Dietary Flavonoids and Adult Neurogenesis: Potential Implications for Brain Aging

Abstract

Adult neurogenesis deficiency has been proposed to be a common hallmark in different age-related neurodegenerative diseases. The administration of flavonoids is currently reported as a 
potentially beneficial strategy for preventing brain aging alterations, including adult neurogenesis 
decline. Flavonoids are a class of plant-derived dietary polyphenols that have drawn attention for their neuroprotective and pro-cognitive effects. Although they undergo extensive metabolism and localize in the brain at low concentrations, flavonoids are now believed to improve cerebral vasculature and interact with signal transduction cascades involved in the regulation of adult neurogenesis. Furthermore, many dietary flavonoids have been shown to reduce oxidative stress and neuroinflammation, improving the neuronal microenvironment where adult neurogenesis occurs. The overall goal of this review is to summarize the evidence supporting the role of flavonoids in modulating adult neurogenesis as well as to highlight how these dietary agents may be promising candidates in restoring healthy brain function during physiological and pathological aging.

1. INTRODUCTION

The functional capabilities of the brain decline progressively with advancing age. Although this decline differs between individuals, it is associated with a decline in learning and memory, attention, sensory perception, and motor coordination. Likewise, age-related changes in the central nervous system (CNS) are characterized by compromised neuronal plasticity, neuronal cell death and decreased adult neurogenesis, the process by which new neurons are generated and integrated into the CNS during adulthood [1, 2]. Therefore, during aging, impaired adult neurogenesis or the progressive exhaustion of neural stem cells (NSCs) in the adult neurogenic niches may contribute to different neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD) [3]. Indeed, adult neurogenesis is a crucial component of neural plasticity, brain homeostasis, and tissue remodeling in the CNS.

Although the occurrence of neurogenesis in the adult brain has been long debated, during the last years, the generation of new neurons has been reported in several restricted areas of the brain where precursor cells reside, such as the two most studied regions, the rostral subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus [4, 5]. However, besides these two main neurogenic areas, adult neurogenesis has been reported in the hypothalamus, substantia nigra, striatum, amygdala, habenula, and cerebellum [5, 6].

It is well known that there are important determinants that regulate neurogenesis in the adult brain. These determinants influence the differentiation and fate determination of NSCs and include intrinsic and extrinsic factors, such as neurotrophins, growth factors, inflammatory cytokines, hormones, physical exercise, environmental enrichment, and dietary components [7].

Many bioactive substances present in food have been shown to regulate and stimulate adult progenitor cells and neurogenesis. Dietary phytochemicals, which are known to possess many neuroprotective effects against neurodegenerative disease, may enhance the proliferation of NSCs in the adult brain [8-11]. In addition to their ability to reduce oxidative stress and neuroinflammation, activate autophagy, and affect growth factors, these compounds alter the specific microenvironments in which adult progenitor cells reside [12]. Flavonoids are an important class of plant polyphenols that are commonly consumed in the human diet via vegetables, fruits, and other plant-based products. Although they are not essential nutrients to humans, flavonoids have a broad spectrum of favorable biochemical effects associated with various diseases, including neurodegeneration and mood disorders [13-15]. Epidemiological studies have repeatedly demonstrated that a higher intake of flavonoid-rich foods may reduce cognitive decline and the risk of dementia [16-18].

Although the limited bioavailability of flavonoids and their low localization in the brain, experimental data clearly support that these dietary components scavenge neurotoxic species and proinflammatory agents produced in the brain as a consequence of aging [19]. Furthermore, the structural diversity of flavonoids allows them to interact with a wide variety of neuronal signaling cascades leading to a possible improvement in age-related cognitive deficits. These interactions within neuronal pathways seem to enhance existing neuronal function, modulate neurotransmitter release, stimulate neuronal regeneration, and induce hippocampal neurogenesis. Likewise, the intake of flavonoids improves both peripheral and cerebral blood flow, promoting vascular effects capable of stimulating new nerve cell growth in the hippocampus [20, 21]. Therefore, it is possible that flavonoids influence adult neurogenesis through the modulation of neuronal pathways and peripheral vascular effects.

The aim of this review is to provide an overview of the current state of knowledge of how flavonoids influence adult neurogenesis in the context of brain aging.

2. FLAVONOIDS

Flavonoids are a class of phenolic compounds that are widely distributed in the plant kingdom. They protect plants from various biotic and abiotic stresses and, together with chlorophylls and carotenoids, represent one of the major pigments in angiosperm families. For example, these compounds are involved in plant-pathogen interactions, photoprotection, pollination, seed development, and allelopathy. Since their levels increase under stress conditions, many flavonoid biosynthetic genes are induced during exposure to metal toxicity, UV radiation, nutrient deprivation, drought, and wounding [22].

2.1. Structure, Classification, and Sources

Flavonoids are plant secondary metabolites and until now, more than 9000 structural variants have been identified in plant tissues [22]. The structures of flavonoids differ greatly in relation to various substitution patterns. These patterns afford flavonoid complexity and can include glycosylation, hydroxylation, and methylation. The various biological properties of these compounds are mostly due to glycosylation, which also contributes to their hydrophilicity. Flavonoids do not occur as aglycones in plants, but the most frequent forms are the glycoside derivatives [23].

These compounds are synthesized from chalcone precursors that are derived from phenylpropanoid and three molecules of malonyl-CoA. Flavonoids are structurally characterized by two aromatic rings (A and B) linked through three carbons that form an oxygenated heterocycle (C ring). Although they share a similar skeleton structure, flavonoids are classified into different subclasses according to substitution patterns and variations in the saturation of the basic ring system. These subclasses include flavones; flavonols; flavan-3-ols; flavanones; anthocyanins; isoflavones (Fig. 1) [22, 24].

Fig. (1).

Major flavonoid classes, their subclasses and dietary sources.

Flavonoids are major constituents of a variety of foods and beverages of plant origin. The estimated flavonoid intakes in US adults average between 200 and 250 mg/day [25, 26]. Although several factors may affect the flavonoid content of foods (e.g., agricultural practices and food processing), the subclasses may have unique major sources. Flavones, such as apigenin, luteolin, and chrysin, are widely present in artichokes, celery, and parsley. Red peppers, citrus fruits, chamomile, mint, and ginkgo biloba are also rich sources of flavones [27]. Most flavones have a hydroxyl group in position 5 of the A ring, while hydroxylation in position 3 of the structure gives rise to flavonols, such as kaempferol, quercetin, myricetin and fisetin. Considering the different glycosylation, methylation and hydroxylation patterns of flavonols, this subclass appears to be one of the largest subgroups of flavonoids in fruits and vegetables. Together with tea and red wine, tomatoes, apples, grapes, berries, onions, kale, and lettuce are the most common sources of flavonols [28].

