and meta-analysis. Ann Neurol. 2013; 73(1):38-47.
  17. Wang L. et al. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes. 2012; 5(6):819-829.
  18. Kojima G. et al. Low dietary vitamin D predicts 34-year incident stroke: the Honolulu Heart Program. Stroke. 2012; 43(8):2163-2167.
  19. Vacek J. L. et al. Vitamin D deficiency and supplementation and relation to cardiovascular health. Am J Cardiol. 2012; 109:359-363.
  20. Houston M. The role of magnesium in hypertension and cardiovascular disease. J Clin Hypertens (Greenwich). 2011; 13(11):843-847.
  21. Zhang W. et al. Associations of dietary magnesium intake with mortality from cardiovascular disease:
    the JACC study. Atherosclerosis. 2012; 221(2):587-595.
  22. González-Costello J. and Comín-Colet J. Iron deficiency and anaemia in heart failure: understanding the FAIR-HF trial. Eur J Heart Fail. 2010; 12(11):1159-1162.
  23. Kris-Etherton P. M. et al. Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler Thromb Vasc Biol. 2003; 23(2):151-152.
  24. Kotwal S. et al. Omega 3 Fatty acids and cardiovascular outcomes: systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2012; 5(6):808-818.
  25. Wang C. et al. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr. 2006; 84(1):5-17.
  26. Mozaffarian D. Fish and n-3 fatty acids for the prevention of fatal coronary heart disease and sudden cardiac death. Am J Clin Nutr. 2008; 87(6):1991S-1996S.
  27. Morris M. C. Nutritional determinants of cognitive aging and dementia. Proc Nutr Soc. 2012; 71(1):1-13.
  28. Parletta N. et al. Nutritional modulation of cognitive function and mental health. J Nutr Biochem. 2013;
    24(5):725-743.
  29. Johnson E. J. et al. Relationship between Serum and Brain Carotenoids, alpha-Tocopherol, and Retinol Concentrations and Cognitive Performance in the Oldest Old from the Georgia Centenarian Study. J Aging Res. 2013; 2013:951786.
  30. Joshi Y. B. and Praticò D. Vitamin E in aging, dementia, and Alzheimer's disease. Biofactors. 2012;
    38(2):90-97.
  31. Harrison F. E. and May J. M. Vitamin C Function in the Brain: Vital Role of the Ascorbate Transporter (SVCT2). Free Radical Biol Med. 2009; 46(6):719-730.
  32. Gillette Guyonnet S. et al. NA task force on nutrition and cognitive decline with aging. J Nutr Health Aging. 2007; 11(2):132-152.
  33. Tucker K. L. et al. High homocysteine and low B vitamins predict cognitive decline in aging men:
    the Veterans Affairs Normative Aging Study. Am J Clin Nutr. 2005; 82(3):627-635.
  34. Crupi R. et al. n-3 Fatty Acids: Role in Neurogenesis and Neuroplasticity. Curr Med Chem. Published online May 2013.
  35. Stewart R. and Hirani V. Relationship between depressive symptoms, anemia, and iron status in older residents from a national survey population. Psychosom Med. 2012; 74(2):208-213.
  36. Lopez H. L. Nutritional interventions to prevent and treat osteoarthritis. Part II: focus on micronutrients and supportive nutraceuticals. PM R. 2012; 4(5):155-168.
  37. Bergman P. et al. Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials. PLoS One. 2013; 8(6):e65835.
  38. Alvarez-Rodriguez L. et al. Age and low levels of circulating vitamin D are associated with impaired innate immune function. J Leukoc Biol. 2012; 91(5):829-838.
  39. Ross A. C. Vitamin A and retinoic acid in T cell-related immunity. Am J Clin Nutr. 2012; 96(5):1166-1172.
  40. Pae M. et al.  The role of nutrition in enhancing immunity in aging. Aging Dis. 2012; 3(1):91-129.
  41. Kim Y. et al. Vitamin C Is an Essential Factor on the Anti-viral Immune Responses through the Production of Interferon-alpha/beta at the Initial Stage of Influenza A Virus (H3N2) Infection. Immune Netw. 2013;
    13(2):70-74.
  42. Calder P. C. n-3 Fatty acids, inflammation and immunity: new mechanisms to explain old actions. Proc Nutr Soc. 2013; 14:1-11.
  43. Prasad A. S. Discovery of human zinc deficiency: its impact on human health and disease. Adv Nutr. 2013; 4(2):176-190.
  44. Sugimoto J. et al. Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism. J Immunol. 2012; 188(12):6338-6346.
  45. Busse B. et al. Vitamin D deficiency induces early signs of aging in human bone, increasing the risk of fracture. Sci Transl Med. 2013; 5(193).
  46. Bischoff-Ferrari H. Vitamin D - from essentiality to functionality. Int J Vitam Nutr Res. 2012; 82(5):
    321-326.
  47. Chung M. et al. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventative Services Task Force. Ann Int Med. 2011; 155:827-838.
  48. Shearer M. J. et al. Vitamin K nutrition, metabolism, and requirements: current concepts and future research. Adv Nutr. 2012 ;3(2):182-195.
  49. Ibold Y. et al. Effect of different ascorbate supplementations on in vitro cartilage formation in porcine high-density pellet cultures. Tissue Cell. 2009; 41(4):249-256.
  50. Huang H.-Y. et al. The effects of vitamin C supplementation on serum concentrations of uric acid: results of a randomized controlled trial. Arthritis Rheum. 2005; 52(6):1843-1847.
  51. Chiang E. P. et al. Inflammation causes tissue-specific depletion of vitamin B6. Arthritis Res Ther. 2005; 7(6):1254-1262.
  52. Ranganathan P. et al. Vitamin D Deficiency, Interleukin 17, and Vascular Function in Rheumatoid Arthritis. J. Rheumatol. Published online July 2013.
  53. Sabbagh Z. et al. Vitamin D Status Is Associated with Disease Activity among Rheumatology Outpatients. Nutrients. 2013; 5(7):2268-2275.
  54. Goldberg R. J. and Katz J. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain. 2007; 129(1-2):210-223.
  55. Yusof H. M. et al. Influence of very long-chain n-3 fatty acids on plasma markers of inflammation in middle-aged men. Prostaglandins Leukot Essent Fatty Acids. 2008; 78(3):219-228.
  56. Cleland L. G. et al. The role of fish oils in the treatment of rheumatoid arthritis. Drugs. 2003; 63(9):
    845-853.