Nutritional Factors Affecting Adult Neurogenesis and Cognitive Function

Abstract

Adult neurogenesis, a complex process by which stem cells in the hippocampal brain region differentiate and proliferate into new neurons and other resident brain cells, is known to be affected by many intrinsic and extrinsic factors, including diet. Neurogenesis plays a critical role in neural plasticity, brain homeostasis, and maintenance in the central nervous system and is a crucial factor in preserving the cognitive function and repair of damaged brain cells affected by aging and brain disorders. Intrinsic factors such as aging, neuroinflammation, oxidative stress, and brain injury, as well as lifestyle factors such as high-fat and high-sugar diets and alcohol and opioid addiction, negatively affect adult neurogenesis. Conversely, many dietary components such as curcumin, resveratrol, blueberry polyphenols, sulforaphane, salvionic acid, polyunsaturated fatty acids (PUFAs), and diets enriched with polyphenols and PUFAs, as well as caloric restriction, physical exercise, and learning, have been shown to induce neurogenesis in adult brains. Although many of the underlying mechanisms by which nutrients and dietary factors affect adult neurogenesis have yet to be determined, nutritional approaches provide promising prospects to stimulate adult neurogenesis and combat neurodegenerative diseases and cognitive decline. In this review, we summarize the evidence supporting the role of nutritional factors in modifying adult neurogenesis and their potential to preserve cognitive function during aging.

Introduction

Aging is the single greatest risk factor for most neurodegenerative diseases, which often are characterized by their irreversibility, their lack of effective treatment, and the poor quality of life they engender, along with social and economic burdens. Lack of effective therapies for these debilitating brain disorders has been attributed to the inability of adult mammalian brains to generate or repair damaged neurons. Although Altman and Das (1) showed continuous adult hippocampal neurogenesis in rat brains in 1965, further studies to reinforce theories such as damaged neuronal replacement by resident precursor cells were conducted mainly after 1989 (2–4). The limiting factor for this delay was that the limited regenerative capacity of the mature brain and its unusual degree of cellular specialization restricted the extent to which residual healthy tissue could assume the functions of damaged brain tissue (5). Many studies since the mid-1990s, however, have established adult neurogenesis in mammalian systems, where adult neural stem cells or precursor cells, located in the rostral subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus, can differentiate and proliferate into new neurons (5–9). The process is a highly complex, multistep process that begins with the proliferation of progenitor cells, is followed by commitment to a neuronal phenotype and morphological and physiological maturation with the development of functional neuronal characteristics, and ends with the existence of a newly functioning, integrated neuron (10). Adult neurogenesis is an integral component of neural plasticity, brain homeostasis, maintenance, and tissue remodeling in the central nervous system (CNS). The migration and repopulation of neural stem cells (NSCs) into other critical regions of the brain and their maturation into functional neurons or other brain cells is determined by both intrinsic and extrinsic factors, including neurotrophins, antidepressants, opioids, seizures, physical activity (10), glucocorticoids (11), sex hormones (12), growth factors (13), excitatory neurotransmission (14), learning (15), physical exercise (16), stress (17), and diet (18). The prospect of continuous genesis and proliferation of new neurons and glial cells and the plastic nature of adult mammalian brains has vast therapeutic potential in combating the exponential rise in the incidence of neurodegenerative diseases.

