Molecular Neurobiology

, Volume 48, Issue 2, pp 353–362

Food, Nutrigenomics, and Neurodegeneration—Neuroprotection by What You Eat!

Authors

    • Research, Innovation and DevelopmentSigma-tau SpA
  • Luigi Pinto
    • Research, Innovation and DevelopmentSigma-tau SpA
  • Zbigniew Binienda
    • Neurophysiology Laboratory, Division of Neurotoxicology, National Center for Toxicological ResearchFood and Drug Administration
  • Syed Ali
    • Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological ResearchFood and Drug Administration
Article

DOI: 10.1007/s12035-013-8498-3

Cite this article as:
Virmani, A., Pinto, L., Binienda, Z. et al. Mol Neurobiol (2013) 48: 353. doi:10.1007/s12035-013-8498-3

Abstract

Diet in human health is no longer simple nutrition, but in light of recent research, especially nutrigenomics, it is linked via evolution and genetics to cell health status capable of modulating apoptosis, detoxification, and appropriate gene response. Nutritional deficiency and disease especially lack of vitamins and minerals is well known, but more recently, epidemiological studies suggest a role of fruits and vegetables, as well as essential fatty acids and even red wine (French paradox), in protection against disease. In the early 1990s, various research groups started considering the use of antioxidants (e.g., melatonin, resveratrol, green tea, lipoic acid) and metabolic compounds (e.g., nicotinamide, acetyl-l-carnitine, creatine, coenzyme Q10) as possible candidates in neuroprotection. They were of course considered on par with snake oil salesman (women) at the time. The positive actions of nutritional supplements, minerals, and plant extracts in disease prevention are now mainstream and commercial health claims being made are subject to regulation in most countries. Apart from efficacy and finding, the right dosages, the safety, and especially the level of purification and lack of contamination are all issues that are important as their use becomes widespread. From the mechanistic point of view, most of the time these substances replenish the body’s deficiency and restore normal function. However, they also exert actions that are not sensu stricto nutritive and could be considered pharmacological especially that, at times, higher intake than recommended (RDA) is needed to see these effects. Free radicals and neuroinflammation processes underlie many neurodegenerative conditions, even Parkinson’s disease and Alzheimer’s disease. Curcumin, carotenoids, acetyl-l-carnitine, coenzyme Q10, vitamin D, and polyphenols and other nutraceuticals have the potential to target multiple pathways in these conditions. In summary, augmenting neuroprotective pathways using diet and finding new natural substances that can be more efficacious, i.e., induction of health-promoting genes and reduction of the expression of disease-promoting genes, could be incorporated into neuroprotective strategies of the future.

Keywords

NutritionNutrigenomicsNeuroprotectionNutraceuticalsl-CarnitinePolyphenolsVitaminsCoenzyme Q10

Introduction

The long-term consequences of nutrition for health were summed up by Ludwig Andreas Feuerbach who wrote in 1864 “Der Mensch ist was er isst” or “Man Is What He Eats.” Indeed the importance of nutrition for disease prevention has been recognized since the days of Hippocrates 460–377 A.C who said “Let food be your medicine and medicine be your food.”

Nutrition is one of the lifestyle factors that could contribute to the development and progression of chronic diseases such as diabetes, cancer, atherosclerosis, cardiovascular disease, and neurodegenerative diseases [13].

Until the early 2000s, the science of pharmacology was based on strong foundations according to which drugs were separated from natural substances and these “synthetic” substances (mainly artificially synthesized chemical entities) had well-studied safety and efficacy profiles. Their mechanism of action was usually well known, e.g., able to modulate a preexisting receptor or enzyme function in the cell and there were well-established screening techniques to find new drug entities [4]. For example, the benzodiazepine class of drugs is able to increase Cl influx through the GABAA receptor to induce inhibitory phenomena in the CNS. However, if we take another molecule, say ethanol, it is able to have an inhibitory action on the CNS. The difference, however, is that ethanol is not a drug (from a pharmaceutical point of view) but mainly a nutrient from which the cell is able to produce ATP, and although its consumption, and in many cases its abuse, is connected to disease and dependence, it is not really a pharmacological agent per se but a molecule found in nature that is also a nutrient [5]. This and other examples of natural molecules that have actions that could be considered “pharmacological” have given rise to the term nutraceutical.

