Perspective: Neuroregenerative Nutrition

Abstract

Good health while aging depends upon optimal cellular and organ functioning that contribute to the regenerative ability of the body during the lifespan, especially when injuries and diseases occur. Although diet may help in the maintenance of cellular fitness during periods of stability or modest decline in the regenerative function of an organ, this approach is inadequate in an aged system, in which the ability to maintain homeostasis is further challenged by aging and the ensuing suboptimal functioning of the regenerative unit, tissue-specific stem cells. Focused nutritional approaches can be used as an intervention to reduce decline in the body’s regenerative capacity. This article brings together nutrition-associated therapeutic approaches with the fields of aging, immunology, neurodegenerative disease, and cancer to propose ways in which diet and nutrition can work with standard-of-care and integrated medicine to help improve the brain’s function as it ages. The field of regenerative medicine has exploded during the past 2 decades as a result of the discovery of stem cells in nearly every organ system of the body, including the brain, where neural stem cells persist in discrete areas throughout life. This fact, and the uncovering of the genetic basis of plasticity in somatic cells and cancer stem cells, open a door to a world where maintenance and regeneration of organ systems maintain health and extend life expectancy beyond its present limits. An area that has received little attention in regenerative medicine is the influence on regulatory mechanisms and therapeutic potential of nutrition. We propose that a strong relation exists between brain regenerative medicine and nutrition and that nutritional intervention at key times of life could be used to not only maintain optimal functioning of regenerative units as humans age but also play a primary role in therapeutic treatments to combat injury and diseases (in particular, those that occur in the latter one-third of the lifespan).

Introduction: A View of the Emerging Field of Regenerative Nutrition

As the tenets of the field of nutritional neuroscience and with the studies and issues discussed herein emerge, the following hold true: 1) the role of nutrition in maintaining cognitive prowess throughout life requires highly sensitive, robust, consistent, and scalable bioassays, both in vitro and in in vivo models, to be run to determine the actions of nutrients on neural cells and their receptors; 2) cell and molecular interactions involved in higher forebrain cognitive and mood functions must be elucidated through use of all of the next-generation “omics” (informal reference to the fields of biology ending in “omics,” including the rapidly emerging field of microbiomics and genomics, proteomics, transcriptomics, and metabolomics) in different models of aging and age-related cognitive decline; and 3) precise mechanisms of immune-brain bidirectional interactions need to be determined and validated with human clinical trials during normal and pathological aging, in the course of neurodegenerative disease, and in brain cancer models for clinicians to better understand and interrelate diet, nutrition, and lifestyle programs for deterring or preventing the negative effects of chronic inflammation during these processes.‬‬

Contributing to changes in the way in which we think about nutrients and improving age-related cognitive decline is a study that illustrates the ability of a 3-mo course of a diet high in cocoa flavanols to enhance hippocampal dentate gyrus–associated memory function in 50- to 69-y-old subjects (1). It cannot be ruled out that in addition to the potential for enhancing cerebral blood flow and the antioxidant effects of such flavanols, memory-associated stem or progenitor cells in the adult human hippocampal dentate gyrus (2–4) are affected and support the notion of a link between nutrition and regenerative units in the central nervous system. Neural stem and progenitor cells within the brain may help to counteract the loss of cells and connections that accompany even normal aging in addition to diseases in which aging is a major risk factor, including Alzheimer disease (AD), Parkinson disease (PD), and other neurodegenerative diseases. Our study of the relation between memory and stem cells in the hippocampus of patients with temporal lobe epilepsy (2) revealed a connection between the 2 that most likely also represents the same relation in the normal human hippocampus of non–seizure-involved, persistent neurogenic cell populations.

In general, it is accepted that as humans age, the “poietic” niches [“poietic” as used here is a colloquial reference to areas of the body that possess persistent cell genesis (e.g., hematopoiesis, neuropoiesis)], including the neurogenic regions throughout the adult mammalian brain, gastrointestinal system, and the bone marrow hematopoietic compartment (5) (see Figure 1 for a summary of the systems and approaches on which we focus here for studying age- and disease-related neuroregeneration and for testing nutrient therapies), also age with the human body and lose some of their proliferative and repair abilities (7). Schultz and Sinclair conclude that “it is feasible to design and test interventions that delay stem cell aging and improve both health and lifespan (7).”

