Keywords

1 Micronutrient Intake in the Elderly

The inadequacy of micronutrient supply in the elderly is documented by an increasing number of studies. Recently, a meta-analysis summarized the data from 41 such studies. These show that, depending on the individual micronutrient, between 15 and 90% of elderly people were at risk of deficiency [1]. The risk was calculated for elderly people who were below the estimated average requirement (EAR). Consequently, according to the definition of the EAR, they are at risk of developing a deficiency with clinical consequences if they stay on the intake below EAR. In particular B-vitamin supply is inadequate—a problem which may be harmful for cognition and mood.

2 Antioxidants

2.1 Importance for Brain Function and Cognition

The brain is considered extremely sensitive to oxidative damage that may occur from reactive oxygen species produced primarily by mitochondria during respiration. The exact amount of ROS produced is around 2% of the total oxygen consumed during respiration, but it may vary depending on several parameters. Some critical components come together in the brain: it is enriched in easily peroxidizable unsaturated fatty acids (20:4 and 22:6), consumes 20% of the total oxygen consumption, and has low antioxidant levels, e.g. 10% of the catalase activity of the liver (Floyd and Carney 1992) and low levels of SOD and GSH (Yoon et al. 2000). Whereas the decrease of endogenous antioxidant enzymes with age cannot really be prevented, exogenous antioxidants may be delivered with the diet or as a supplement to accumulate in the brain. Ascorbic acid seems to be the major-water soluble antioxidant in human brain, at a 15-times higher concentration than in human plasma (Floyd 1999). There is some evidence that oxidative stress contributes to the onset and development of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) (Barenham 2004). Improving the cellular defense against ROS-induced oxidation of neuronal tissue might prevent cognitive impairment and neurodegeneration. In cases of AD, PD and ALS, reduced levels of catalase, super-oxide dismutase and oxidized and reduced glutathione have been documented (Andersen 2004). Deficiencies in antioxidant micronutrients may further contribute to the progression of neurodegenerative diseases and at least cognitive decline with age. At least three prominent changes occur in the brain resulting in cognitive impairment:

  • Accumulation of non-essential substances (lipofuscin prominently in cortical neurons), loss of myelin (e.g. in the limbic cortices), and a general shrinkage;

  • Reduction in the branching of dendrites and reduction of neurotransmitter availability; and

  • Reduction of cerebral blood flow and decline of cerebral blood volume, or at least ischemia.

Accumulation of lipofuscin mainly appears as a result of oxidative stress. The reduction of blood flow may also be a consequence of oxidative modification and, as discussed in the chapter on B-vitamins in this book, the consequence of high homocysteine. With respect to memory, the metabotropic receptors acting via G-proteins are of importance. After binding of a neurotransmitter to that receptor type, the production of a second messenger molecule is induced within the neuron. The induction of the second messenger, travelling in the neuron, results in different cellular reactions. Of greatest importance is the activation of kinases. These enzymes, which can remain active for up to a couple of hours, are involved in long-term changes of the neurons and at least gene expression. The latter may contribute to the formation of novel protein expression and, in some cases, formation of dendrites and new (more or less stable) networks, resulting in a memory. The appearance of a cognitive impairment might be based on a reduced production of neurotransmitters and subsequently reduced activation of kinases. Studies with aging rats revealed that a long-term diet rich in antioxidants can slow down the onset of neuronal degeneration and cognitive impairment (Floyd et al. 1998, 1999). Furthermore, it was shown that the age-related decline in the neuronal process controlled via metabotropic receptors is compensated by a diet rich in antioxidants. The compensation is a result of an improvement of the G-protein on- and off-action (Joseph et al. 1999). Indeed, the animals fed a high antioxidant diet had higher vitamin E levels in the hippocampus compared to the control animals. The hippocampus however, is involved in memory functioning. From the above-described aspects of oxidative stress and its impact on memory, it is suggested that deficiency of antioxidants may contribute to the development of cognitive impairment.

2.2 Antioxidant Deficiencies in the Elderly

Age is an important determinant of the serum values of antioxidants, predominantly vitamin E, vitamin C, and ß-carotene [2, 3]. The data from the European SU.VI.MAX trial clearly showed that plasma levels of retinol, tocopherol and ß-carotene decrease with age in 12,741 volunteers aged 35–60 years [3]. Female senior citizens from Germany aged 60–70 years showed inadequate intake and a poor antioxidant status (selenium, vitamin E, vitamin C and ß-carotene) (Wolters et al. 2006). The Iowa Rural Health Study revealed that in 420 individuals aged 79 years or older, 60% had inadequate intake of vitamin E and 25% of vitamin C (Marshall et al. 2001). Interactions of micronutrients with drugs, more frequently consumed by the elderly, increases the problem of antioxidant deficiency [4]. The occurrence of a low antioxidant status is not restricted to a few countries or areas with low socio-economic status: it seems to be a general and unrecognized problem of the aging population. The consequences of a low antioxidant intake are frailty, degenerative diseases, walking disabilities, and higher mortality (Semba et al. 2006, 2007; Michelon 2006). A low intake of antioxidant contributes to a decline in cognition and promotes the development of dementia.