Flavanones are found at high concentrations in all citrus fruits and tomatoes. They are characterized by a saturated C ring with the saturated bond between positions 2 and 3. Moreover, the hydroxy groups of flavanones can be methylated and/or glycosylated. Naringenin and hesperetin are prominent examples of this subclass. Flavanonols are the 3-hydroxy derivatives of flavanones and include taxifolin. Flavan-3-ols, also called flavanols, are another important class of flavonoids. The hydroxyl group is always bound to position 3 of the C ring. They can exist as monomers and oligomers, known as condensed tannins or proanthocyanidins. These molecules include catechin, epicatechin, epigallocatechin, epicatechin gallate, and epigallocatechin gallate, which may be found abundantly in tea, red wine, cocoa, and fruits such as apples and many berry fruits [29]. Isoflavones are a large subclass of flavonoids characterized by extensive structural variability. They are classified according to the oxidation level of the central pyran ring and may be found in soybeans and other leguminous plants. Isoflavones, such as genistein and daidzein, show structural analogies with estrogens and thus are defined as phytoestrogens [30]. The most studied anthocyanins are cyanidin, delphinidin, malvidin, pelargonidin, and peonidin. In general, anthocyanins are pigments responsible for colors in plants. Color variations depend on the pH environments but also on the methylation at the hydroxyl groups on the rings. The sources of anthocyanins include black currants, red grapes, cranberries, raspberries, strawberries, blueberries, bilberries and blackberries [31]. Anthocyanins tend to exist at high concentrations in plant food; for instance, a serving of 200 g eggplant or black grapes can contain 1,500 mg of anthocyanins [32].

2.2. Metabolism and “Neuro-Availability” of Flavonoids

In the last decade, absorption and bioavailability of flavonoids have been research topics of increasing interest. Although flavonoids have antioxidant capacities in vitro, their bioavailability is limited in vivo due to extensive metabolism and rapid excretion. During and after absorption, flavonoids undergo extensive modifications in intestinal and liver cells and accordingly, they appear as metabolites in the bloodstream and urine. Importantly, the biological activities of these metabolites can be more effective than those of their parent compounds [33, 34].

Several factors influence the bioavailability of dietary flavonoids, including interactions with the food matrix, detoxification pathway, and composition of gut microbiota. Non-covalent interactions between flavonoids and macro- and micro-nutrients in foods affect the bioavailability and mechanism of action of flavonoids in humans. Although the exact mechanisms remain unclear, it has been proposed that reduced bioavailability might be due to the entrapment of flavonoids to the food matrix. Furthermore, the collected evidence suggests that milk proteins might reduce flavonoid absorption, while carbohydrates and fats may enhance their absorption and change their absorption kinetics [35, 36].

Flavonoids are recognized as xenobiotics, and, therefore, they are rapidly transformed by phase II detoxification enzymes to form glucuronidated, methylated, and/or sulphated derivatives. These transformations increase the solubility and facilitate excretion in the bile and urine. However, further metabolism occurs in the large intestine, in which gut microbial enzymes induce the breakdown of flavonoids into simple phenolic molecules. The enzymes of the gut microflora transform flavonoids, through deglycosylation, demethylation, and dihydroxylation, into metabolites with low molecular weights that can undergo absorption and/or be further metabolized in the liver. However, the metabolic fate and bioavailability of dietary flavonoids appear strictly dependent on the composition of colonic bacteria. Despite the interindividual variability, the activity of colonic bacteria may lead to transformations of the parent compounds into more bioavailable metabolites [37-39].

Once absorbed, dietary flavonoids or their metabolites must be distributed to tissues via systemic circulation. However, in order to influence brain function, they need to penetrate the blood-brain barrier (BBB) to be “neuro-available”. Multiple studies have demonstrated that some flavanones or their metabolites, along with some dietary anthocyanins, can cross the BBB in experimental models [40-42]. The extent of BBB penetration is associated with compound lipophilicity and it seems that less polar derivatives (i.e., O-methylated metabolites) have greater brain uptake than the more polar derivatives (i.e., glucuronidated and sulphated metabolites). Importantly, current findings and mathematical correction methods indicate that when flavonoids cross the BBB, they reach tissue levels below 1 nmol/g [42-44]. Many in vitro studies using similar concentrations reflect these physiological levels revealing that some flavonoid subclasses may be retained in neural tissue longer than in plasma, increasing their effectiveness in the brain [45-49].

Despite differences in endogenous metabolism and gut microflora, animal studies offer several advantages to assess the neuro-availability of flavonoids. For example, pigs, a suitable model for human digestive absorption, are used to examine the deposition of dietary phytochemicals in tissues, including the brain. The results of the study conducted by Kalt et al. revealed that anthocyanins may accumulate in the cortex and cerebellum of pigs after supplementation of blueberry for 4 weeks [45]. The same authors also demonstrated that, when fed to pigs, blueberry anthocyanins are bioavailable, transit the BBB, and can be found in the cortex, cerebellum, midbrain, and diencephalon of pigs 18 h after the last anthocyanin feeding [46]. Other studies examined brain tissue concentrations of anthocyanins using a model of an aged rat. Andres-Lacueva et al. noted malvidin galactoside to be the most prevalent anthocyanin in the cortex, and the next most prevalent anthocyanins were cyanidin 3-galactoside and delphinidin 3-galactoside [50].

Wang and colleagues administered to rats an oral grape extract of proanthocyanidins enriched in monomeric or polymeric forms, and then they examined the metabolites in the brain. Interestingly, only monomeric compounds were effective in reaching the brain at a concentration of ∼400 nM. The effects of the metabolite 3’-O-methyl-epicatechin-5-O-b-glucuronide were then studied further in vitro on hippocampal physiology. These authors found that this metabolite enhances both basal synaptic transmission and long-term potentiation at a concentration of 300 nM [51]. A study has also reported that 4'-demethylnobiletin, a metabolite of the flavonoid nobiletin, was detectable in the brain after intraperitoneal injection [52]. However, flavonoids can also indirectly influence the CNS by modulating pathways from peripheral organs to the brain. Indeed, there is evidence that flavonoids, in particular flavan-3-ols, are capable of promoting improvements in vascular health through their potential to lower blood pressure, improve endothelial function, inhibit platelet aggregation, and reduce the inflammatory response [53-57]. These peripheral vascular effects may increase cerebral blood flow that is known to deteriorate with age. The improvement of peripheral and cerebral blood flow indicates that some benefits on brain functions can be associated with the surrounding vasculature and not necessarily through a direct effect on neurons or glia [58, 59]. The vascular effects of flavonoids are particularly relevant, as an improved cerebrovascular function can enhance vascularization and facilitate adult neurogenesis, two processes important in the maintenance of cognitive performance [60, 61].