Diet is becoming an important factor for human health and can no longer be considered simply nutrition, but in light of recent advances in research, especially nutrigenomics, it can be shown to be intimately linked via evolution and genetics to cell health status capable of modulating apoptosis, detoxification, and appropriate gene response. Nutritional deficiency and disease, especially lack of vitamins and minerals, were well known and associated with specific disease conditions, e.g., lack of vitamin C was associated with scurvy, niacin (vitamin B3) with pellagra, etc. [6]. More recently, epidemiological studies suggest that it is not just deficiency of a particular element but also presence in diet in adequate amount of various other compounds from fruits and vegetables, as well as from plants and animal sources of specific essential amino acids and fatty acids and even compounds in red wine such as resveratrol (French paradox), all play a role in maintaining health and protection against disease [7].

In the early 1990s, various research groups started talking about use of antioxidants (e.g., melatonin, resveratrol, green tea, lipoic acid) and metabolic compounds (e.g., nicotinamide, acetyl-l-carnitine, creatine, coenzyme Q10) as possible candidates in neuroprotection. They were off course considered on par with snake oil salesman (women) at the time. The positive actions of nutritional supplements, minerals, and plant extracts in disease prevention is now mainstream and commercial health claims that are being made are subject to strict regulation in most countries. Apart from providing proof of efficacy for a particular health claim, other factors such as finding the right dosages, the safety profile, and especially the level of purification and presence of solvents and contaminants, heavy metals, bacteria, fungi, etc. are all issues needed to be considered as their use becomes widespread [8, 9].

From the mechanistic point of view as mentioned above, most of the time these substances replenish the body’s deficiency and restore normal function. However, they also exert actions that are not sensu stricto nutritive and could be considered pharmacological especially that, at times, higher intake than recommended (RDA) is needed to see these effects.

This nutraceutical approach, together with strong emerging research techniques such as nutrigenomics, metabolomics, and proteomics, opens a strong new front towards disease prevention and treatment that is innovative and holds great possibilities.

The use of “natural” substances to modulate metabolic pathways and to manage disease conditions is becoming a new frontier field of study that shows a high promise to treat pathological conditions.

Is It Possible to Modulate/Treat Pathology such as Neurodegeneration with Nutraceuticals?

In severe pathology characterized by neurodegeneration in the CNS, the treatment options to date have been very disappointing. There are enormous personal, family, and social costs associated with these conditions due to deterioration of the neurological and psychological status of the afflicted individual.

Free radicals and neuroinflammation processes are thought to underlie many of the neurodegenerative conditions, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Studies suggest that many natural compounds such as curcumin, carotenoids, acetyl-l-carnitine, coenzyme Q10, vitamin D, and polyphenols and other nutraceuticals have the potential to target multiple pathways in these conditions [1, 10].

The classical mechanism for the actions of minerals, vitamins, and nutrients as substrates and cofactors in various enzyme- or receptor-related activities is well known. For example, pantothenic acid (vitamin B5) is needed for oxidative metabolism of carbohydrates and lipids and is also involved in hormone and neurotransmitter synthesis. Deficiency of pantothenic acid leads to the appearance of symptoms such as headache, fatigue, and insomnia, as well as an increased possibility of neuropathy. In this way, neuronal function and cognitive processes that are dependent on the synthesis of neurotransmitters/hormones, as well as on cellular energy metabolism, can be affected.

Effects on Cellular Free Radical Stress

Additional functions have been found for these compounds when used in times of particular stress and deficiency states and/or at higher than normal dosages, in particular, their ability to modulate cell health status, inducing for example apoptosis or detoxification, especially in response to free radical stress, e.g., reactive oxygen species (ROS) and reactive nitrogen species (RNS) or both [11]. In this particular group are substances that can be classified generally as antioxidants. Belonging to this group are the polyphenols, such as the catechins found in green tea, which exert neuroprotective action in part due to their antioxidant properties and in part since they are able to protect mitochondrial function and therefore cellular energy production [12, 13]. Other antioxidant compounds such as melatonin also exert a protective role against neurodegeneration [14].