Age-related decline in cognitive function has been characterized by compromised neuronal plasticity, decreased neurogenesis, and neuronal death (19). Impaired adult neurogenesis also has been well characterized in patients with neurological diseases, including Alzheimer disease (AD), Parkinson disease, Huntington disease, epilepsy, ischemia, autism spectrum disorders, and prion diseases, leading to continuous loss of neurons and subsequent cognitive and motor disabilities (20). Aberrant neurogenesis appears to be a common hallmark for most neurodegenerative diseases, even though distinct proteins are responsible for different diseases and cause the loss of different neural populations in different regions of the brain. Adult hippocampal neurogenesis has a direct effect on cognitive function, because the hippocampal formation has been widely linked to memory storage and processing (21) and, in most neuropathologies, the hippocampal region has been shown to be the brain region that is the most affected (22). It has been shown that neurogenesis can be induced in the SVZ and hippocampus in response to neuronal death (23). Moreover, some neuronal precursors reach these degeneration-prone areas and in some cases replace dead neurons (24). Treatment of neurologic diseases using endogenous neurogenesis is limited by the continuous decline in number and capacity of NSCs as a result of the disease process and aging (6, 23). Regeneration of damaged neurons with site-specific transplantation of NSCs also has limitations because the transplanted NSCs sometimes are unable to differentiate into specific types of neurons and because of the increased risk of malignant transformation and immune rejection after NSC transplantation (6). Therefore, determination of a clear mechanism in the development and activation of endogenous neurogenesis may be an ideal approach to the prevention and treatment of neurological diseases.

Many exogenous modulators of neural activity such as physical activity, enriched environment (e.g., containing tunnels, platforms, toys, and running wheels), caloric restriction, and vitamin E have been shown to regulate and stimulate adult progenitor cells and neurogenesis (25–27). Furthermore, dietary phytochemicals, which are known to possess many neurogenic properties, play a beneficial role in brain aging and neurodegenerative disease. Compounds such as curcumin, resveratrol, blueberry polyphenols, sulforaphanes, salvionic acids, PUFAs (e.g., omega-3 and DHA), the LMN diet (a patented diet by the company La Morella Nuts enriched with polyphenols and PUFAs), and flours rich in soluble fibers have been shown to induce neurogenesis in the adult brain (20, 28–33). Although the molecular mechanisms by which these compounds influence neurogenesis have yet be established, these compounds reduce oxidative stress and neuroinflammation, enhance cell signaling, activate autophagy, and affect growth factors (34). Many of these compounds have been shown to improve learning and memory by affecting specifically the hippocampal brain region. Dietary compounds also have been shown to induce adaptive stress–response molecules and alter the specific microenvironments in which adult progenitor cells reside (34). These compounds enhance the ability of the brain to resist more severe stress in the event of larger insults by promoting cell repair and survival, via inducing and activating trophic factors, antioxidant and DNA-repair enzymes, and proteins involved in mitochondrial biogenesis (20, 28–34). Although the potential roles of adult neurogenesis have been widely established in neurophysiologic processes such as motor function, learning and memory, olfaction, and the regulation of the hypothalamus-pituitary-adrenal axis (35), its therapeutic applications have been limited because it is a complex multistep process, and accurate biomarkers to establish each of these steps are still being discovered.

Although the individual effects of dietary compounds on adult neurogenesis are not yet fully understood, evidence supports the notion that some of the bioactive compounds from fruits and vegetables can modulate brain structure and function, as well as cognitive ability, throughout the lifespan of an organism. In this review, we focus primarily on studies that have investigated the effects of dietary factors that influence hippocampal neurogenesis and brain plasticity in the context of cognitive function, aging, and neurodegenerative disease.

Factors Negatively Affecting Adult Neurogenesis

Aging negatively affects the proliferation of neural progenitor cells and the survival of immature neurons, thus reducing neurogenesis (36–39). Proposed mechanisms include the modulation of inflammation and hormonal concentrations, as well as structural changes to brain vasculature. Although the functional consequences of a decline in neurogenesis are not understood fully, performance on hippocampus-dependent learning and memory tasks is closely linked to the amount of hippocampal neurogenesis in adult rodents (24, 36, 40–43).