3. ADULT NEUROGENESIS

Adult neurogenesis is preserved throughout adulthood in the mammalian brain resulting in the production of new neurons, but this phenomenon is not ubiquitous and it occurs in specific and restricted areas of the brain, the neurogenic niches, which are special microenvironments where stem cells are located [5]. The occurrence of neurogenesis in humans has been widely studied by immunohistochemistry, producing limited and often contradictory results caused principally by the use of in vitro proliferating cell models [62, 63]. In this context, animal models have helped to add important information to the adult neurogenesis picture; however, the existence of phylogenetic differences between humans and rodents has evidenced different stages of neuronal maturation, including the striatal neurogenesis found only in humans and the olfactory bulb neurogenesis absent in humans, but present in other mammals [62, 64].

As mentioned above, the adult mammalian brain contains two “traditional” neurogenic niches: the SVZ of the lateral ventricles and the DG of the hippocampus, in which adult neurogenesis has been extensively described and where several well-characterized stages of the neurogenic process have been defined, from cell proliferation to neuronal differentiation, maturation, and functional integration.

In detail, the reservoirs of regenerative NSCs, known as type B1 cells, are specialized microenvironments comprising cells from the NSC lineage, endothelial cells (i.e., blood vessels), and microglia. In SVZ, they resemble astrocytes and then differentiate mainly into neurons that populate the olfactory bulb (OB) and, to a lesser extent, into astrocytes and oligodendrocytes throughout a person’s life [4]. In the adult SVZ, these cells express the glial fibrillary acidic protein (GFAP), one of the several astrocytic features, lipid-binding protein and glutamate aspartate transporter and are present in one of two stages: quiescent or actively diving NSCs [4, 65]. The activation of B1 type cells involves the expression of nestin, an undifferentiated neuronal precursor cell (NPC) marker, and the asymmetric division for self-renewal, resulting in type C cells expressing chaete-scute homolog 1 and distal-less homeobox 2 [66]. Also these type C cells divide and differentiate in neuroblasts (type A cells) asymmetrically; lastly, neuroblasts divide one or more times and migrate through the rostral migratory stream providing new γ-aminobutyric acid (GABA) and dopamine (DA)-containing interneurons in the olfactory bulb [67]. Several factors, such as growth factors, hormones, and neurotransmitters, can modulate and preserve neurogenesis in the adult SVZ [7]. Therefore, SVZ neurogenesis plays an important role in the development of optimal olfactory circuitry and is associated with different olfactory functions, including odor discrimination, olfactory learning and memory and probable sexual function [68-70].

The NSCs are also located in the SGZ of the hippocampal DG, in a niche along the border of the inner granule cell layer, where the generation of new neurons persists throughout adulthood. The hippocampus is probably one of the regions in the brain characterized by extensive plasticity, representing an essential property for the function and role in learning, memory and mood regulation; in this context, adult hippocampal neurogenesis may be an evolutionary system that increases its functional plasticity [5,71].

Consequently, hippocampal neurogenesis is a complex, highly regulated, multi-step process [6, 72, 73]. Similar to the SVZ, type 1 cells are radial-glia-like cells expressing nestin and GFAP, and the maintenance of this pool is a critical event for neurogenesis preservation regulated by numerous factors, such as the transcription factor sex-determining region Y-box 2 (Sox 2), brain-derived neurotrophic factor (BDNF) and activation of the hypothalamus-pituitary-adrenal axis [74-76]. Type 1 cells are able to divide asymmetrically, giving rise to transit amplifying type-2 cells [77, 78]. These transient cells that are GFAP-negative, capable of tangential migration and highly proliferative can be classified, according to the expression of the immature neuronal marker doublecortin (DCX), into less differentiated DCX- type 2A cells and more differentiated and committed to the neuronal lineage DCX+ type 2B cells [78-80].

Type-2B cells further differentiate into type-3 cells, which are DCX+ and nestin- and express the neuronal marker polysialylated neuronal cell adhesion molecule (PSA-NCAM) [77, 81]. Newly generated cells enter a post-mitotic stage characterized by the expression of post-mitotic neuronal markers, neuronal nuclei (NeuN) and calretinin (CR) [81,82]. The number of neuroblasts (immature neurons) rapidly declines, only 20% survive and are incorporated into the existing neuronal circuitry [82-84]. After exiting the cell cycle, neuroblasts attempt to establish functional receiving neurotransmitter signals as well as trophic support from pro-survival factors, contributing to neuronal maturation in granule cells and their completing functional maturation and integration into the existing hippocampal circuitry, contributing to spatial and contextual memory, pattern separation and mood regulation [73, 85-89].

However, during the last years, new pools of NSCs with neurogenesis activity, often limited under normal physiological conditions, but induced in response to different pathological and pharmacological stimuli, were reported in other several brain areas with possible functional implications [4, 5]: the hypothalamus with activities related to the energy balance and various hypothalamic homeostatic mechanisms [90-93], the substantia nigra [94], the striatum [95-97], the amygdala [98]. The cortex [99], the habenula [100], and the cerebellum [101].

However, the presence of neurogenesis in these brain areas is still debated, often linked to the absence of spontaneous or constitutive adult neurogenesis in mammalian: some studies have suggested that new neurons originate from endogenous stem pools located within these brain regions, others have shown the migration of neurons from the SVZ to these regions [4].

3.1. Adult Neurogenesis and Aging

Aging is associated with a gradual reduction in the effectiveness of mechanisms involved in the maintenance of homeostasis of the organism and its organs and tissues, including the brain and adult neurogenesis. Indeed, aging negatively affects the proliferation of NSCs, reducing the ability of these cells to generate new neurons. The decline of neurogenesis during physiological aging is accompanied by a broad range of functional consequences, including impaired performance on learning and memory tasks and reduced olfactory discrimination. In elderly individuals, the decrease in neurogenesis has been associated with higher susceptibility to cognitive impairment and neurodegenerative disorders, such as AD, where impaired neurogenesis is a potential relevant mechanism underlying memory deficits [102-107]. Supporting evidence reports the reduction of the number of NSCs in SVZ during aging, resulting in neurogenesis impairment [108-110].

What factors contribute to the decrease in adult neurogenesis upon aging? A complex combination of factors are thought to underlie the loss of neurogenic niches activity during aging (Table 1). As described above, adult neurogenesis requires a specific microenvironment, the so-called niche, which provides the signals that are needed to maintain and control the proliferation and differentiation of the precursor cells. During aging, the decline in precursor cell activity is related to the increased cell quiescence, with fewer NSCs in the actively dividing state, and the imbalance of internal homeostatic maintenance of the neurogenic niche [111-113]. In this context, many signaling pathways have been described as crucial for the survival of adult-born neurons. Numerous studies have shown that Wnt/β-catenin pathway components operate in the hippocampal neurogenic niche. This pathway is involved in progenitor proliferation, differentiation, migration and integration into the granule layer, maintenance of pluripotency, and synaptogenesis [114, 115]. The downregulation of the Wnt pathway strongly contributes to the quiescence of NPCs and reduces hippocampal neurogenesis during the aging process [116, 117].