2.3 Human Studies

Based on recent published data, the intervention with antioxidants to decrease either the progression or the onset of cognitive impairment is controversial. However, subdividing the studies into short- and long-term interventions, it becomes clear that an interventional approach needs more than one year to be effective. The EVA study evaluated in 980 subjects aged 62–72 years the relationship between the enzymatic system—restricted to copper and zinc superoxide dismutase (Cu/Zn SOD) and the seleno-dependent glutathionperoxidase (GSH-Px)—and decline in cognitive function. Cognitive decline over a four-year period was associated with a lower activity of the GSH-Px and a higher Cu/Zn SOD. Table 6.1 summarizes trials with antioxidants. Five out of six studies which examined the effect of antioxidant supply via food documented statistically significant inverse associations (**). Four out of five observational studies found an inverse relationship between antioxidant intake from supplements (vitamin E, vitamin C) and the risk of AD (*) or cognitive decline (***).

Table 6.1 Data of prospective and intervention studies with antioxidants
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Table 6.1 summarizes the data of prospective and intervention studies with antioxidants.

The above-cited studies clearly show that antioxidants play a preventive role against the development and progression of dementia. Intake of supplements containing antioxidants (vitamins A, C and E, Se and Zn) over a longer period (five years and more) in six studies with more than 800 participants (one with 162) showed prevention of dementia or a benefit to cognitive function. Three studies with a rather low number of participants (<250) were without effect. This shows that, dependent on the statistical power, the effect of antioxidants on cognitive decline becomes evident.

The clinical trials showed controversial results. In the Kang trial, there was an 8% reduction in the decline of the global score. The Peterson trial seems to be without effects of antioxidants on cognitive decline or AD development. However, nearly one third of all patients developed AD within three years. Based on a couple of epidemiological and observational studies, the development of AD in patients with MCI is around 5% per year and not more than 10%, as is the case in that study. This difference might be due to an increased number of early AD patients in the MCI group at the beginning of the trial. Antioxidants however, have nil or only a very moderate impact in cases of existing AD.

3 Homocysteine-Lowering Vitamins

3.1 Importance of B-Vitamins for Cognition

B-vitamins (B6, B12, folic acid) are involved in the methylation of homocysteine (Hcy). Low intake, higher demand or polymorphism of enzymes (MTHFR; GCPII) results in hyperhomocysteinemia. Hcy is a non-protein-forming sulfhydryl-containing amino acid. Because Hcy is highly cytotoxic, the i.c. concentration is kept low by catabolism and by a cellular export mechanism into plasma. Consequently, a high plasma concentration documents a high cellular Hcy formation. A couple of diseases are discussed as related to high homocysteine levels, such as arteriosclerosis, myocardial infarction, stroke, and peripheral vascular disease, as well as Parkinson’s disease and Alzheimer- and vascular-dementia (***). Epidemiological studies show an increase of Hcy with increasing age and a negative correlation with cognitive function. Differing pathomechanisms are discussed as responsible for the effect of Hcy on brain structure and function, such as direct toxicity on dopaminergic neurons (Imamura et al. 2007), or on the vascular endothelium (**). High Hcy or low folate or B12 show an influence on cellular redox status, including up-regulation of redox-sensitive transcription factors (NFkB, AP-1), thus promoting calcium influx, amyloid and tau protein accumulation, apoptosis and neuronal death (***). Under conditions of hyperhomocysteinemia, neural cells are exposed to the neurotoxic activity of Hcy. The consequences are a disturbed metabolism of excitatory neurotransmitters (e.g. glutamate), which causes excitotoxic effects associated with increased ROS formation and at least oxidative damage of neuronal tissues (**). This excitotoxic effect of Hcy is assumed to be realized via NMDA receptors (Sachdev 2005). Indeed, Streck and coworker (2003) demonstrated significant increased lipid peroxidation in rat hippocampus following Hcy treatment. The involvement of oxidative stress in the pathogenesis of dementia has been frequently shown in in vitro and in vivo experiments (**). Oxidative stress activates gene expression of a couple of components related to apoptosis and at least neuronal degeneration, such as caspase 3- and 6-dependent activation of apoptotic pathways (Anantharam et al. 2007). Oxidative stress induces apoptotic cell death in dopaminergic-derived N27 cell line and, to a lesser extent, in GABAergic striatum derived and hippocampal cell lines (Anantharam et al. 2007). Cell death was mediated via caspase 3-dependent pathways. The active proteases caspase 3/6 cleave tau proteins at specific sites, generating toxic tau fragments or enhancing the aggregation properties of these microtubule-associated proteins (Park and Ferreira 2005). Caspase 6, a potent cleaving protease of the tau protein (Guo et al. 2004), has been detected in neurofibrillary tangles of humans with MCI, and it is concluded that the activity of caspase 6 precedes the clinical and pathological diagnosis of AD (Albrecht et al. 2007). The interactions of hyperhomocysteinemia, oxidative stress and caspase activation may explain the beneficial effect of lowering Hcy and antioxidative treatment on cognitive impairment (McCaddon 2015; de Lau et al. [5]).