The aging process, and to a greater degree neurodegenerative disorders such as AD, are characterized by a proinflammatory state [(44–46), as reviewed in (47, 48)]. In rodent models, injection of LPS to induce systemic inflammation results in a decrease in hippocampal neurogenesis (49, 50). Activation of microglia and the release of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 can inhibit neurogenic differentiation of neural progenitor cells (51). With aging, blood vessels become more permeable for proteins that normally would be blocked by the blood-brain barrier, potentially initiating an inflammatory response (52, 53). The role of inflammation in adult neurogenesis is complex; however, there is evidence that microglia, depending on the phenotype or state of activation, may be beneficial and support progenitor proliferation, survival, and differentiation (54). Both astrocyte and microglial cells remain quiescent under normal physiologic conditions and respond to an infection, injury, or neurotoxicity by releasing neuroinflammatory molecules. The balance between the beneficial and harmful effects of neuroinflammation on neurogenesis depends on the magnitude of the inflammatory response. This response is classified as acute or chronic inflammation, with the former being an early defensive response leading to the protection or repair of the damaged CNS area and the maintenance of neurogenesis as a mechanism of brain repair. On the one hand, the mobilization of neural precursors for repair, remyelination, and even axonal regeneration could facilitate long-term neuronal survival. On the other hand, chronic inflammation leads to long-lasting damage to adult neurogenesis processes (55) and plays a mechanistic role in neurodegenerative disease.

The aging process also affects a number of hormone classes. Ghrelin, an orexigenic hormone produced in the stomach, has been shown to promote neurogenesis and synaptic plasticity in the hippocampus and to have neuroprotective effects (56, 57). Ghrelin concentrations are reduced in aged animals (58), and young knock-out rats lacking the ghrelin receptor growth hormone secretagogue receptor have reduced hippocampal neurogenesis (59). Likewise, vascular endothelial growth factor and insulin growth factor-1 decrease with age and may contribute to a decline in hippocampal neurogenesis (60).

Diets high in fat and refined sugars contribute to age-related cognitive decline and dementia (61–63). Although the negative effects of high-fat and –refined sugar diets on brain function result in part from cardiovascular and cerebrovascular diseases (e.g., atherosclerosis), there appear to be direct effects on the brain from diet. Lindqvist and colleagues (64) found that feeding a high-fat (but not high-sugar) diet for 4 wk decreased hippocampal neurogenesis and increased serum corticosterone concentrations in male but not female rats as compared with controls. Other studies have found that high-fat and –refined sugar diets affect neurogenesis and neuroplasticity through a decrease in hippocampal brain-derived neurotrophic factor (BDNF) (65–67), a vital mediator of neurogenesis and neuronal plasticity implicated in the formation of long-term memory. Reduced hippocampal neurogenesis (68) and impaired spatial memory (69) also have been linked to high fructose consumption and insulin resistance (66). Conversely, calorie restriction appears to increase BDNF, neurogenesis, and the survival of newly generated cells in the DG (70, 71). Findings from studies by Hornsby and colleagues (72) and Kim and colleagues (73) suggest that the beneficial effects of calorie restriction on adult hippocampal neurogenesis and memory may be mediated by the ghrelin receptor.

Oxidative stress has been considered one of the most potent environmental factors negatively affecting neurogenesis because it inhibits various stages of adult neurogenesis (74, 75). Oxidative stress is known to suppress the proliferation of precursor cells, migration, integration, and survival of newly formed cells (74, 75). Oxidative stress has been shown to diminish neurogenesis in aged animals to a much greater extent than in their younger counterparts (76). Oxidative stress in the CNS, marked by an increased release of reactive oxygen species, is a critical factor in cellular injury and in the activation of both acute and chronic neuroinflammation, thereby inhibiting the adult neurogenesis process (77). Many dietary components have been shown to reduce oxidative stress and neuroinflammation, provide protection from cellular damage, and improve cognitive function (78); therefore, improving the neuronal atmosphere could be the key to enhancing adult hippocampal neurogenesis.

Dietary Enhancement of Adult Neurogenesis

During the last decade there has been a steady increase in research into the dietary factors that affect the brain. Although the overall diet can have profound effects on the brain, accumulating evidence suggests that consumption of specific dietary compounds can improve cognition. Many of these compounds have antioxidant and anti-inflammatory properties; however, increases in adult neurogenesis may also contribute to some of the observed cognitive improvements. Investigations into improving adult neurogenesis have thus far focused primarily on vitamins B-9 and E, ω-3 PUFAs, and nonnutrient phytochemicals.

