expert opinion

The role of vitamin E in age-related diseases

March 1, 2014

Italian National Research Centre on Ageing, Ancona, Italy

“Aging is a complex biological phenomenon, often accompanied by various socio-economic changes which have a great impact on the nutritional status and needs of an elderly individual as well as on the increased incidences of disability due to the frequent onset of various chronic diseases. Among the latter, cardiovascular and neurodegenerative diseasesdiabetes, cancer and infections are closely related to a deficiency in the nutritional status and to the presence of a chronic inflammatory condition. Various factors contribute to the nutritional deficiency in aging with subsequent chronic inflammation. Among them, malnutrition and the intestinal malabsorption are the more common causes of inadequate nutritional support in elderly. These physio-pathological conditions lead to a worsening of the condition of the bodies of older people, which al- ready suffer from chronic inflammation and oxidative stress. Under this profile, the free radicals produced by the oxidative stress lead to a damage of DNA, lipids and proteins, with subsequent altered cellular home- ostasis and integrity. In young adults, the cell has a complex and efficient system to maintain a proper balance between the levels of free radicals and antioxidants, ensuring the integrity of cellular components. 
In contrast, in old age this balance is not very efficient, compromising cellular homeostasis (1).

It has long been postulated that supplementation with dietary antioxidants can alleviate the redox imbalance and thereby protect against the deteriorating effects of oxidative stress, progression of degenerative di- seases, and aging. In this context, many micronutrients in the diet may fight oxidative stress and delay aging. Among them, vitamin E is considered one of the most potent lipo-soluble antioxidants to delay aging and to prevent some age-related degenerative diseases (2). Vitamin E is a lipid-soluble vitamin found in cellmembranes and circulating lipoproteins that functions as a non-enzymatic antioxidant scavenging toxic free radicals. It refers to a group of eight compounds that possess a similar chemical structure (four tocopherols and four tocotrienols). Its most active and abundant form is alpha-tocopherol, which is considered the major chain-breaking antioxidant in plasma, in cell membranes and in tissues, protecting polyunsaturated fatty acids in membranes and lipoproteins by interrupting the oxidative chain reactions. Apart from its antioxidant properties, vitamin E has also been reported to enhance immune response (3) and to modulate DNA repair systems (4) and signal transduction pathways (5).

Gene variations (polymorphisms) involved in vitamin E tissue uptake, export and metabolism may be impor- tant determinants for the biological activity of vitamin E. Genetic determinants as well as environmental and lifestyle factors therefore play important roles in the effective biological activity of vitamin E in aging and in the development of age-associated diseases. Decreased food intake, a sedentary lifestyle, reduced energy expenditure in older adults, together with genetic determinants and the risk factors for malabsorption in vitamin E, may further contribute to the decline of bodily functions and to the development of chronic age- related diseases. This last point is very important because conflicting results regarding the effects of vitamin E supplementation in reducing the levels of free radical damage have been reported from human trials. Some authors report vitamin E involved in reaching longevity, whereas others report a dangerous role of vitamin E affecting mortality. Three meta-analyses of randomized controlled trials found that vitamin E sup- plementation did not reduce mortality, implying that vitamin E does not lead to universal systemic benefits against the processes that lead to chronic disease (6-8).

The picture of the role played by vitamin E as a beneficial nutrient for the correct maintenance of many body homeostatic mechanisms is therefore very complex, especially in aging. The available data is inconclusive and contradictory. This is perhaps due to the influence of vitamin E on some genes (9), that in turn may negatively affect the antioxidant and immune response, especially in conditions of chronic oxidative stress, such as in aging and in some degenerative age-related diseases. Therefore, in addition to adequate intakes, vitamin E–gene interactions have to be considered for a correct personalized supplementation in order to achieve healthy aging. The recommendations for vitamin E intake have been established without considering its possible role in enhancing important body functions and preventing chronic diseases, as well as its neces- sity for the elderly people. The intake, the absorption and the distribution within the body of vitamin E is not only relevant for the antioxidant defense against reactive oxygen species with a binding of vitamin E to lipo- proteins on cell membrane, but also for the cell signaling, in particular in immune cells. This fact becomes relevant in aging because of the presence of an impaired inflammatory/immune response and an altered lipid composition in immune cells (10) associated with a possible diet vitamin E deficiency due to the pre- sence of the intestinal malabsorption (2).

Immune cells are particularly enriched in vitamin E because their high polyunsaturated fatty acid content puts them at especially high risk for oxidative damage. Free-radical damage to immune cell membrane lipids may ultimately impair their ability to respond normally to pathogenic challenges, with subsequent impaired inflammatory/immune responses and development of inflammatory diseases. There is some available evi- dence from clinical trials that suggest beneficial effects of supplemental vitamin E on immune function and related diseases (3). From all these findings, it emerges that vitamin E is an antioxidant and immune system-regulating nutrient with an effect especially in cell-mediated and innate immunity. It therefore has a possible role to play in preventing some inflammatory diseases such as cardiovascular diseases (CVD). The reduction of oxidative stress and the inhibition of LDL oxidation by vitamin E are thought to be major actions for which it has received considerable attention as a health benefit in reducing the risk of atherosclerosis. The effect of vitamin E alone in clinical trials on CVD prevention is inconclusive (11-13). The type and dose of vitamin E and co-nutrients (e.g., vitamin C), dietary habit and lifestyle as well as the genetic background of studied subjects might have contributed to the differential results in these studies. For example, while data regarding the beneficial role of vitamin E in protecting against cardiovascular complications in diabetic patients is con- tradictory, research indicates that vitamin E may be beneficial in a genetically defined subgroup of diabetic patients, namely, with a variant of the serum protein haptoglobin (Hp 2-2 genotype) increasing the risk for CVD complications (14).

