**4. Neuro-nutraceuticals: definition, examples and mechanisms of action**

Nutraceuticals are defined as "*food or food product that provides medical or health benefits including the prevention and treatment of diseases*" [46]. This concept is partially overlapping with the term "bioactive compounds" – "secondary plant metabolites eliciting pharmacological or toxicological effects in man and animals" [47]. Neuro-nutraceuticals are, by extrapolation, active compounds, obtained from food products or plants that exert effects on the CNS. They can be represented by vitamins, amino acids, minerals, trace elements, etc., with presumed health-promoting or disease-preventing effects. Oxidative stress, dysregulation of redox metals homeostasis and inflammation represent the main leading causes of brain aging and therefore the administration of antioxidant and anti-inflammatory molecules can be an important strategy for preventing brain aging and several brain age-related diseases such as Parkinson's disease, Alzheimer's disease, dementia and depression [48, 49].

However, the evaluation of nutraceutical efficacy and safety represents a big challenge due to the complex chemical compositions and multiple mode of actions [50]. Starting from chemical classification of bioactive compounds [47], several classes have been repeatedly associated with beneficial neurological effects. *Flavonoids* consist of a central three-ring structure and may occur as oligomers *-proanthocyanidins*. All compounds contain phenol groups with antioxidant effect. Many different polyphenols have been reported to retard age-related declines in CNS function, cognition and behavior. A polyphenol with the ability to modulate a multitude of signaling molecules and with antibacterial, anti-inflammatory and neuroprotective properties is *curcumin,* the active ingredient in the spice turmeric. Curcumin acting as an antioxidant, anti-inflammatory and lipophilic agent can improve the cognitive functions in animal models and patients with Alzheimer's disease by several mechanisms. Short-term supplementation of curcumin to aged rats enhanced the frequency of polysialylated cells in the dentate infragranular zone and significantly improved both spatial learning and memory in adult and aged rats [51]. The long-term curcumin-supplemented diet had a important effects on hippocampal cellular proliferation, cognitive function and transcriptional responses in aged rats and this response is dependent of the length of curcumin treatment [52]. Curcumin administration supported the immune system to reduce beta-amyloid plaques, ensures the delayed degradation of neurons and decreased microglia activation resulting in the improvement of overall memory [53]. Curcumin treatment could also improve the outcome of patients with traumatic brain injury by reducing acute activation of microglia/macrophages and neuronal apoptosis, demonstrated by *in vivo* experiments [54]. *Eugenol (*4-allyl-2-methoxyphenol), an antioxidant and anti-inflammatory molecule, found in various plants such as basil, cinnamon and other herbs is another nutraceutical with demonstrated roles in brain physiology. In the *Drosophila* model, eugenol manifests neuroprotective effects in acrylamide-induced neuropathy models. *In vitro* studies showed that eugenol enhanced the viability of neuroblastoma cell lines by reducing oxidative stress in experimental hyperglycemia. Moreover in diabetic rats, eugenol administration results in reduction of oxidative markers in brain with restoration of activities of mitochondrial complexes I, II and III [55, 56]. Other polyphenols (anthocyanin extract, pomegranate or resveratrol), exerted their anti-inflammatory effects by reducing TNF-a brain level and microgliosis or sirtuin activation in correlation with improving brain plasticity in non-transgenic AD animal models [57, 58]. *Resveratrol* positive effects were also related to the activation of AMP-activated kinase (AMPK) and the antioxidant transcription factorNrf2 (nuclear factor (erythroid derived 2)-like 2) [59]. In a randomized, double-blind, placebocontrolled, phase II trial of resveratrol for patients with Alzheimer's disease, resveratrol was detected in cerebrospinal fluid with beneficial effects such as the alteration of Alzheimer's disease biomarker trajectories, the preservation of blood-brain barrier integrity and the modulation of the central nervous system immune response [60].