Effects on Cellular Bioenergetics

Antioxidants such as alpha lipoic acid [13] and coenzyme Q10 [15] and metabolic agents such as nicotinamide [16] and others protect mitochondrial biogenesis and have protective effects on the brain. Carnitines, in particular acetyl-l-carnitine, have been shown to improve mitochondrial function and exert neuroprotective actions [17]. Studies suggest that part of the action of the carnitines could be via gene modulation (Fig. 1). The carnitines seem capable of acting biologically on Keap1 (an inhibitor of NrF2 family of transcription factors) and allow the expression of phase II detoxifier genes, thereby reducing oxidative stress [17].
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Fig. 1

Action of acetyl-carnitine on Kelch-like ECH-associated protein (KEAP1) and expression of phase II genes. Key: KEAP1 is acetylated by acetyl-l-carnitine and the nuclear factor (erythroid-derived 2)-like 2 (NrF2) transcription factor is hence free to bind to the antioxidant response element (ARE) and allows the expression of phase II detoxifier genes heme oxygenase-1 (HO-1, Heme-Ox 1), whereas polyphenols act directly on NrF2 to improve its binding ability with AREs

Epigenetic Modulation

The effects of nutrition on the body are also mediated by epigenetic mechanisms [18]. The three known, closely interacting mechanisms are DNA methylation, histone modification, and noncoding microRNAs. Nutritional factors may induce epigenetic changes via three pathways: (a) direct influence on gene expression, (b) activation of nuclear receptors by ligands, and (c) modification of membrane receptor signaling cascades [19]. Therefore, epigenetic mechanisms provide the organism with a robust and time-responsive system for adapting gene expression that is (a) tissue type specific, (b) appropriate for the developmental state of the organism, and (c) responsive to signals from the external and internal environment [20].

This has led to a promising line of research, nutrigenomics, which is beginning to explain the role of gene expression in the ability of various substances to modulate cell health. Interesting links are beginning to emerge between the various protective pathways such as caloric restriction, sirtuins (resveratrol), and age-related disease. This opens new strategies for augmenting neuroprotective pathways using diet and finding new natural substances that can be more efficacious, i.e., by induction of health-promoting genes and reduction of the expression of disease-promoting genes and other as yet unknown pathways/mechanisms.

The science behind nutraceuticals research for disease prevention is therefore quite promising and a highly important and challenging task. Modulation of what we eat may provide health benefits, including the prevention and treatment of disease and could be incorporated into neuroprotective strategies of the future.

A Common Denominator in Understanding Neurodegeneration Process—Aging

As mentioned before, a common denominator in understanding how nutrigenomics is linked to neurodegenerative diseases is represented by the aging process [21]. In many respects, neurodegeneration is similar to accelerated or dysfunctional aging. In aging, the progressive decrease in physiological capacity and the reduced ability to respond to environmental stresses leads to increased susceptibility and vulnerability to disease.

Studies to date suggest that aging is in part linked to dysfunctional cell modulation possibly resulting from three principal signaling networks that end in ROS/RNS detoxification, cell cycle arrest, and apoptosis induction, and these signaling networks can be acted upon by dietary restriction, hormonal signaling, and oxidative stress. The first is modulated by polyphenols (i.e., resveratrol) [22] in general and act through the sirtuins family proteins; the second act via AKT/SGK and is represented by insulin-like growth factor or tumor growth factor as the primary receptors. This network ends in foxO genes family modulation that manages ROS/RNS detoxification and cell cycle regulation. Last but not the least, oxidative stress network signaling started by oxidative stressors that modify the peroxides the plasmalemma lipids and these are stimuli for the start of this network that act through MKKK via JNK and together ends in modulation of the foxO genes family.

We focus the attention in this review on the dietary restriction effects on signaling network that is regulated at nuclear level through three particular families of genes: sir, foxA, and NrFs (Fig. 2).
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Fig. 2

Intranuclear targets of caloric restriction, resveratrol, and polyphenol. Resveratrol, a type of polyphenol, is able to act on sirtuin (SIRT) and forkhead box (FoxA) genes, miming the caloric restriction signaling through AMP-activated protein kinase (AMPK), or it can interact directly with NrF2 and allow its translocation onto the ARE elements. FoxA and NrF2 play a role in ROS detoxification

Dietary (or caloric) restriction is thought to act through ROS/RNS detoxification and/or through induction of apoptosis of the cell [23]. Specifically, sir family genes act on the telomeres and genome maintenance (cell cycle arrest and apoptosis) whilst FOXA and the NrF family transcription factor act on the processes of detoxification from ROS/RNS, even if the former can also act on cell cycle regulation.