FIGURE 1.

This perspective focuses on a need for more sensitive, reliable, and real-time bioassays for testing personalized and precision diets in which individual nutrient components, along with standard-of-care and integrated medicine practices, can help to treat and prevent degenerative and neoplastic diseases. A focus on stem cells in different growth niches in the brain and body, and the negative consequences on their growth and reparative properties that disease and chronic inflammation have, affords the emerging field of neuroregenerative nutrition to be studied in cell cultures, animal models, and human subjects. The human brain (upper left) contains different populations of indigenous stem and progenitor cells (red and purple cells) that reside in the periventricular subependymal zone along the lateral ventricle and the hippocampus, and has small numbers of stem or progenitor cells within the brain parenchyma (e.g., cerebral cortex) that are amenable to nutrient therapies. These cells also can undergo neoplastic transformation, giving rise to primary brain tumors (green mass in the temporal lobe). The brain stem cell niches interact with parts of the body, including bone marrow and lymph and immune systems (at right, cells in, for example, leg bone marrow and spleen), which is a basis for brain-body-immune system interactions that are compromised during abnormal aging and disease. Stem or progenitor cells that are at risk for both age-related degenerative and neoplastic diseases, along with patient-matched immune cells, can be isolated from these poietic niches and grown together in vitro or following xenotransplantation in host animals to create patient- or disease-specific avatars that are amenable to drug and nutrient testing on a precision medicine level (e.g., a “laboratory on a chip”) with microfluidomic growth and analysis conditions (6) to monitor disease onset, progression, and response to therapies via the interrogation of biomarkers, including exosomes. Chronic inflammation, which often accompanies disease course and treatments, is also a focus of this perspective because of its prevalence in so many disease and tissue injury settings. The use of a combination of omics analyses and computational and systems biology, in particular key regulatory gene and protein pathways, can be predicted to be a nutrient-druggable target, in addition to whole foods that contain these nutritional components as potential preventives and treatments, when higher concentrations of the components are demanded so as to be therapeutic; then they can be combined as polymolecular botanical drug compounds. Micronutrients and probiotics, along with dietary regimens (e.g., low-carbohydrate or ketogenic diet), can be implemented to help deter carbohydrate-enhanced cancer cell growth as well as neural cell loss, as seen in neurodegenerative disorders. Correlating such diet and nutrient administrations with a patient’s unique circadian clock provides critical timing of administration information for both pharmaceutical and dietary choices, which can be important for strategically targeting at-risk cells and tissues.

As the body ages, the reparative prowess of its cells diminishes, most likely a result of increased tissue inflammation; this has a deleterious effect on stem cell survival, growth, and differentiation (8), but it also may be a result of telomere shortening with relevance to nutrition and immune function (9–11). Other cell biological processes, including increased numbers of genetic mutations (12), invariably put all humans at risk for cancers, including hematologic (5) and brain (13) malignancies, as well as neurodegenerative diseases, which have many aspects of etiology and disease course in common with cancer (14, 15). Indeed, aging is the major risk factor for AD, PD, and other neurodegenerative diseases, because cell replacement of compromised, at-risk neurons and glia for these diseases becomes less feasible as a result of stem cell pathologies in the potentially reparative regenerative units (15). On the one hand, the body of evidence is increasing for the presence of stem-like cells in cancer whereby mutations and abnormal functions within these populations of highly dynamic and heterogeneous cells contribute to hyperplasia and neoplasia within a tissue. On the other hand, loss of the requisite ability of a stem cell to attempt repair and replacement of lost cells following injury or disease contributes to a hypoplastic tissue response. It is thus clear that any factor that can influence the ability of an adult stem or progenitor cell to better respond to disease with ageless reparative competence would be an important element in the arsenal of therapies for so many age-related disorders.