3.2 Deficiencies of B-Vitamins in the Elderly

Elderly people with low circulating folate or vitamin B12 have higher fasting total homocysteine concentrations. Supplementation with B-vitamins results in normalization of elevated Hcy plasma levels. Data from NHANES III, including 3563 male and 4523 female participants, clearly showed that high homocysteine concentrations were significantly associated with low serum vitamin (folate, B12) concentrations (Selhub 2011). With increasing age, Hcy increases in plasma, mainly due to a low folate intake. Sixty-six percent of the participants (747) aged 67–96 years had a folate intake below the recommended 400 µg, and 16.7% were below 200 µg. Data from the German nutrition survey show that 60% of the population (aged 18–79 years) has an intake of folate below 75% of the recommendation. Low folate and B12 intake is a general problem in the elderly and critically contributes to cognitive decline and arteriosclerosis.

3.3 Human Studies

Studies estimating intake of foods rich in B-vitamins revealed a clear-cut inverse relationship between the highest intake of fruit and vegetables and fish consumption and cognitive decline in the elderly (Table 6.2).

Table 6.2 Nutrition and prevention of cognitive decline: data from prospective studies on food groups and dietary patterns
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Despite the fact that pure nutrition studies have certain limitations, the data show that a diet rich in phytochemicals and water-soluble vitamins may protect against accelerated cognitive decline. Furthermore, fish intake was inversely correlated with cognitive decline. This preventive effect might be attributed to either n-3 fatty acids and/or vitamin D—essential nutrients that are both present mainly in fish. The data from the nutrition studies show that a mixed diet, rich in antioxidants (fruits, vegetables), which also contains edible oil (vitamin E), meat as a source for selenium and optimum bioavailable folate, and at least B12 (Mediterranean diet) does indeed prevent the progression of MCI.

To further elucidate whether single micronutrients are responsible for the preventive effect, studies are carried out which measure either biomarkers of intake of selected micronutrients or else plasma levels of these micronutrients.

Table 6.3 summarizes trials with either dietary or supplemental intake of B-vitamins and cognitive impairment.

Table 6.3 Trials with B-vitamins and cognitive impairment
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High dietary intake of folate and other B-vitamins was associated with a lower rate of cognition decline and at least incidence of AD in nine out of 12 studies. No study showed any negative effect. Plasma levels of homocysteine are correlated with an increased risk of AD or increased cognitive decline in four out of five studies. One study with 1033 participants documented an inverse relationship between plasma folate and cognition and performance independent of Hcy concentration (de Lau et al.) [5]. Taken together, a sufficient intake of Hcy-lowering vitamins results in a decreased decline of cognitive function and a decreased risk of AD.

To further elucidate the role of Hcy-lowering vitamins, clinical intervention studies were carried out (Table 6.4).

Table 6.4 Nutrition and prevention of cognitive decline: data from prospective studies and randomized clinical trials on homocysteine-related B vitamins
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Intervention studies reveal conflicting results. This may in part be due to differences in treatment time, dosage and at least study population. Nevertheless, the WHICAP study shows that persons with MCI indeed may benefit from a long-term treatment with Hcy-lowering vitamins. Based on the pathomechanisms discussed above, it seems important to treat patients with MCI with a combination of Hcy-lowering vitamins and antioxidants. Studies combining these micronutrients are at present not available. However, prospective studies estimating the effect of nutrition containing Hcy-lowering and anti-oxidative vitamins do exist (Table 6.4).

4 Summary: Key Messages

  • Micronutrients support the maintenance of cognitive function during aging.

  • Besides genetics and lifestyle, nutrition is claimed as an important factor which interacts with basic pathologies of cognitive decline.

  • Vitamins, trace elements and minerals can mitigate the risk of cognitive decline, especially in elderly people at risk of deficiencies.

  • Epidemiological studies demonstrate that with increasing age, the prevalence of nutritional deficiencies increases, in particular deficiencies of antioxidants and B-vitamins.

  • Micronutrient deficiencies may contribute to, or even promote, cognitive impairment.

  • A strategy to improve micronutrient status may help improve cognition or delay the onset of MCI and at least Alzheimer dementia (AD).