Since vitamin E interacts with cell receptors (e.g., LDL receptor) and transcription factors, thereby driving (redox-regulated) gene expression, it modulates protein levels (e.g., glutathione) and changes enzyme activity levels (e.g., protein kinase C). The interaction of vitamin E and the genes codifying these proteins is therefore crucial for the effects of vitamin E supplementation. The modulation of enzyme transcriptions and/or activity by vitamin E has been shown in genes involved in oxidative stress, proliferation, inflammation and apoptosis (15). Experimental findings suggest that vitamin E has more long-term rather than short-term effects especially on liver gene expressions and on genes that play an important role in many inflammatory age-related diseases, especially atherosclerosis and CVD.

In conclusion, it is clear that vitamin E is relevant as antioxidant and anti-inflammatory compound for the whole life of an organism, with a special emphasis in aging and in some inflammatory age related diseases. The best known isoform of vitamin E (alpha-tocopherol) seems to have the major properties either as antioxidant or anti-inflammatory agent in various experimental conditions, while other forms (gamma-tocopherol and delta-tocotrienol) may have more precise antioxidant properties. It is possible that inade- quate study participant selection (by vitamin E status and genetic polymorphisms), the presence of advanced lesions, and the dosage and chemical form of vitamin E administered may partly explain the incongruence between the reporting trial data. It is also relevant to note that the effect of vitamin E is more long-term than short-term and the dosage of the vitamin should not exceed 400 IU/day. However, the major incongruence in human clinical trials may be related to the specific genetic background of each individual. Such an as- sumption is supported by approaches with vitamin E supplementation in restoring the inflammatory/immune response in aging (16), in reducing the insulin resistance in diabetes mellitus (17), in decreasing CVD risk in diabetics (18) and in reducing oxidative stress and inflammation in late Alzheimer’s disease (19) on the basis of genetic polymorphisms. Therefore, the interaction of vitamin E with genes related to its bioactivity is fundamental for the success of the clinical trials with vitamin E supplementation in aging and in inflammatory age-related diseases. As such, the essential micronutrient vitamin E can be correctly used on an individual level, either to combat a certain pathological finding or to achieve healthy aging and longevity without any adverse effects.”

Based on: Mocchegiani E. et al. Vitamin E–gene interactions in aging and inflammatory age-related diseases: Implications for treatment. A systematic review. Ageing Research Reviews. Published online January 2014.

1. Poljsak B. and Milisav I. The neglected significance of “antioxidative stress”. Oxid. Med. Cell. Longev. 2012; 480895–480907.

2. Niki E. and Traber M. G. A history of vitamin E. Ann. Nutr. Metab. 2012; 61:207–212.

3. Pae M. et al. The role of nutrition in enhancing immunity in aging. Aging Dis. 2012; 3:91–129.

4. Claycombe K. J. and Meydani S. N. Vitamin E and genome stability. Mutat. Res. 2001; 475:37–44.

5. Azzi A. et al. Vitamin E mediates cell signaling and regulation of gene expression. Ann. N. Y. Acad. Sci. 2004; 1031:86–95.

6. Bjelakovic G. et al. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst. Rev. 3, Art. No: CD007176.

7. Abner E. L. et al. Vitamin E and all-cause mortality: a meta-analysis. Curr. Aging Sci. 2011; 4:158–170.

8. Biesalski H. K. et al. Reexamination of a meta-analysis of the effect of antioxidant supplementation on mortality and health in randomized trials. Nutrients. 2010; 2:929–949.

9. Rimbach G. et al. Gene-regulatory activity of alpha-tocopherol. Molecules. 2010; 15:1746–1761.

10. Molano A. et al. Age-dependent changes in the sphingolipid composition of mouse CD4+ T cell membranes and immune synapses implicate glucosylceramides in age-related T cell dysfunction. PLoS ONE. 2012; 7:e47650.

11. Rimm E. B. et al. Vitamin E consumption and the risk of coronary heart disease in men. N. Engl. J. Med. 1993; 328:1450–1456.

12. Stephens N. G. et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996; 347:781–786.

13. Yusuf S. et al. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N. Engl. J. Med. 2000; 342:154–160.

14. Vardi M. et al. Haptoglobin genotype and cardiovascular outcomes in diabetes mellitus – natural history of the disease and the effect of vitamin E treatment. Meta-analysis of the medical literature. Eur. J. Int. Med. 2012; 23:628–632.

15. Zingg J. M. et al. Genetic polymorphisms as determinants for disease-preventive effects of vitamin E. Nutr. Rev. 2008; 66:406–414.

16. Belisle S. E. et al. Polymorphisms at cytokine genes may determine the effect of vitamin E on cytokine production in the elderly. J. Nutr. 2009; 139:1855–1860.

17. Testa R. et al. Effect of 4G/5G PAI-1 polymorphism on the response of PAI-1 activity to vitamin E supplementation in Type 2 diabetic patients. Diabetes Nutr. Metab. 2004; 17:217–221.

18. Milman U. et al. Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective double-blinded clinical trial. Arterioscler. Thromb. Vasc. Biol. 2008; 28:341–347.

19. Tanzi R. E. and Bertram L. New frontiers in Alzheimer’s disease genetics. Neuron. 2001; 32:181–184.