Current Status of Knowledge

The emerging concept of regenerative nutrition posits that diet and nutrients affect not only the standard operation of differentiated cells and cellular networks throughout the body but also stem and progenitor cells that reside within poietic niches and all tissues and organs. Because the idea of stem cells and regeneration of tissues in response to aging, disease, and injury is a relatively new concept, the research methods used to create this article included literature reviews that relied on PubMed (one of several search engines used) with the use of key words such as “stem cells,” “nutrition,” “regeneration,” “aging,” and “disease” we relied on discussions with colleagues across disciplines to establish for this article the topics that may have relevance to how diet and nutrition can play a role in supporting the growth and differentiation of newly generated cells. Regenerative nutrition is thus possibly a new way to envision reversing the clock of aging of reparative stem cells throughout the lifespan. Regenerative nutrition targets detrimental, chronic inflammation and associated gene networks (e.g., NF-κB, mechanistic target of rapamycin) and brain-immune-body interactions (16) to slow down or even reverse systemic aging through diet and targeted nutrient combinations.

Aging involves chronic inflammation and other tissue-compromising events that can make stem cells, especially neural stem cells, age (8, 17), and a growth-inhibiting microenvironment makes the cells less proliferative and effective at repair because their differentiation into requisite populations of replacement but at-risk somatic cells is diminished. Because chronic inflammation is a well-accepted contributor to different cancers and autoimmune and degenerative diseases, including rheumatoid arthritis, AD, and PD (18), we propose that intervening with functional foods, in both dietary and highly bioactive forms and in combinations that act as potent food-drugs (polymolecular botanical compounds), can target aberrant genetic and other omic-associated (including the metabolome and microbiome) (19) pathways in association with horizontal and vertical gene and/or omic networks (e.g., those within an omic target and those across distinct but related gene networks) to help prevent and fight degenerative and neoplastic diseases.

Supported by the findings of Small and colleagues (1), a position can be assumed for the role of phytonutrients in stem cell biology and regenerative medicine. In their study, Small and colleagues found that a short course of consumption of cocoa flavanols by older adults gave rise to substantial increases in the growth of their neuropoietic (20) hippocampal dentate gyrus and improved their cognitive functioning. A study of human hippocampal stem or progenitor cells in vitro and in vivo (patients undergoing temporal lobectomy for intractable epilepsy and who participated in memory testing) showed the importance of these cells for lifelong memory prowess (2), which corroborated work with animal models (21). Patients having high-proliferation-capacity hippocampal stem cells exhibited normal memory performance before surgery, whereas patients with low-proliferation-capacity stem cells showed severe cognitive impairment. These studies reveal at-risk stem or progenitor cells to be functional food-drug targets, including those that inhabit the aging hippocampus, where mood and cognition can be compromised. There is growing interest in the role of inflammation that is thought to be attenuated by polyphenols [e.g., resveratrol via action on the histone deacetylase SIRT1 (22)], but this attenuation has not been proven in human clinical trials. Studies also point to the ability to enhance potentially different aspects of survival, differentiation, and redox-dependent astroglia compared with neuronal fate choice of at-risk neural precursor cells (23).

The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (24) has shown that in addition to exercise and cognitive training, a diet rich in fruits, vegetables, grains, and low-fat and low-carbohydrate foods, along with fish ≥2 times/wk, facilitated the capability of working memory and overall health. Bredesen has shown the positive effects of a multimodal therapeutic program for reversing cognitive decline; the program includes units on diet, ketogenesis, sleep, and gastrointestinal health (25); the Bredesen study also emphasizes the shortcomings of focusing on monotherapeutics for AD or any disease of substantial complexity. These 2 studies together support a notion that overall good health may have the potential to enhance stem cell function (26) and facilitate more successful reparative attempts by these regenerative units during pathological aging.