*Probiotics* are "viable microorganisms, sufficient amounts of which reach the intestine in an active state and thus exert positive health effects" [72]. The most commonly used probiotics are bacterial species (frequently, *Lactobacillus* and *Bifidobacterium*, but also some *E. coli* and

Role of Nutraceuticals in Modulation of Gut-Brain Axis in Elderly Persons

http://dx.doi.org/10.5772/intechopen.73005

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Both types of nutraceuticals exert positive effects beyond local, intestinal environment. Prebiotics were demonstrated to exhibit triglycerides and cholesterol-lowering effects [70], with beneficial effect on blood-brain barrier integrity and brain lipid metabolism. Among many local effects, it is worth mentioning that, related to gut-brain axis, probiotics modify the gut microbiota, which is the main determinant of tryptophan levels, the serotonin precursor,

Throughout the next sections, some evidence of modulation of gut-brain axis with nutraceuticals in the elderly will be discussed, in relationship with experimental results from preclinical

Diet and altered gut physiology, together with age-related changes in intestinal microbiome and a weakened immune system [74, 75] result in low-grade inflammation in the gut, that is associated with systemic release of pro-inflammatory metabolites. Finally, the inflammatory process is related to glial cells activation, neuroinflammation and to cognitive decline in the elderly [37, 41].

A useful model for the study of gut-brain axis is the germ-free (GF) mouse. GF mice have socially impaired behavior [12] and present an exaggerated stress response [76] that can be directly correlated with changes occurring in different regions of the brain [13], depressed neurogenesis [77] and prefrontal cortical hypermyelination [78]. However, preclinical studies reveal that oral administration of probiotics and/or nutraceuticals is sufficient to reduce anxiety-like and depressive-like behaviors and to induce changes in brain chemistry [10, 79]. For example, the impaired microglial function in GF animals was rescued by the oral treatment with short-chain fatty acids [80]. Also, Distrutti et al. [81], showed that a *probiotic* mixture (VSL#3) induced a significant change in the composition of gut microbiota of aged rats and increased brain tissue expression of genes associated with inflammation and neural plasticity such as BDNF and synapsin.

The gut microbiome is also essential to the bioavailability of *polyphenols*, *unsaturated fats* and *antioxidants,* all of which may help protect against neuronal and cell aging under normal circumstances [82]. For example, the diet supplemented with blueberries (rich in anthocyanin and flavanols) improved spatial working memory in aged animals [83]. This process is accompanied by increases in neural stem cells proliferation, extracellular receptor kinase activation and increase of insulin-like growth factor-1 (IGF-1) level, the key modulator of hippocampal neurogenesis [84]. Also, aged rats consuming berry diets exhibited enhanced motor performance and improved cognition, correlated with increased hippocampal neurogenesis and

*Bacillus* species), but the yeast *Saccharomyces cerevisiae* and can also be employed [73].

hence the documented effect of these food supplements as anxiety alleviators.

**5. Modulation of gut-brain axis with nutraceuticals in the elderly:** 

**evidence-based benefits in animal models**

and clinical studies.

expression of IGF-1 [85].

*Methylxanthine alkaloids* (found in coffee and cocoa) elicit stimulating neurological effects. Some *tropane alkaloids* are analgesics [61]. Aromatic compounds, terpenes/terpenoids and aliphatic molecules, particularly with low molecular weights, found in plant essential oils, were mentioned as free radicals scavengers and acetylcholine esterase inhibitors [62]. Some volatile oils were associated with anxiolytic and antidepressant effects, along with strong antioxidant effects [63].

*Creatine* is a nitrogenous organic acid found in animal tissues being involved in several critical processes in the brain such as the sustaining of energy supply, antioxidant processes and neuroprotection. Increased dietary intake of creatine can elevate brain creatine levels which can sustain cognitive function under oxidative and nitrosative stress. Several *in vitro* or even preclinical studies showed that creatine directly preserves mitochondrial function in adult neurodegenerative conditions [64, 65]. Clearly, mitochondrial impairment contributes directly and/or indirectly to the pathogenesis of numerous neurodegenerative disorders [66]. Exogenous creatine supplementation reduced neuronal cell loss in acute and chronic neurological diseases and promoted differentiation of neuronal precursor cells [67]. *In vivo* studies showed that maternal creatine supplementation during pregnancy protects the brain against the effects of severe birth asphyxia [68, 69].

A special class of food derivatives or food ingredients includes prebiotics and probiotics.

*Prebiotics* are defined as "nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth or the activity of one or a limited number of bacteria (*Bifidobacteria* and *Lactobacilli*) in the colon" [70]. From chemical perspective, they are fructooligosaccharides, enzymatically processed in the colon with positive impact on commensal flora. Fermentation of prebiotics generates short-chain fatty acids [71], which exert positive effects on integrity of epithelial barrier, but also on brain metabolism, as discussed later.