Table 1.

Principal causes involved in adult neurogenesis impairment during aging.

Causes of Adult Neurogenesis Impairment During Aging	Aging-related Functional and Molecular Alteration	References
Decline in precursor cell activity and alteration of proliferation/survival pathways	Increased cell quiescence; Decreased Wnt and CREB pathways	[111-113, 116, 117, 119]
Variation of the expression of growth factor	Decreased EGF, NGF, BDNF, GDNF and FGF2 levels; Increased TGF-β1 levels	[120-124]
Vasculature deterioration and permeabilization	Decreased VEGF levels; Increased proinflammatory mediators transition through BBB	[127, 138]
Alteration of nutrient-sensing pathways	Increased insulin/IGF1 signaling; Decreased FoxOs transcription factors levels	[129-130]
Alteration of mitochondrial function and oxidative stress	Decreased mitochondrial abundance and membrane potential, ATP levels and oxygen consumption; Increased ROS levels	[132, 133, 143]
Neuroinflammation	Increased microglia activity and proinflammatory cytokines release	[135-137]
Imbalance of hormones	Decreased sex hormones levels	[144]
Epigenetic changes	Increased inactivation of pluripotency genes	[145]

Abbreviations: CREB, cAMP response element-binding protein; EGF, epidermal growth factor; NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; GDNF, glia-derived nerve factor; FGF2, fibroblast growth factor 2; TGF-β1, transforming growth factor β1; VEGF, vascular endothelial growth factor; BBB, blood-brain barrier; IGF1, insulin growth factor 1; FoxOs, forkhead box transcription factors O; ATP, adenosine 5′-triphosphate; ROS, reactive oxygen species.

In the adult brain, the transcription factor cyclic adenosine monophosphate (cAMP)-responsive element-binding protein (CREB) participates in learning and memory through its involvement in adult neurogenesis. CREB is a major downstream target of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway that contributes to neuronal differentiation and brain neuroplasticity. The presence of phosphorylated CREB (pCREB) has been found in many newborn immature neurons in the most important neurogenic niches, including the DG in the SGZ [118]. CREB levels and activity are decreased in the aged brain, suggesting that increasing CREB activity could ameliorate age-related deficits [119].

Furthermore, those alterations in the secretory profile of neighboring niche cells are particularly relevant: these changes that occur in aging are known to influence the conditions necessary to maintain stemness and neurogenesis in the niche microenvironment. Changes in growth factor levels might underlie changes in neurogenesis as a consequence of disease or aging. The age-dependent reduction of the expression of some growth factors, such as epidermal growth factor (EGF), nerve growth factor (NGF), BDNF, glia-derived nerve factor (GDNF) and fibroblast growth factor 2 (FGF2), which are well-known mitogens that promote the self-renewal of NSCs, and increased secretion of proinflammatory cytokines by microglia in the SVZ are known to impair neurogenesis may be a cause of the decline in neurogenesis [120-123]. Although, some factors could decrease with age, others, such as cell-cycle regulator transforming growth factor β1 (TGF-β1), might increase, causing the inhibition of the proliferation of early precursor cells [124].

Other factors, such as accumulation of DNA damage, deficient proteostasis, and vasculature deterioration, may lead to impaired NSC self-renewal and increased NSC dormancy and death [125, 126]. Indeed, blood vessels are an integral and functional part of stem cell niches: level of the vascular endothelial growth factor (VEGF), a promotor of angiogenesis and a known positive effector of neurogenesis, decreases in the hippocampus upon aging [127].

Furthermore, the microenvironment of neurogenic niches is sensitive to changes in nutrient availability. Depending on their state, the various cell types in the niche have very different metabolic needs. Several studies revealed that nutrient-sensing pathways, such as the insulin/insulin growth factor 1 (IGF1)-forkhead box transcription factor (Fox) O pathway, are essential regulators of NSCs function and maintenance in the SVZ and DG [128]. FoxOs transcription factors are the downstream effectors of the insulin/IGF1 pathway, and their loss leads to premature exhaustion of the NSCs: suppression of insulin/IGF1 signaling with subsequent activation of FoxOs is beneficial for long-term maintenance of the NSCs pool [129, 130]. Similarly, suppression of the mammalian target of rapamycin (mTOR), which integrates nutrient sensing with cellular processes that fuel cell proliferation, may enhance NSC maintenance [130, 131].

Relevant to brain aging, it has been found that age-related alterations in mitochondrial function negatively affect adult hippocampal neurogenesis: hippocampal NSCs mitochondria become more densely packed, with decreased membrane potential and lower levels of adenosine 5′-triphosphate (ATP) and in SVZ mitochondrial abundance and the oxygen consumption rate decrease with age [132, 133]. Therefore, restoring mitochondrial function could help to preserve NSC function during aging and boost neurogenesis. For example, ectopic expression of proliferator-activated receptor gamma coactivator 1α (PGC1α), a factor that promotes mitochondrial biogenesis and aerobic capacity, improves neurogenic activity in the aged SVZ [134].

The role of inflammation in adult neurogenesis is complex, with beneficial and detrimental consequences. This dual effect depends largely on the magnitude of the inflammatory response and can result in enhancement and/or inhibition of neurogenesis. Although this subject remains under intense investigation, it is well documented that inflammatory mediators released during acute inflammation usually lead to the maintenance of neurogenesis as a mechanism of brain repair. This is a rapid and short response involving the mobilization of neural precursors for repair, remyelination, and axonal regeneration. Conversely, uncontrolled chronic inflammation is a long-lasting response associated with increased microglia activity and detrimental effects for adult neurogenesis. Since normal aging is a situation characterized by a chronic low-grade inflammatory state (i.e., inflammaging), a persistent inflammatory response impairs neurogenesis, making individuals more susceptible to cognitive deficits and neurodegeneration [135-137]. It should be also noted that blood vessels become more permeable with aging, allowing the circulation of proinflammatory mediators in the brain that normally would be blocked by the BBB [138]. More recently, an age-dependent increase in the soluble form of vascular cell adhesion molecule 1 (VCAM1) was reported to cause a potential decrease of hippocampal neurogenesis in the inflammatory transcriptional profile [139].

Oxidative stress also contributes to impaired neurogenesis in aging because it inhibits various stages of the process. Although oxidative stress occurs as a result of routine adult neurogenesis, an overload of reactive oxygen species (ROS) during aging can alter the proliferation, differentiation, migration, integration, and survival of newly generated neurons in the adult brain [140]. Several studies have reported that chronic oxidative stress impairs neurogenesis in aged animals to a much greater extent than in their younger counterparts [141, 142]. Furthermore, an increased release of ROS is a crucial factor in the activation of chronic neuroinflammation, thus inhibiting the process of adult neurogenesis [143].