Cognitive decline can also be a hallmark of another prevalent neurodegenerative disease, PD, which has dietary components that increase the risk for disease onset and progression. Certain nutrient compounds contained within foods have been shown, however, to enhance cognition and other behavioral limitations that are imposed by the disease process. Dairy products, including milk and cheese, have been shown to increase the risk for PD in men (27), and other studies have found that the consumption of milk by women is associated positively with PD (28); the precise mechanism underlying a possible connection between dairy and PD needs to be studied further, but these aforementioned studies denote a possible role for the presence of neurotoxic pesticide residues. Sääksjärvi et al. also reported that there was an inverse association between eating meat products and PD in women (28). Interestingly, they also found that a high amount of consumption of fresh fruits and berries increased the risk of developing PD in men, whereas there was a weak inverse association in women; the authors also reported that vegetables in the diet were not associated with the risk of developing PD in either men or women. Large ongoing cohort studies have shown effects on PD risk from dietary patterns and the consumption of particular nutrients and dietary components; for example, Gao and colleagues (29, 30) showed that total flavonoids and their different subclasses (e.g., anthocyanins) and caffeine are associated with having a lower risk for developing PD. Greater consumption of flavonoids, particularly those in berries, has been shown to positively affect certain nonmotor symptoms in PD, including those associated with cognition and mood (31).

The identification of tumor-initiating stem-like cells in different cancers, including brain cancer (32, 33), with use of approaches similar to those that we used in our studies of normal human neuropoiesis (34) established that genetically altered, hyperproliferative stem or progenitor cells contribute to tumorigenesis and metastatic disease that also can be targeted by dietary interventions (e.g., ketogenic; see NCT01535911, NCT02286167, NCT01754350 at clinicaltrials.gov) (35–37) and particular dietary components (e.g., curcumin, epigallocatechin-3-gallate) (38–40). The literature is replete regarding the role of regenerative nutrition, stem cell biology, and dietary and metabolic control (41) in cancer prevention and therapy; it appears that standard-of-care therapies could benefit from adjunct dietary and nutritional interventions that potentially thwart disease, while simultaneously combating the adverse effects of the treatments (42). Targeting reparative cells in poietic niches, including the blood-brain barrier–accessible periventricular neurogenic system (43) and stem or progenitor cells throughout the brain parenchyma that we previously showed respond to epigallocatechin-3-gallate with a possibility of deterring enhanced proliferation that often accompanies neoplastic transformation (44), together offer promise for phytochemicals being innovative therapeutic tools against cancer stem cells (45). We believe that it is worth focusing on the emerging concept of “cancer stem cells … as a potential target for bioactive food components” (46), as well as how diet, nutrition, and lifestyle can alter aberrant cell behaviors and genetic and molecular pathways that more than coincidentally are involved in both cancer and neurodegenerative diseases (47, 48).

Examples of putative cognitive-enhancing foods include blueberries (49, 50), nuts (51, 52), and spirulina and certain combinations of bioactive phytocompounds (53, 54). Other dietary components such as lipids and a high-fat and reduced carbohydrate and ketogenic diet can have effects on the normal neural stem cells involved in maintaining cognitive function, along with the pathological stem cells involved in brain cancer (37). Studies clearly show a role for the “nutrient control of neural stem cells” (55), whereby enhancing cell numbers through diet can result in profoundly positive outcomes in cancer; in cancer, sugar is a crucial, continuous source of energy for tumor cell genesis (the so-called Warburg effect, the phenomenon whereby most cancer cells generate cellular energy via high rates of cytosolic glycolysis compared with the low rates seen in normal cells, which rely on high rates of oxidation of pyruvate in mitochondria) (56, 57).

Certain nutrients also can support brain circuitry protection and repair in neurodegenerative diseases or following traumatic injuries, with consequential improvements in mood, lifelong learning, and memory (e.g., as seen in a human clinical trial using blueberries in the diet) (58). Many of the same supportive nutrients appear to target the inflammatory microenvironment that accompanies neoplasia and standard-of-care chemotherapies. Hence, our goal was to create an emerging model of applying omics to precision medicine, assaying particular diet and nutritional combinations for attenuating chronic inflammation to deter disease progression, and simultaneously reducing the adverse effects of chemotherapy, including “brain fog” (59) and neuropathy (60). There are many other aspects of applying diet to neuroprotection and enhancing aspects of brain function, including roles for the endocannabinoid system, which has even been implicated in oxytocin-driven social reward (61). Oxytocin, a neuropeptide hormone, plays numerous roles in brain function. Its implicated effects on compliance (62, 63) warrant much more study and understanding to ensure that individuals follow diet and nutrient protocols assiduously to prevent disease and stem disease progression.