There are numerous triggers that are thought to lead to neurodegeneration; however, in the general aging process, the underlying biological mechanism by which degeneration occurs does so in all cells independent of an obvious trigger. The free radical theory of aging postulates that aging and its related diseases are the consequence of free radical-induced damage to cellular macromolecules and the inability to counterbalance these changes by endogenous antioxidant defenses. The biochemical consequence of this situation is reduced energy and excitotoxicity possibly as a consequence of mitochondrial dysfunction [24].

The mitochondria are the power generators of the cell and impairment of their function leads to reduced energy but also increased ROS escaping into the cell. This happens in conditions such as stroke/ischemia or in the presense of prooxidants such as quinolinic acid [25, 26]. The use of antioxidant substances able to reduce or quench ROS and prevent mitochondrial and cellular dysfunction may therefore counteract neurodegeneration.

Nature Has Evolved Protective Mechanisms as well as Substances

Cells utilize vitamin E to reduce or avoid the lipoperoxidation of lipids and counteract the consequences of free radical generation. The consequences of excitotoxicity are not also counteracted by polyphenols, e.g., epigallocatechins, and in particular epigallocatechin gallate (EGCG), but also curcumin and others [25, 26]. In part, these compounds probably prevent the consequences of the calcium overload and mitochondrial dysfunction [25, 27, 28]. Studies have shown that resveratrol protects against damage to the brain and spinal cord associated with ischemia–reperfusion [29] and traumatic injury [30].

Antioxidants Can Also Act on Apoptosis/Cell Cycle Regulation

The effectors of intracellular death are enzymes called caspases. The mitochondrial membrane depolarization and influx of calcium into the cell are stimuli for induction of apoptosis because these conditions also activate caspase-3 and consequently apoptosis [3135]. Two polyphenols, magniferin and morin, are able to reduce the number of active caspase-3 neurons after activation of the glutamate receptor in vitro [36]. Various in vivo studies also demonstrate the ability of polyphenols to reduce apoptosis after ischemia conditions [36]. Flavonoids such as quercetin, puerarin, narinigenin, and genistein protect dopaminergic neurons against oxidation and apoptosis [37].

Free radical production also induces inflammatory processes due to the misfolding of proteins and other mechanisms. In the brain, this phenomenon is called neuroinflammation and in this condition antioxidants also exert a protective action (see below). Indeed, in pathologies such as AD or PD, flavonoids can exert positive actions [38] since they:
  • Attenuate the release of cytokines as IL1β or tumor necrosis factor (an inflammatory molecule)

  • Exhibit inhibitory actions against the production of iNOS (responsible for the production of NO)

  • Inhibit the activation of NADH oxidase and ROS

  • Have a regulatory activity on the action of NFkB that is a modulator of inflammation

  • Can modulate the MKKK network (typical network signaling of oxidative stress pathway)

One of the main components of green tea, EGCG, demonstrates neuroprotective actions via MAPK, Akt, and protein kinase C. EGCG acts via alpha secretases to allow the processing of amyloid beta peptide typical of AD [39].

Neurodegeneration Role of Mitochondria and Inflammation

Neurodegenerative conditions such as AD, PD, and multiple sclerosis (MS) are characterized by a high rate of inflammation, ascribed to wide cellular disruption phenomena typical of these conditions, which is in part related to mitochondrial DNA (MtDNA) damage [40]. The hypothesis is that MtDNA damage triggers or at least contributes to the etiology of these disease conditions [41, 42]. Damage to MtDNA results in aberrant functionality of the respiratory chain and oxidative phosphorylation [43]. Mutations of MtDNA involves mainly the functionality of complex I and IV and changes in complex I are generally observed in PD, while mutations in complex IV are typically found in AD [44, 45].

Autoimmune pathology is thought to underlie MS with a chronic inflammatory component of the CNS due to extensive neuronal disruption (necrosis) from an immune system that does not recognize as “self” the myelin sheath, determining an interruption of neuronal communication. Free radical-mediated mechanisms due to mitochondrial injury may be the initial triggers in MS [4653]. This ROS-induced oxidation involves not only MtDNA but also lipids of the myelin sheath [5456]. Studies show improvement in MS by antioxidants, mitochondrial protection, and anti-inflammatory compounds [57].