Accumulating evidence also points to an important role of hormones as factors that modulate adult neurogenesis. For example, sex hormone levels decline with age, coinciding with reduced proliferation and survival of newly born neurons [144]. Likewise, as reviewed by Morales et al., epigenetic changes in NSCs are widely considered key players in the decline of neurogenesis during aging [145]. All these alterations may underlie the higher susceptibility to cognitive impairment and neurodegenerative disorders of aged individuals.

4. FLAVONOIDS AND ADULT NEUROGENESIS

Flavonoids modulate several cascades and effectors involved in the regulation of adult neurogenesis, such as CREB-BDNF signalling and the ERK1/2 pathway. Flavonoids are also molecules endowed of antioxidant and anti-inflammatory properties and these effects are under study as a potential strategy for preventing brain aging alterations associated with adult neurogenesis decline [146-148]. All these actions, discussed in detail in the sections below and summarized in Table 2, can likely contribute to flavonoids' beneficial effects on neurogenesis, especially with advancing age.

Table 2.

Details of preclinical and clinical studies reporting the effects of various flavonoids on adult neurogenesis.

Model	Flavonoid	Outcome Measurement (Technique)	Pathway	Outcome	References
Mouse C17.2 cells Male C57BL/6 mice (6 weeks old)	Baicalein In vitro (1 or 10 mM) In vivo (10 mg/kg/day)	ROS measurements, cell counting, immunohistochemistry, immunostaining, and BDNF assay	Decreased oxidative stress and increased BDNF-pCREB signaling	Attenuate impaired hippocampal neurogenesis Protected neural progenitor cells against irradiation-induced necrotic cell death	[151]
Male Sprague-Dawley rats (5 weeks old)	Hesperidin (100 mg/kg)	Immunofluorescence, cell counting, Western blot, and biochemical analysis	Increased levels of BDNF, Nrf2, and antioxidant enzymes	Alleviated methotrexate-induced neurogenesis decline	[162, 163]
Male Fischer 344 rats (20 months old)	Flavonoid-rich extract from blueberry and green tea (135 mg/kg/day)	Immunohistochemistry, stereology, real time PCR, and ELISA	Anti-inflammatory effects, increased Nrf2, and activated Wnt/ β-catenin pathway	Increased neurogenesis and the number of proliferating cells in SVZ Activated pro-neurogenic gene expression in the hippocampal SGZ and SVZ	[168-169]
Male Fischer 344 rats (19 months old)	Flavonoid-rich blueberry extract (20 g/kg)	Immunohistochemistry and cell quantification	Activated IGF-1, IGF-1R, and ERK1/2	Increased hippocampal neurogenesis and hippocampal plasticity	[171]
C. elegans nematodes	Multiple flavonoids including isoquercitrin	Drug screening and network-based analysis, genetic tests, drug assays, real time PCR, and Western blot	Increased daf-16/FoxO sir2-1/SIRT1 and ucp-4/UCP	Promoted neuronal function in C. elegans nematodes with neuronal stable expression of human polyglutamine-expanded (128Q) exon-1 huntingtin	[172]
Male Wistar rats	Naringin (40 and 80 mg/kg)	Biochemical analyses	Attenuated mitochondrial oxidative damage and acetyl cholinesterase activity	Neuroprotective effects against aluminium chloride-induced cognitive dysfunction	[175]
Male ICR mice (6 weeks old)	Spinosyn (5 mg/kg)	Immunohistochemistry, immunofluorescence, Western blot, and cell counting	Increased pERK, pCREB and mature BDNF	Increased proliferation and survival of neuronal cells, and the number of immature neurons	[177]
Male ICR mice (6 weeks old)	Oroxylin A (1.25, 2.5, 5, or 10 mg/kg)	Immunohistochemistry and immunofluorescence	-	Increased progenitor cell proliferation and new-born cell survival	[178]
Ts65Dn mice (12 weeks old)	Luteolin (10 mg/kg)	Immunohistochemistry, Nissl staining, and Western blot	Activated ERK1/2 and increased BDNF levels	Enhanced neuron proliferation in the hippocampal DG	[179]
Rat PC12 cells	Luteolin (5, 10, and 20 μM)	Cell culture, neurite outgrowth analysis, real time PCR, Western blot, and analysis of Nrf2	ERK-dependent induction of Nrf2-driven HO-1 expression	Induced neurite outgrowth and neuronal differentiation	[180]
Rat PC12 cells	Luteolin (20 mM)	Quantification of neurite outgrowth, real time PCR, Western blot, and enzyme immunoassay	Activated cAMP/PKA and ERK-dependent CREB signaling pathways	Enhanced neurite outgrowth	[182]
Male C57BL/6 mice (9 weeks old)	Heptamethoxyflavone (25 or 50 mg/kg/day)	Western blot and immunofluorescence microscopy	Activated ERK1/2 and increased pCREB and BDNF	Enhanced neurogenesis after brain ischemia	[183]
Male C57BL/6J mice (6-7 weeks old)	Baicalin (40, 80 or 160 mg/kg)	Immunohistochemistry and Western blot	Normalized GR function through SGK1- and FKBP5-mediated GR phosphorylation	Restored corticosterone; induced suppression of hippocampal neurogenesis	[184]
Male ICR mice (7-8 weeks old)	Baicalin (50 and 100 mg/kg)	Nissl staining, immunofluorescence, Western blot, and real time PCR	Activated Wnt/β-catenin pathway	Restored stress-induced suppression of hippocampal neurogenesis and improved nerve cells’ survival	[185]
Male ICR mice (6 weeks old)	Quercetin (50 mg/kg/day)	Immunohistochemistry and Western blot	Increased Akt phosphorylation	Enhanced NSC neurogenesis in the hippocampal DG	[186]
Female Sprague-Dawley rats and C57B6/BL mice Hippocampal NPC from day 18 rat fetuses	Ginkgo biloba extract containing quercetin (3-15 μM)	Cell proliferation assay, immunostaining, and immunoblotting	Increased pCREB and BDNF	Enhanced hippocampal cell proliferation Restored amyloid-β oligomer-induced synaptic loss	[187]
Male ICR mice NPCs from brain of embryonic day 12-14 and SH-SY5Y cells	Quercetin In vivo (15 or 30 mg/kg) In vitro (0-90 μM, NPCs; 0-480 μM, SH-SY5Y)	Immunofluorescence and immunohistochemistry	Activated FoxG1/ CREB/BDNF pathway	Increased neurogenesis markers in the hippocampal DG	[188]
Pathogen-free female mice (4 weeks old)	Purple cauliflower (174.32 mg/g anthocyanin)	Western blot, immunohistochemistry, and Golgi staining	Activated ERK/CREB/ BDNF pathway	Enhanced hippocampal neurogenesis and dendrite development	[189]
NSCs from SVZs of 3-week-old and 23-month-old C57BL/6 mice C57BL/6 mice (12 months old)	Ribes meyeri anthocyanins (100 mg/kg) Naringenin (20 mg/kg)	Cell counting, cell cycle analyses, real time PCR, telomere length measurement, ROS assay, neurosphere and differentiation assays, immunofluorescence, RNA-sequencing, and ELISA	Decreased NSC senescence markers, and downregulated TNF-α	Accelerated NSC proliferation, and reversed age-dependent neuronal loss	[190]
Male ICR mice	Cyanidin (25 or 50 mg/kg)	Immunofluorescence and Western blot	Activated PI3K/AKT/ FoxG1/FGF-2 pathway	Enhanced neurogenesis	[191]
Male C57BL/6J mice (3 months old)	(-)-Epicatechin (1 mg/kg) (+)-Epicatechin (0.1 mg/kg)	Immunohistochemistry, immunofluorescence, nitrate/nitrite measurements, and Western blot	Enhanced capillary formation and nitric oxide triggering	Increased neuronal proliferation and neurofilament	[194]
Healthy subjects (50-69 years old)	High-flavanol cocoa (900 mg/day flavanols, 138 mg/day (-)-epicatechin)	fMRI and cognitive testing	-	Enhanced DG function	[195]
Male C57BL/6J mice (10 weeks old)	Cinnamtannin A2 (100 mg/kg)	Immunohistochemistry	-	Enhanced neurogenesis in the hippocampal DG	[196]
Female Balb/c mice (6 weeks old)	Puerarin (80 mg/kg/day)	Histology analysis, immunostaining, and real time PCR	Increased GR, DCX, and BDNF expression	Ameliorated d-galactose-induced loss of neurogenesis	[197]
Female C57BL/6J mice (12 months old)	Daidzein (25 mg/kg)	Tissue sectioning, molecular marker analyses, immunohistochemistry, optical dissector analysis, morphometric analysis, fluorescence intensity analysis	-	Increased markers of hippocampal neurogenesis, such as: increased numerical densities of late transient amplifying progenitors, neural progenitors, immature granule cells, and arborization of dendrites	[198]