Numerous studies exist of polyphenols and flavonoids affecting the central nervous system, including the neuropoietic niches in the forebrain (64); affecting synaptic transmission and circuitry function, including the importance of structural phospholipids (e.g., plasmalogens) (65); and their role in the nutritional formulation Souvenaid (a combination of uridine, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B-12, B-6, C, and E, and selenium) (66), proposed to maintain the structural integrity of brain membranes in AD (65) that also may contribute to cell genesis and synaptogenesis from newly generated neurons. Such “lipid nutrition” also has been a focus of studies looking directly at membranes of neural stem and progenitor cells (67); it was found that lipid signals, including fats, fatty acids and their metabolites and intracellular carriers, cholesterol, and vitamins, have substantial effects on proliferation and differentiation.

Dietary and Nutrient Targets during Normal and Aberrant Neurogenesis for AD, Other Neurodegenerative Diseases, and Cancer: From Nutrient Screening to Biological Clocks

Nutrition control of neural stem cells studies have focused on particular morphogenetic molecules, including insulin and insulin-like growth factor, reaching consensus that diet and particular nutrients are crucial for the “physiological status of an organism to be able to influence stem cell behavior to ensure that stem cells meet the needs of the organism during growth, and in response to injury and environmental changes” (55). Even maternal diet, which is a high-fat diet, has an effect on transcription factor signaling in neural stem cells of offspring mice (68). Human brain neuropoietic sites, the periventricular subependymal zone, and the hippocampus (2, 69) are extremely amenable to positive growth effects from not only flavonoids such as cocoa (1) but also a variety of vegetable- and fruit-derived polyphenols, stilbenes, anthocyanins, and other biogenic alkaloids that have shown efficacious improvements in cognition. The well-established prowess of blueberries (70) and other fruit- and nut-derived (e.g., walnut) (51, 52) individual nutrients (e.g., pterostilbene) (71) exhibits antioxidant and anti-inflammatory biological actions that counter neuronal aging and enhance structure, function, and resultant cognitive (e.g., maze-associated navigational skills) behaviors associated with the hippocampus (72). Micronutrients, including B and other vitamins (73), also play roles in the cognitive impairment that can accompany aging, and often seem to be in association with vascular processes. The genetics and molecular biology of normal and cancerous neurogeneses make available numerous networks of genes that are amenable to control from neurobioactive compounds derived from plants and the diet. There is evidence that diet can enhance normal neural cell genesis and simultaneously target at-risk omics to eradicate cancer stem cell populations along with emerging precision, standard-of-care therapies (unpublished observations mentioned in reference 37).

We have reviewed the literature for articles regarding the enhancement of neurogenesis in neurodegenerative diseases (e.g., AD) (74), pointing out that many pharmacologic interventions (including fluoxetine) have been shown to increase adult hippocampal neurogenesis in animal models (75), as well as to exhibit the potential to enhance memory function and cognition in patients (76). There has even been a study that examined the potential of a well-recognized poietic enhancer—granulocyte colony-stimulating factor—which exhibited some positive effects on a hippocampal-dependent task of cognitive performance in patients with AD (77). In addition to data on pharmaceuticals, we summarized data on naturally derived compounds such as plants and herbs and posited that polyphenolic compounds could act as antiaggregation agents targeting pathological proteins or exhibit anti-inflammatory actions that support a counterbalancing, reactive neurogenesis to help maintain neural circuitry structure and function (74).