Vitamins

Folic acid and folate (vitamin B-9) can be found in a wide variety of plant and animal foods and is a necessary regulator of CNS development. As such, many grain-based foods are fortified with folates and the intake of folic acid and folate by women of childbearing age is encouraged. In later life, low concentrations of folates are associated with reduced cognitive ability (79). Supplementation with folic acid has been shown to slow cognitive and clinical decline in people with mild cognitive impairment, in particular in those with elevated homocysteine, which is a risk factor for AD (80). In a randomized, double-blind, placebo-controlled study by Durga and coworkers in 2007 (81), folic acid supplementation for 3 y greatly improved domains of cognitive function that tend to decline with age. In vivo studies have shown that folate plays a critical role in DNA methylation and epigenetic phenomenon in the CNS along with vitamins B-6 and B-12, which is critical for the maintenance of adult neurogenesis (82). Folate deficiency substantially affects adult hippocampal neurogenesis and depletes neurotransmitter concentrations in the hippocampus (82); therefore, it may be inferred that folic acid plays a critical role in the cognitive function through the regulation of neurogenesis.

Vitamin B-12 (cobalamin) is known to play a major role in proper brain development and function. Many clinical studies have indicated that “low-normal” (150–300 pmol/L) vitamin B-12 status in the serum is strongly correlated with cognitive impairment. One plausible mechanism for this cognitive impairment extrapolates the white matter damage in the spinal cord characteristic of vitamin B-12 deficiency to the white matter in the brain, damage which is known to be associated with cognitive deficits. Another possible mechanism is related to DG being one of the few regions of the adult brain where neurogenesis occurs; because vitamin B-12 is needed for DNA replication, an inadequate supply could impair neurogenesis. A potential third mechanism is the impairment of methylation caused by insufficient vitamin B-12, leading to loss of myelin from axons of the perforant path (83).

In a 2012 study (84), male Sprague-Dawley rats were administered folic acid (0, 4, or 12 mg ⋅ kg⁻¹ ⋅ d⁻¹) for 28 d before middle cerebral artery occlusion. Neurogenesis was increased following occlusion; however, folic acid potentiated this response, further increasing hippocampal neurogenesis and attenuating ischemia-induced cognitive impairments by improving cognitive performance following occlusion to the level of sham controls.

Vitamin E is a fat-soluble vitamin found in nuts, seed oil, and leafy green vegetables. Along with vitamin C, it is known for its antioxidant and anti-inflammatory properties (85). Preclinical studies have shown that vitamin E can regulate adult neurogenesis (85). In an initial study (86), Sprague-Dawley rats (age 1 mo; male) were fed a standard diet or one that lacked vitamin E. After 5 mo, vitamin E–deficient rats showed increased cell proliferation and density in the DG, relative to diet controls. In a subsequent study (87), it was determined that, although vitamin E deficiency increased cell proliferation, it also increased cell death in the DG. Furthermore, supplementation with α-tocopherol (2 mg ⋅ kg⁻¹ ⋅ d⁻¹; subcutaneously) reversed these effects, decreasing cell proliferation but increasing cell survival in the DG (88). Vitamins are a key component of the diet; however, not all vitamins are consumed adequately. In the United States (89), both folates and vitamin E are underconsumed; therefore, supplementation with these vitamins may help individuals achieve recommended intake amounts and improve neurogenesis.