Abbreviations: ROS, reactive oxygen species; BDNF, brain-derived neurotrophic factor; CREB, cAMP-response element binding; pCREB, phosphorylated CREB; Nrf2, nuclear factor erythroid 2-related factor 2; PCR, polymerase chain reaction; ELISA, enzyme-linked immunosorbent assay; SVZ, subventricular zone; SGZ, subgranular zone; IGF-1, insulin-like growth factor 1; IGF-1R, IGF-1 receptor; ERK, extracellular signal-regulated kinase; pERK, phosphorylated ERK; FoxO, forkhead box transcription factor O; sir2-1/SIRT1, sirtuin 1; DG, dentate gyrus; HO-1, heme oxygenase-1; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; GR, glucocorticoid receptor; FKBP5, FK506 binding protein 5; SGK1, serum- and glucocorticoid-inducible kinase 1; NSC, neural stem cell; NPC, neuronal precursor cell; FoxG1, forkhead box G1; TNF-α, tumor necrosis factor alpha; PI3K, phosphoinositide 3-kinases; FGF-2, fibroblast growth factor 2; fMRI, functional magnetic resonance imaging; DCX, doublecortin.

4.1. Flavonoids, Oxidative Stress, and Neuroinflammation

Given that oxidative stress and neuroinflammation have been recognized as among the major causes of the decline of adult neurogenesis, the antioxidant and anti-inflammatory properties of flavonoids can potentially contribute to their beneficial effects on neurogenesis, especially with advancing age [143, 149, 150]. Flavonoids may exert multiple antioxidant actions, such as inhibition of the major enzymes involved in ROS reactions, regulation of redox metal homeostasis, and prevention of metal deposition. Adult neurogenesis is a high-energy consuming process, and therefore, may lead to ROS accumulation. It has been proved that high ROS levels impair adult neurogenesis during ageing, enhancing neuroinflammation and neurodegeneration [140]. Due to the presence of hydroxyl groups in their structure, flavonoids can scavenge different types of ROS. Administration of baicalein or naringenin can scavenge free radicals, improving hippocampal neurogenesis and neurocognitive deficits in animal models [151, 152]. These properties have important implications for neurodegenerative diseases, including AD and PD [153, 154]. Moreover, flavonoids exert antioxidant effects by acting on transcription factors such as nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor κB (NF-κB) that, in turn, enhance the expression of endogenous antioxidant systems and anti-inflammatory enzymes [155-158].

Nrf2 is a basic-region leucine zipper cytosolic transcription factor that regulates redox homeostatic responses to multiple stressors by stimulating the expression of antioxidant and detoxification gene families. This transcription factor is known as the master regulator of redox metabolism, neuroinflammation, and proteostasis. The overall activity of Nrf2 is compromised during aging and in several neurodegenerative diseases [146, 159]. Although many gaps still exist in our knowledge of the specific role that Nrf2 plays in specialized brain areas, it has been demonstrated that the maintenance and differentiation ability of the NSCs is regulated by Nrf2 and Nrf2-dependent gene pool. Deficiencies in Nrf2 expression and function significantly reduce the clonogenic, proliferative, and differentiating capacity in mouse NSCs, but these deficiencies are compensated by ectopic expression of Nrf2 [160]. It has been also reported that a decrease in the number of NSCs caused by aging is directly associated with the downregulation of Nrf2 and related target gene, especially glutamate-cysteine ligase modifier subunit (GCLM) [161]. Hesperidin is a major flavonoid found in citrus fruits, which appears to have several neuroprotective properties, including amelioration of neurogenesis in the DG of the hippocampus [162]. A recent study showed that this compound may be able to prevent the neurotoxic effects of methotrexate by reducing oxidative stress and enhancing hippocampal neurogenesis in adult rats. The administration of hesperidin prevents the reductions in Nrf2 expression caused by methotrexate treatment, increasing the levels of BDNF, DCX, and Nrf2-dependent enzymes in the hippocampus and prefrontal cortex [163]. Similarly to hesperidin, tiliroside, a dietary glycosidic flavonoid, appears to be involved in the modulation of the Nrf2 pathway. Experimental results show that tiliroside increased protein levels of Nrf2, heme oxygenase-1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1), indicating an activation of the Nrf2 protective mechanisms in cultured mouse hippocampal neurons [164].