It also is crucial to consider the most efficacious timing of administration of any single or combination of potentially preventive or therapeutic nutrients, in association with standard-of-care treatments, for neurodegenerative diseases and cancers (Figure 1). Timing of administration may be extremely important in cases in which metabolism is inextricably connected to the biological or circadian clock; disruption of such rhythms and nonstrategic dosing patterns could contribute to failed attempts at slowing disease progression based on distinct patterns of active cell cycle and metabolic genes, which are under the control of circadian regulation. SIRT1, which has been shown to be a key regulator of metabolism, also is part of the “machinery” of the circadian clock (78). In addition, dynamic changes in the cancer cell cycle reveal a mechanism for successful treatment paradigms that also reflect clock behaviors; DNA damage responses are cell-state dependent, and a recent study revealed the importance of understanding signal dynamics and cellular states (79) for designing standard-of-care chemotherapies as well as introducing conjunctive food-drug applications that together will work more efficaciously with timing of administration in mind. Roles for the metabolome and especially the microbiome in exploiting the most useful production of by-products of food and therapeutic nutrients from the most productive populations of gut microbiota are discussed briefly below.

Neuroimmunology, Inflammation, Roles for Microglia, and Brain-Body Communication during Aging, Cognitive Decline, and Cancer, Nutrition, and Hormesis

Brain microglia uniquely support normal (80–82) and potentially cancerous (83) neurogenesis in highly unique and regionally specific ways. Phytocompounds and probiotics (84) can affect substantially the newly characterized lymphatic (85) and brain immune systems (86, 87) with relevance to AD and the “sanctuary status” in oncology. In the sanctuary status, diseased cells can evade detection and treatment in certain microenvironmental settings (88) while interacting with the choroid plexus neurogenic sites; at these sites, neuroinflammation, in addition to neuropoiesis, seems to be strategically positioned and seated (89). Inflammation and cell-stress roles in AD and other neurodegenerative diseases, as well as during gliomagenesis, need further study with regard to the roles that diet and nutrition may play in their prevention or mitigation. It is becoming clear that the brain and body communicate via inflammation and immune system messengers to help mediate the hormonal control of both brain and body aging. It is possible that this central and peripheral interaction can be modulated by diet and nutrition. A landmark study (16) has described the hypothalamus as being crucial to the development of whole-body aging in mice via the mediators of inflammation, inhibitor of NF-κB subunit β and NF-κB, which substantially alter gonadotropin-releasing hormone. These molecular events lead to impaired hypothalamic neurogenesis and acceleration of aging. Inhibiting the inhibitor of NF-κB subunit β and NF-κB lead to a deceleration of the aging process and increase of the lifespan, which was mediated via gonadotropin-releasing hormone and its influence on hypothalamic cell genesis. It is not surprising that the brain’s resident immune cells, the microglia, mediate the inflammatory cascade. If the hypothalamus can control systemic aging and this is mediated at least in part by inflammation, which is correlated with age, then it can be hypothesized that dietary intervention can play a role in reducing age-related central nervous system inflammation, microglial activation, and stimulation of immune pathways that reduce cell genesis and accelerate hypothalamus-influenced systemic aging.

The discovery that the hypothalamus may play a key role in systemic aging and that this is influenced by inflammation of the brain draws a direct link between age-related inflammation and aging. It also raises the possibility that attenuating age-associated brain inflammation may positively affect overall brain aging and systemic aging. Findings on lymph and immune-related cells (e.g., T cells) and molecules, for example type I interferon, in the brain (86, 87, 90), meninges, ventricular system, and choroid plexi, along with a lymphatic system that helps to rid the brain of toxic proteins and metabolic waste products (91, 92), support the notion that targeting the immune system following infectious and degenerative disease is potentially beneficial. Studies have inquired into how aging affects the brain’s infection-fighting and overall immune function, studies in which it has been shown that inflammatory challenges (e.g., infectious disease) are involved and for which humans are more susceptible during aging. This could include changes in the blood-brain barrier; there also are actual increases in T-cell recruitment and expression of associated molecules including intercellular adhesion molecule-1 (93) during aging.

It has been shown in mouse models of AD that prior brain infection may be involved in seeding the proteinopathies, including β-amyloid and τ, that are involved in the disease process (94). Along with potential infectious exosomal transfer of disease (47), there is strong evidence in support of the use of exosomes as biomarkers of the AD disease state and interference with their synthesis and transport; these can have positive effects on amyloid burden, disease progression, and cognition in mouse models of AD (95, 96). Xu et al. (97) have shown that environmental enrichment also prevents the microglia-mediated inflammation that is associated with the proteinopathies. Finally, different infectious microbial agents can influence disease course and resistance to treatment-associated hormesis (i.e., favorable biological responses to a low dose of a toxic bioactive compound that in higher doses is poisonous and potentially lethal) and oncogenesis (98). Hormesis in this regard is related to the utilization of poisonous cellular toxins involved in standard-of-care therapies, many of which owe their origin and action at least in part to plants that have been considered dangerous to consume.