ω-3 FAs

ω-3 FAs are a form of PUFA commonly found in fatty fish, walnuts, flaxseed, and their respective oils. ω-3 FAs are necessary to the structure and function of the brain, and their role in brain health has been studied extensively. Supplementation trials with ω-3 FAs suggest, however, that their effects on cognition may be beneficial only in certain compromised populations and not in healthy older adults (90–97). These clinical studies indicate an improvement in cognitive function with DHA or PUFA supplementation in the population with habitual diets low in DHA (98). Preclinical research suggests that one mechanism by which ω-3 FAs could improve cognition is by increasing adult neurogenesis. In an early study (99), aged Wistar rats (age 18 mo; male) were administered a 5% gum arabic solution with or without DHA (300 mg ⋅ kg⁻¹ ⋅ d⁻¹; per os). After 7 wk, rats in the DHA group showed increased neurogenesis in the DG. When aged Wistar rats (25–26 mo; male) were compared with young Wistar rats (age 3–4 mo; male) (100), 12 wk of feeding with a diet containing ω-3 FAs (EPA:DHA: 1.5:1; 270 mg ⋅ kg⁻¹ ⋅ d⁻¹; per os) partially attenuated age-related declines in adult neurogenesis, relative to diet controls. A systematic meta-analysis by Yurko-Mauro and colleagues in 2015 (101), using clinical trials and observational studies to establish the relation between DHA intake and cognitive outcomes, showed a substantial improvement in specific memory domains such as episodic, working, and semantic memory, linking the possible role of adult neurogenesis to improved cognitive function.

Phenolics

Polyphenols are a class of phytochemicals present in a wide variety of plant foods. Polyphenols have received increasing attention in recent years, both as bioactive compounds underlying the health benefits of fruits and vegetables and for their potential utility as dietary supplements. In addition to their known antioxidant and anti-inflammatory properties, polyphenols and polyphenol-rich whole foods can increase neurogenesis.

Berry fruit has been shown to improve cognition in both animals (102) and humans (103–106). Blueberry has been shown to increase neurogenesis (107). Aged F344 rats (age 19 mo; male) were fed a modified NIH-31 control diet or a diet containing 2% blueberry (∼20 g/kg). After 8 wk, blueberry-fed rats showed improved performance (fewer errors) on a spatial memory task, which was associated with an increased proliferation of precursor cells in the DG, relative to control-fed rats. Recently, strawberry also has been shown to improve neurogenesis (31); in this study, aged F344 rats (age 19 mo; male) were randomly assigned to a 2% blueberry diet, a 2% strawberry diet, or a control diet (NIH-31). After 8 wk, blueberry-fed rats showed increased coordination, and rats in both diet groups showed improved spatial working memory, relative to diet controls. Strawberry-fed rats showed increased survival in the precursor cells in the DG, relative to controls. No substantial improvements in cell survival were achieved in blueberry-fed rats in the study by Shukitt-Hale et al. (31); however, changes in cognition were positively correlated with changes in cell proliferation in blueberry-fed rats.

Similarly, grapeseed extract has been shown to improve adult neurogenesis. Middle-aged C57BL/6 mice (age 12 mo; male) were administered grapeseed extract (0, 25, 50, or 100 mg ⋅ kg⁻¹ ⋅ d⁻¹) for 28 d. Grapeseed extract increased proliferation, differentiation, and integration in the DG, in a dose-dependent manner, relative to controls. Although the effect of grapeseed extract on neurogenesis has not been assessed in humans, acute administration has been shown to increase serum concentrations of BDNF, which plays a regulatory role in neurogenesis (108).