The NF-κB signaling pathway has been extensively studied in the immune and inflammatory responses, but many studies have consistently shown that it is also a key regulator of a number of physiological processes in the nervous system. In particular, NF-κB has been studied in the hippocampus, where it has been shown to regulate neurogenesis and neuritogenesis [165]. Genetic ablation of NF-κB resulted in severe defects in the DG of the hippocampus, but its reactivation led to a re-expression of the downstream targets, such as FoxO1 and protein kinase A (PKA), contributing to axonal and neuronal regeneration [87]. In addition, NF-κB plays a critical role in regulating the transcription of inflammatory mediators (e.g., tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-18) involved in neuroinflammation and neuronal degeneration processes [166]. Indeed, pharmacological inhibition of NF-κB prevents the occurrence of inflammation in different experimental models of brain aging [167]. The study conducted by Velagapudi et al. highlights that tiliroside inhibits NF-κB acetylation through activation of sirtuin 1 (SIRT1), attenuating neuroinflammation and protecting differentiated human neural progenitor cells [164]. Several studies reported that a flavonoid-rich extract of blueberry and green tea activates antioxidant and anti-inflammatory pathways in the hippocampus, attenuating inflammaging, enhancing the hippocampal expression of pro-neurogenic genes, and promoting neurogenesis in old mice [168, 169]. Therefore, it is reasonable that flavonoids, through the maintenance and activation of SIRT1, and the consequent inhibition of NF-κB, can prevent oxidative stress and neuroinflammation, contributing to adult neurogenesis [170].

4.2. Regulation of Adult Neurogenesis by Flavonoids

Accumulating evidence indicates that flavonoids may activate adult neurogenesis with beneficial effects on learning and memory function. Flavonoids, such as luteolin and spinosin, significantly increase cell proliferation in the hippocampal neurons through multiple pathways. Supplementation with flavonoid-rich blueberry in aged animals improved hippocampal plasticity and cognitive performance via mechanisms involving neurogenesis, IGF-1, and its receptor [171]. It was also demonstrated that multiple flavonoids prolong the function of neurons in Huntington's disease by modulating the activity of FoxO transcription factors [172]. Flavonoids are also modulators of cellular pathways associated with mitochondrial biogenesis and mitophagy. It has been shown that these compounds enhance mitochondrial function through multiple mechanisms, including modulation of PGC1α, mTOR, and SIRTs. Chronic administration of naringin, a flavonoid belonging to the flavanones subclass, improved cognitive performance and attenuated mitochondria oxidative damage, acetyl cholinesterase activity, and aluminum concentration in aluminum-treated rats [173-175]. In literature, there is an increasing amount of data showing that flavonoids can modulate CREB, BDNF, and ERK1/2 pathways, contributing to the proliferation, survival, and differentiation of neuronal cells [176].

As mentioned, spinosin, a C-glycoside flavone, affects adult hippocampal neurogenesis and cognitive performance in mice. The subchronic administration of this compound for 14 days increases the proliferation of NSCs and promotes the survival and differentiation of the newly generated cells in the DG. It was also demonstrated that spinosin treatment increases the expression levels of phosphorylated ERK, CREB, and mature BDNF in the hippocampus, indicating that these mechanisms could play a significant role in increasing adult hippocampal neurogenesis [177].

Oroxylin A is a flavone found in the medicinal plant Scutellaria baicalensis. The administration of this compound stimulated cell proliferation in the SGZ of DG in a dose- and time-dependent manner. These results suggested that the increase in neurogenesis by oroxylin A could be, at least in part, be associated with its cognitive enhancing and/or neuroprotective effects [178].

Luteolin is an important flavone with multiple pharmacological and biological effects. Results of in vitro studies revealed that luteolin induces neurite outgrowth, increasing the expression of Growth Associated Protein 43 (GAP43), a differentiation marker also known as neuromodulin, and activates the ERK1/2 pathway in the PC12 cell line. In addition, this flavonoid enhanced the expression of nestin, glial fibrillary acidic proteins, and the number of DCX+, a microtubule-related protein expressed in immature neurons in the granular layer. Luteolin also increases NeuN+ neurons in the subgranular area of DG. Adult hippocampal neurogenesis is impaired in Down syndrome, and this impairment has been observed in a variety of animal models. Luteolin increased the protein levels of BDNF and p-ERK1/2 in the hippocampus, enhancing neurogenesis and improving learning and memory abilities in a mouse model of Down syndrome. These effects of luteolin might be associated with its strong antioxidant capacity, inhibition of neuroinflammation and ferrous ion chelating activity [179-181]. It has been also demonstrated that luteolin increases the levels of miR-132, which serves as an important regulator for neurite outgrowth in PC12 cells. The authors also identified the involvement of the cAMP/PKA- and ERK-dependent CREB signaling pathways in the luteolin-mediated miR-132 expression and neuritogenesis of PC12 cells [182].

Heptamethoxyflavone, a citrus flavonoid, has an enhancing effect on BDNF synthesis and neurogenesis in the hippocampus following cerebral global ischemia in mice. The administration of this compound to ischemic mice induced the phosphorylation of both ERK1/2 and CREB in the hippocampus, enhancing neurogenesis after brain ischemia through the induction of BDNF production, which is mediated by activation of ERK1/2 and CREB [183].

Baicalin is another interesting flavone predominantly found in the Scutellaria genus. The scientific evidence showed that baicalin has the potential to regulate the expression of glucocorticoid receptors (GRs) and promote neurogenesis in in vivo models. High concentrations of glucocorticoids induce GR activation, which impairs hippocampal neurogenesis. Administration of baicalin normalized GR level induces neurogenesis through activation of FK506-binding protein 51 (FKBP5) and serum- and glucocorticoid-inducible kinase 1 (SGK1) in a mouse model of anxiety/depression. Therefore, these findings suggest that baicalin improves anxiety/depression behaviors and promotes hippocampal neurogenesis [184]. Xiao et al. have also demonstrated in vivo that baicalin may induce hippocampal neurogenesis exerting its effect via regulation of the Wnt/β-catenin signaling pathway [185].

Quercetin is a versatile flavonoid belonging to the class of flavonols. It is widely distributed in vegetables and fruits and exerts several biological activities, including antioxidant, anti-inflammatory, and neuroprotective effects. Quercetin is primarily found in the plasma or the brain as quercetin-3-O-glucuronide (Q3GA). An elegant study by Baral et el. demonstrated that Q3GA enhances NSC proliferation via the Akt/BDNF signaling pathway and promotes migration in vitro and in adult mouse brains [186]. Quercetin, along with bilobalide, a terpenoid found in Ginkgo biloba extract, enhanced neurogenesis and synaptogenesis, increasing phosphorylation of CREB in a mouse model of AD [187].

FoxG1 is a member of the Fox family, which modulates the fate of NSCs and the development of telencephalon. This transcription factor potentiates the role of quercetin in adult hippocampal neurogenesis by regulating the phosphorylation level of CREB and protein expression of BDNF [188].

Anthocyanins, the glycosides of anthocyanidins, have been found to accumulate in several of the key areas of the mammalian brain underpinning cognitive function. After intragastric administration with purified anthocyanin from purple cauliflower, the treatment promoted neurogenesis and dendrite development in a mouse model of depression. The anthocyanin extract increased the expression of BDNF and phosphorylation levels of ERK1/2 and CREB in the hippocampus [189]. Using 23-month-old mice, Gao et al. investigated the effects of an anthocyanin extract from Ribes meyeri on NSC proliferation, senescence biomarkers, and cognitive abilities. They also analyzed the effect of naringenin, which belongs to the flavanone subclass of flavonoids and is mainly found in fruits and vegetables, including Ribes meyeri. The results revealed that treatment with both compounds improved adult neurogenesis, accelerating NSC proliferation and decreasing senescence and inflammatory biomarkers. The treatment also enhanced spatial learning in aging mice [190].