It is likely that the nutritional requirements for maintaining a healthy young adult and middle-aged brain are different from those for the older adult brain. Consuming a diet that is higher in anti-inflammatory substances will likely be more important in the older adult population, to reduce inflammation in the central nervous system; this can not only positively affect brain aging and age-related dysfunction but also influence systemic aging. Studies on animal models of AD have shown that a Western diet exacerbates glial reactivity and age-related degenerative changes (99), and such inflammation and effects on the aging immune system put the nervous system at risk for cell loss or hyperplasia in neurodegenerative diseases and cancers. With regard to mechanisms underlying inflammation-associated carcinogenesis, we have shown (100) that the putative release of proinflammatory paracrine mediators by both cancer stem cells and immune-related cells (e.g., cytokines, including IL-6 and IL-8) in a colitis-to-colon cancer model potentiate abnormal proliferation of the cancer cell population and thus contribute to tumorigenesis. Other inflammation-associated genes and networks (101), including those related to Toll-like receptor family members and resident and infiltrating immune cells (102), are the most likely contributors to an inflammatory, malignant cancerous microenvironment. There is evidence that the immune system changes well before the earliest detectable onset of cancer (e.g., glioma) (103). Subtle changes in allergy, cytokine expressions, and other immune system–associated behaviors occur decades before neoplastic transformation (at least in its overt compared with covert cancer stage) (5, 104). Chronic inflammation thus provides a conducive environment for the evolution of cancers and degenerative diseases. Mechanistically, a neuroinflammatory priming has been shown to occur following the expression of, for example, the alarmin high-mobility group box 1, and blocking it can desensitize aged microglia and help make them less prone to contribute to such a neural inflammatory microenvironment (105).

There is no question then that a better understanding of the key cellular players (e.g., microglia, T cells, all of the blood-derived cells including monocytes that can inhabit an aging and diseased brain) involved in brain immunity, which help fight degeneration and hypoplasia, will assist in elucidating roles for targeted nutrient therapies to facilitate immune functions that counteract chronic inflammation and disease. Diet and nutrition are certain to play a prominent role in combining standard-of-care medicine with multimodal diet, nutrient, and lifestyle platforms to enhance innate disease-fighting cells in neurodegenerative disease and cancer. It is noteworthy that studying plant hormesis and discovering neurohormetic toxic chemicals that plants synthesize and release to deter pests confers the ability to help build, along with standard-of-care medical practice, brain resilience to disease via potentially possessing neuroprotective properties for the at-risk neuronal and glial populations in diseases such as AD, PD (106), and cancers (98). Diet, nutrient, and microbiota status are certain to be key elements in the performance of standard-of-care medicine for supporting efficacious therapeutic regimens, based on countless examples of the negative interactions of certain foods with pharmaceuticals. Neurodegenerative diseases are typified by symptomology that appears long after the degenerative process is under way; therefore, it is important to be proactive once risk is established based on the use of genetic profiling and other markers of susceptibility. The use of diet and nutrition as conduits for nutrient-rich preventive therapies in prodromal populations (i.e., populations that possess at-risk genetics or idiopathic disease risk but are not yet phenotypically or behaviorally symptomatic) has few disadvantages, especially early in life; changes in dietary practices and lifestyle and the development of routines or habits with incentive for a healthy and long life leading to compliance are easier to incorporate at a young age.