Mitochondrial function may be protected by various compounds. Coenzyme Q10 and l-carnitine play a fundamental role in mitochondrial bioenergetics processes (Fig. 3). Mitochondrial function and energy production may be partly protected by carnitines [58, 59] and coenzyme Q10 [60].
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Fig. 3

Role of carnitines and coenzyme Q10 in mitochondrial functions. l-Carnitine translocates free fatty acids into the mitochondria for beta-oxidation and energy is produced in the Krebs cycle and the oxidative phosphorylation processes

Although the classical role of l-carnitine is to shuttle fatty acid molecule into the mitochondria for beta-oxidation, studies are showing other roles for this molecule. l-Carnitine as an antioxidant able to scavenge free radicals in several ways, i.e., physically, chemically, and biologically. Thus, l-carnitine protects tissues in a physical way for example from ionizing radiations [61], in the chemical way by quenching of ROS [62] and in the biological way by induction of NrF2 transcription factor thereby allowing the expression of phase II detoxifier genes [17, 63] (Fig. 1).

l-Carnitine is also able to protect against inflammatory processes [64] since ROS triggers protein misfolding which may lead to increased inflammation in disease states such as Huntington disease (HD) [65, 66]. l-carnitine was able to revert the condition of neurodegeneration caused by excitotoxicity in the brains of rats treated with quinolinic acid and 3-nitropropionioc acid, two strong oxidant agents, the former source of HD-like convulsions and the later a molecule that causes mitochondrial impairment and oxidative damage [67].

Positive Modulation of Genes in Aging … Yes Sir!

Probably the most relevant evidence of the influence of diet in gene modulation is the discovery that the antioxidant resveratrol and dietary restriction are modulators of an important family of genes, the silent information regulator (sir) family [27]. The sir genes code for NAD+-dependent histone deacetylases called sirtuins. These enzymes are responsible for deacetylating DNA [68, 69].

Several studies depict sir genes as “longevity genes.” The reason could be that the sir family of genes permits the positive modulation of a particular genes family called progastricsin (pepsinogen C) pgc into the PGC-alpha protein. This protein is basilar in allowing mitochondrial biogenesis and at the same time ROS detoxification [70].

Sirtuins, dietary restriction, and as discussed above a number of natural agents are coming to light that can influence longevity genes and may modify not only the biological processes underlying aging but possibly also neurodegeneration [59].

System Biology in Neuroprotective Strategies—Future Perspective

The system biology approach lends itself perfectly to the study of neurodegeneration. It looks at the underlying biology as an information science and studies systems as a whole and their interactions with the environment. In particular, it takes into count five principal features [71]:
  • Quantify and measure: Various biological information at a global level

  • Integration of information: Analyze not only the cellular metabolism or physiology but also their roles and changes in relation to the environment.

  • Study of dynamic changes: Through a full range analysis taking into account not only the current status of the cell and of the relationship with the environment but also their possible development.

  • Modeling: Uniform data obtained to develop biological hierarchies (system evolution biology).

  • Test and improvement: All the data collected can be really useful to test and make predictions.

This has led to the “new” discipline of “System Medicine” which we may divide arbitrarily into at least three typical applications:
  • Immunomodulation: Capability to realize intrinsic and inducted modulation of the immune system [72].

  • Pharmacogenomics: Based on the development of new drugs and DNA-oriented, mainly vaccines, that shed new light principally on the host–pathogen interaction [73, 74].

  • Nutrigenomics: Study how nutrition influences metabolic pathways and homeostatic control, how this regulation is disturbed in the early phase of a diet-related disease, and to what extent individual sensitizing genotypes contribute to such diseases [75].