Cyanidin is one of the most abundant anthocyanidins found in grapes and blueberries. A recent study demonstrated that cyanidin is efficacious in modulating phosphoinositide 3-kinase (PI3K)/Akt/FoxG1/(FGF-2) pathway, enhancing neurogenesis and dendritic maturation [191].

Accumulating evidence has demonstrated a clear relationship between dietary consumption of flavan-3-ols and hypertension. These effects have also been investigated by intervention trials showing that administration of flavan-3-ols from cocoa can consistently improve blood pressure, cardiovascular parameters, and inflammatory biomarkers [192, 193]. The pro-neurogenic effects of flavan-3-ols have been assessed in a recent animal study. The results demonstrated the stimulatory capacity of epicatechin enantiomers on mouse frontal cortex neurogenesis markers and short-term memory. The levels of NeuN, DCX, capillary (cluster of differentiation 31, CD31), and neurofilaments (NF200) were increased, demonstrating increased neuron proliferation. Furthermore, epicatechin enantiomers upregulated neurogenesis markers through stimulation of capillary formation and NO triggering [194]. Previous human studies revealed that B-type procyanidin-rich cocoa is associated with neuromodulation and neuroprotection. Using functional magnetic resonance imaging, it was found that consumption of B-type procyanidin-rich cocoa enhances hippocampal DG function [195]. Recently, Fujii et al. evaluated the effects of a short-term dose of cinnamtannin A2, a tetramer of B-type procyanidin, on spatial memory and adult hippocampal neurogenesis in mice. The treatment increased the number of hippocampal bromodeoxyuridine-labeled cells in the DG. This effect was also associated with increased exploratory behavior, particularly behavior related to spatial memory [196].

Puerarin is an important isoflavone isolated from several leguminous plants of the genus Pueraria with beneficial vascular effects. As mentioned above, GRs exert crucial actions on the hippocampus, regulating CREB and BDNF expression. Evidence indicates that age-related vascular dysfunction impairs the expression and function of GRs. Li et al. demonstrated that the combined action of two hypotensive agents, such as puerarin and amlodipine, alleviates impairments of behavior and neurogenesis in an aging mice model. The treatment improved GR gene expression declines, and this effect was also correlated with enhanced expression of DCX and BDNF in the hippocampus [197]. Another study from Japan reported that adult hippocampal neurogenesis is promoted by isoflavone daidzein in middle-aged female mice. The authors found that daidzein enhanced the numerical densities of late transient amplifying progenitors, neural progenitors, and immature granule cells. Arborization of dendrites was also promoted by daidzein [198].

CONCLUSION

Dysfunction of adult neurogenesis appears to be a hallmark in the development of age-related neurodegenerative diseases. Despite multiple shortcomings, it seems that modulating neurogenesis represents an important target for manipulations that could help in the fight against neurodegenerative disorders and cognitive decline. Recently, modulation of adult neurogenesis by dietary compounds has emerged as a potential approach by which nutrition impacts mental health. Because human brain tissues are particularly inaccessible for direct study, research attempting to find a link between the action of flavonoids and adult neurogenesis are heavily dependent on animal models. Therefore, an important limitation is that metabolic differences can produce different metabolites after the ingestion of the same parent compound across species. Furthermore, although in vitro studies using low micromolar concentrations or below may reflect reasonable physiological levels in the brain, the exact concentration of the active form of flavonoids is an area open for further studies. Despite this, the data summarized in this manuscript provide an indication that dietary flavonoids are underpinned by an ability to modulate neuronal signaling pathways crucial in inducing adult neurogenesis. The modulation of these pathways along with the activation of neurotrophic factors, may reduce the loss of neurogenic niches activity during physiological and pathological aging, improving cognitive functions. Although these results are encouraging, and dietary flavonoids appear to be promising candidates, the clinical utility of these compounds to improve adult neurogenesis in human aging is largely undetermined. Future studies on human subjects are needed to assess the role of flavonoids and their metabolites on adult neurogenesis, possibly using vehicles that increase neurobioavailability.

LIST OF ABBREVIATIONS

AD

Alzheimer’s Disease

ATP

Adenosine 5′-triphosphate

BBB

Blood-brain Barrier

BDNF

Brain-derived Neurotrophic Factor

cAMP

Cyclic Adenosine Monophosphate

CNS

Central Nervous System

CR

Calretinin

CREB

cAMP-responsive Element-binding Protein

DA

Dopamine

DCX

Doublecortin

DG

Dentate Gyrus

EGF

Epidermal Growth Factor

ERK

Extra-cellular Signal-regulated Kinase

FGF2

Fibroblast Growth Factor 2

FKBP5

FK506-binding Protein 51

Fox

Forkhead box Transcription Factor

GABA

γ-aminobutyric Acid

GAP43

Growth Associated Protein 43

GCLM

Glutamate-cysteine Ligase Modifier Subunit

GDNF

Glia-derived Nerve Factor

GFAP

Glial Fibrillary Acidic Protein

GRs

Glucocorticoid Receptors

HO-1

Heme Oxygenase-1

IGF1

Insulin Growth Factor 1

IL-18

Interleukin-18

IL-1β

Interleukin-1β

mTOR

Mammalian Target of Rapamycin

NeuN

Neuronal Nuclei

NF-κB

Nuclear Factor κB

NGF

Nerve Growth Factor

NPC

Neuronal Precursor Cell

NQO1

NAD(P)H Quinone Dehydrogenase 1

Nrf2

Nuclear Factor Erythroid 2-related Factor 2

NSCs

Neural Stem Cells

OB

Olfactory Bulb

pCREB

Phosphorylated CREB

PD

Parkinson’s Disease

PGC1α

Proliferator-activated Receptor Gamma Coactivator 1α

PI3K

Phosphoinositide 3-kinase

PKA

Protein Kinase A

PSA-NCAM

Polysialylated Neuronal Cell Adhesion Molecule

Q3GA

Quercetin-3-O-glucuronide

ROS

Reactive Oxygen Species

SGK1

Serum- and Glucocorticoid-inducible Kinase 1

SGZ

Subgranular Zone

sir2-1/SIRT1

Sirtuin 1

Sox 2

Sex-determining Region Y-box 2

SVZ

Subventricular Zone

TGF-β1

Transforming Growth Factor β1

TNF-α

Tumor Necrosis Factor α

VCAM1

Vascular Cell Adhesion Molecule 1

VEGF

Vascular Endothelial Growth Factor

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.