Curcumin is a polyphenol found in turmeric, a staple of Asian cuisine. Curcumin has been studied widely for its potential health benefits (109); however, research shows that it may promote brain health by increasing or stabilizing adult neurogenesis. Aged Sprague-Dawley rats (age 15 mo; male) were administered a 0.048% curcumin diet or unpurified diet for 6 or 12 wk (110). Curcumin-fed rats showed improved performance on an olfactory cortex–based social recognition memory task at both 6 and 12 wk, and on a hippocampus-dependent spatial learning and memory task after 12 wk, relative to controls. Curcumin-fed rats also showed increased proliferation in the DG at 12 wk, relative to diet controls. Similarly, Xu et al. showed that curcumin can reverse stress-induced reductions in neurogenesis (111). In this study, Sprague-Dawley rats (190–200 g) were administered a peanut oil solution containing curcumin (0, 5, 10, or 20 mg ⋅ kg⁻¹ ⋅ d⁻¹; per os) during 20 d of unpredictable chronic stress. Whereas control rats showed decreased proliferation and BDNF concentrations in the DG, curcumin-fed rats showed attenuated amounts of proliferation and BDNF, in a dose-dependent manner, with the highest dose (20 mg ⋅ kg⁻¹ ⋅ d⁻¹) being consistent with the amount of proliferation seen in imipramine hydrochloride–treated positive controls (110 mg ⋅ kg⁻¹ ⋅ d⁻¹; intraperitoneally).

Resveratrol is a stilbene found in peanuts, tree nuts, grapes, cocoa, wine, and berry fruits (112). Resveratrol is well known for its activation of sirtuin 1 (113), and it can also induce neurogenesis. In one study (114), 2-mo-old female BALB/c mice were administered Brucella abortus antigen to induce chronic fatigue, which reduced the amounts of cell proliferation in the SGZ of the DG and hippocampal BDNF mRNA, relative to controls. Subsequent treatment with resveratrol (40 mg ⋅ kg⁻¹ ⋅ d⁻¹) for 1 mo fully attenuated the reduction of cell proliferation and normalized the amounts of hippocampal BDNF mRNA, relative to vehicle controls.

Synergy

As in other areas of nutritional research, an emerging line of inquiry is whether the combination of specific foods or their constituent compounds can produce a synergistic effect when combined in the diet or through supplementation. One study (28) examined the effect of a specially formulated diet, the LMN, that includes both FA and phenolic components, specifically nuts, cocoa, vegetable oils, and high-fiber flour. Ten-week-old 129S1/SvImJ mice that consumed a 9.27% LMN diet for 40 d showed increased cell proliferation and differentiation in the subventricular rostral migratory stream and olfactory bulb, and in the SGZ of the DG, relative to age-matched diet controls. A subsequent study (115) examined the effect of the LMN diet on 18-mo-old Tg2576 transgenic mice, which develop amyloid (Aβ) plaques at 12 mo. Both Tg2576 mice and wild-type controls that were fed the LMN diet showed improved spatial learning and memory at 18 mo, and these improvements were correlated with increases in cell proliferation in the SVZ of the DG. Dietary compounds, both individually and in combination, can improve adult neurogenesis. Combining whole foods or their bioactive constituent compounds may result in additive or synergistic (or both) improvement in adult neurogenesis and thereby further increase their therapeutic potential.

Summary

This review has highlighted the latest evidence that hippocampal neurogenesis and brain plasticity can be improved by dietary factors, leading to possible improvement in age-related cognitive deficits. The US population is experiencing an increase in the proportion of older people, such that ∼20% of the US total population will be >65 y by 2050, which is almost double what it is today. As people age, the incidence of age-related pathologies, including decreases in cognitive function, will also increase, with a concomitant increase in health care costs. As shown in this review, neurogenesis also decreases with age, and because of its role in neural plasticity, brain homeostasis, maintenance, and tissue remodeling, it plays a critical role in cognitive function. Although factors associated with aging, such as oxidative stress and inflammation, have been shown to decrease neurogenesis, dietary compounds that mitigate aging and age-related behavioral declines have been shown to increase neurogenesis. Some of these food compounds include the folates, vitamin E, ω-3 FAs, and polyphenols found in fruits, vegetables, nuts, and spices. Because these studies have been conducted in animal models, it is unclear whether the results will translate to humans. Although these studies are needed for proof of concept, the difficulty of assessing neurogenesis in human intervention studies precludes their feasibility in clinical trials. Given that increasing intake of these foods and food components is relatively safe and easy, however, their potential beneficial effects on neurogenesis should be considered for the prevention of or delay in age-related neurological dysfunction and cognitive decline.