*Probiotics* are "viable microorganisms, sufficient amounts of which reach the intestine in an active state and thus exert positive health effects" [72]. The most commonly used probiotics are bacterial species (frequently, *Lactobacillus* and *Bifidobacterium*, but also some *E. coli* and *Bacillus* species), but the yeast *Saccharomyces cerevisiae* and can also be employed [73].

memory [53]. Curcumin treatment could also improve the outcome of patients with traumatic brain injury by reducing acute activation of microglia/macrophages and neuronal apoptosis, demonstrated by *in vivo* experiments [54]. *Eugenol (*4-allyl-2-methoxyphenol), an antioxidant and anti-inflammatory molecule, found in various plants such as basil, cinnamon and other herbs is another nutraceutical with demonstrated roles in brain physiology. In the *Drosophila* model, eugenol manifests neuroprotective effects in acrylamide-induced neuropathy models. *In vitro* studies showed that eugenol enhanced the viability of neuroblastoma cell lines by reducing oxidative stress in experimental hyperglycemia. Moreover in diabetic rats, eugenol administration results in reduction of oxidative markers in brain with restoration of activities of mitochondrial complexes I, II and III [55, 56]. Other polyphenols (anthocyanin extract, pomegranate or resveratrol), exerted their anti-inflammatory effects by reducing TNF-a brain level and microgliosis or sirtuin activation in correlation with improving brain plasticity in non-transgenic AD animal models [57, 58]. *Resveratrol* positive effects were also related to the activation of AMP-activated kinase (AMPK) and the antioxidant transcription factorNrf2 (nuclear factor (erythroid derived 2)-like 2) [59]. In a randomized, double-blind, placebocontrolled, phase II trial of resveratrol for patients with Alzheimer's disease, resveratrol was detected in cerebrospinal fluid with beneficial effects such as the alteration of Alzheimer's disease biomarker trajectories, the preservation of blood-brain barrier integrity and the modula-

*Methylxanthine alkaloids* (found in coffee and cocoa) elicit stimulating neurological effects. Some *tropane alkaloids* are analgesics [61]. Aromatic compounds, terpenes/terpenoids and aliphatic molecules, particularly with low molecular weights, found in plant essential oils, were mentioned as free radicals scavengers and acetylcholine esterase inhibitors [62]. Some volatile oils were associated with anxiolytic and antidepressant effects, along with strong antioxidant effects [63].

*Creatine* is a nitrogenous organic acid found in animal tissues being involved in several critical processes in the brain such as the sustaining of energy supply, antioxidant processes and neuroprotection. Increased dietary intake of creatine can elevate brain creatine levels which can sustain cognitive function under oxidative and nitrosative stress. Several *in vitro* or even preclinical studies showed that creatine directly preserves mitochondrial function in adult neurodegenerative conditions [64, 65]. Clearly, mitochondrial impairment contributes directly and/or indirectly to the pathogenesis of numerous neurodegenerative disorders [66]. Exogenous creatine supplementation reduced neuronal cell loss in acute and chronic neurological diseases and promoted differentiation of neuronal precursor cells [67]. *In vivo* studies showed that maternal creatine supplementation during pregnancy protects the brain against

A special class of food derivatives or food ingredients includes prebiotics and probiotics.

*Prebiotics* are defined as "nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth or the activity of one or a limited number of bacteria (*Bifidobacteria* and *Lactobacilli*) in the colon" [70]. From chemical perspective, they are fructooligosaccharides, enzymatically processed in the colon with positive impact on commensal flora. Fermentation of prebiotics generates short-chain fatty acids [71], which exert positive effects on integrity of epithelial barrier, but also on brain metabolism, as discussed later.

tion of the central nervous system immune response [60].

252 Gerontology

the effects of severe birth asphyxia [68, 69].

Both types of nutraceuticals exert positive effects beyond local, intestinal environment. Prebiotics were demonstrated to exhibit triglycerides and cholesterol-lowering effects [70], with beneficial effect on blood-brain barrier integrity and brain lipid metabolism. Among many local effects, it is worth mentioning that, related to gut-brain axis, probiotics modify the gut microbiota, which is the main determinant of tryptophan levels, the serotonin precursor, hence the documented effect of these food supplements as anxiety alleviators.

Throughout the next sections, some evidence of modulation of gut-brain axis with nutraceuticals in the elderly will be discussed, in relationship with experimental results from preclinical and clinical studies.