Nutrigenomics, the System Biology Approach

An integrated approach to analyze the metabolic and the proteic (signaling) pathways in the cell has opened up new approaches in treating neurodegeneration. Metabolomics is the study of metabolic pathways in their complexity and fullness [76] and when integrated with transcriptomics and proteomics gives a fuller picture of the underlying processes of the pathology (Fig. 4).
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Fig. 4

System biology and nutrigenomics. This is an integrated approach to simultaneously analyze signaling pathways components and the metabolic, genomic, transcriptomic, and proteomic data

Transcriptomics is the analysis of the total mRNA of a cell or tissue, or more generally of organs or systems. In proteomics, the proteome is the entire set of proteins of a cell at a given moment of the cell cycle or phase of a metabolic pathway, is dynamic and varying according to cell type and functional state. Proteomics and metabolomics have a wide range of applications in nutrigenomics and provide information on the metabolic alteration produced by the effects of nutrients or bioactive foods in different metabolic pathways. It is difficult to describe briefly the wide range of techniques, but the most important applications are microarray technology, sequencing-based technologies, and bioinformatics [77].

Regulatory Aspects of Nutraceuticals

The use and abuse of these “natural” compounds has to be investigated and eventually treated in all purposes as pharmacological agents. In particular, excessive dosages and types of solvents used in extraction as well as possible toxicity due to contaminants have to be controlled.

Nutrigenomics: Current Status, Future, and Perspective

Nutrition intervention strategies may be preventive or supportive in the general healthy population, or in case of disease, they may also be therapeutic.

This opens new scenarios not only to study nutragenetics and nutrigenomics but to realize personal therapies tailored on the basis of individual genetic patterns [78]. For this reason, single nucleotide polymorphisms (SNPs) are taken into consideration that have a frequency of about 1/1,000 (0.1 % variation).

There are about 10 million common SNPs in the human genome, and through the systems biology approach, it is possible to correlate SNPs to typical nutrition-related diseases [78, 79]. The development of functional foods is based on clinical, epidemiological, and experimental evaluation of a population and of the frequency of its diseases; together with data on the role of gene expression modulation [17], it is an innovative way to treat diseases.

In this context, the ENCODE project must be mentioned which is cataloging every human gene and identifying for each its functional expression pattern. Currently, researchers estimate that there are about 30,000 human genes [80] and the vast majority (80.4 %) of the human genome is implicated in at least one biochemical RNA- and/or chromatin-associated event in at least one cell type [81, 82]. Many different kinds of specific DNA regions which play a role in expression and regulation of functionality of other genes have been found:
  • Transcribed and protein coding regions: Through the analysis of cellular RNA, these are referred not only to coding RNA but also to ncRNA (lncRNA and sRNA) and pseudo genes. Similarly, untranslated regions have also been identified (Table 1).
    Table 1

    Main definitions about newly discovered DNA elements

    Main definitions

    SNP—Single nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide—A, T, C, or G—in the genome (or other shared sequence) differs between members of a species (or between paired chromosomes in an individual)

    Pseudogene—DNA sequence that resembles a gene and may be derived from one but lacks a genetic function

    ncRNA—Noncoding RNA is an RNA that do not codify for any protein, can be long noncoding RNA (lncRNA) and small RNA (sRNA)

    UTR—Untranslated regions that is part of the DNA that are not subjected to translation

  • Protein bound regions: These are regulatory regions determined using 119 different DNA-binding proteins and several polymerases elements.

  • DNase I hypersensitive sites and footprints: Region where it is possible to identify a high sensitivity for DNase I showing in this way the sites of chromatin accessibility.

  • Regions of histone modification: Are histone domains subjected to the application of “Histone Code” and recent studies show a role for acetyl-l-carnitine in this region [83].

  • DNA methylation sites: Methylation of cytosine, usually at CpG dinucleotides, is involved in epigenetic regulation of gene expression. Promoter methylation is typically associated with repression, whereas genic methylation correlates with transcriptional activity.

  • Chromosome-interacting regions: Regions separated by hundreds of kilobases that through spatial rearrangement make possible the physical interaction between chromosome regions as another important way to regulate gene expression [81].

In conclusion, the above discussion shows that a nutrigenomics approach may in the future allow for the elucidation of the genomic and cellular regulating mechanisms, and in particular their role in the deterioration of normal healthy processes and in the initiation of disease processes. In disease states such as neurodegeneration, this type of information could be leveraged to augment neuroprotective pathways using the diet as well as through use of new natural substances that can be more efficacious (i.e., by induction of health-promoting genes and reduction of the expression of disease-promoting genes) and this type of approach could be incorporated into the neuroprotective strategies of the future.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Disclaimer

The views presented in this article do not necessarily reflect those of the US Food and Drug Administration.

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© Springer Science+Business Media New York (outside the USA) 2013