Diet, the Gut Microbiome, Neurogenesis, and Cognitive and Mood Flexibility

The body of literature in the emerging field of microbiomics with relevance to neuroregenerative nutrition is growing tremendously. With an eye toward chronic inflammation and the role it plays in neurological diseases associated with aging, a study that used a Western, high-sugar and high-fat diet in rodents found profound correlative changes in the species of gut microbiota that had a substantial negative impact on anxiety, memory, and cognitive flexibility in different long-term, short-term, and reversal training tests (107). Supplemental administration of particular probiotic combinations can have positive effects on inflammation-associated diseases via modifying interactions between the body, immune system, and nervous system (84). Likewise, ketone bodies and the ketone metabolite β-hydroxybutyrate have been shown to block the leucine-rich repeat containing protein 3 inflammasome-mediated inflammation (108) involved in age-related neurological disease; sodium butyrate binds to G protein–coupled receptors in both the peripheral and central nervous systems (109) and has strong anti-inflammatory effects on immune function via inhibition of IL-12 and IL-10 production by human monocytes (110). Gut microbiota metabolic by-products that include these ketosis-related factors are significant for cancers and neurodegenerative diseases. Studies have shown the potential importance of a ketogenic diet (Figure 1) in combination with standard-of-care therapies for prolonging survival in mouse models of brain cancer (37) and systemic metastatic disease (111).

Discussion: The Future of Neuroregenerative Nutrition—In Vitro and In Vivo Patient Avatars Could Be Important for the Screening of Unique Combinations of Botanical-Derived Polymolecular Compounds for Preventing and Treating Neurological and Other Diseases

We have only begun to see the fruits borne of historic and emerging diet and nutrient approaches for delaying cognitive decline, the brain neoplasias, and systemic deleterious aging. Insights from studies of plant-derived polymolecular compounds also can be applied to the design of next-generation pharmaceuticals for both preventing and treating different neurological diseases; this can be done by way of targeting distinct networks of genes involved in building the reserve and readiness of neural stem or progenitor cells to protect from and repair degenerative diseases or control the aberrant proliferation of tumor-initiating cells. A patient’s unique omics and physiology need to be precisely modeled to use therapeutic phytocompounds; interactions with diet and standard-of-care therapies need to be exploited for effectiveness and deterring the generation of adverse effects. In vitro and in vivo patient avatars, both of which would contain crucial normal and disease-related cellular elements (e.g., at-risk and immune cells from that patient), represent one such approach that offers the chance to screen for next-generation precision therapeutics (Figure 1). Such avatars afford disease and remission modeling steps ahead of the patient’s disease in a unique patient-specific cellular and molecular environment.

Chronic degenerative diseases such as PD and AD, as well as cancer, share common origins, similar molecular courses of disease diagnosis, course and spread and treatment; in particular, the exploitation of small extracellular vesicles, often referred to as exosomes (47), are promising biomarkers of disease states (and amenable to omics-driven personalized standard-of-care and nutrient medicine) and critical elements potentially involved in the transmission of disease. In diseases such as PD, exosomes mirror the abnormal cell and molecular environment of disease and along with patient- and/or disease-specific in vitro and in vivo avatars provide a unique means for precisely modeling disease course and monitoring response to personalized therapies. Advances in stem cell technology that have provided medicine with cellular reprogramming abilities, including induced pluripotent stem cell approaches (112), allow the generation of patient avatars that use gene-identified cell and tissue samples to bioassay countless biogenic compounds that target druggable mutations gleaned from the omics performed on these cells.

With the goal of using genetic, molecular, and cellular approaches, researchers could screen for nutrient compounds in combination that have disease progression–halting effects. For example, both AD and PD avatars can be generated with the ability to mirror individual disease, with the potentially higher sensitivity and less invasive liquid biopsy approach using exosomes (whose membranes protect biomarkers, disease-related nucleic acid and protein cargoes from normally harsh molecular environments of plasma, and cerebrospinal and other body fluids that contain nucleases, proteases, and other degrading elements) as molecular readouts of a disease state and response to therapy. It is anticipated that precision, personalized medicine can be applied to patients with a highly informed rationale. It also is anticipated that this new model could lead to the discovery and refinement of new pathways for drug development in PD, AD, cancer, and many more diseases. Microvesicles and exosomes may not only precisely mirror onset and transmission of pathology but also represent the biological basis for such by way of the exosomal transcellular conveyance of “infectious” proteins and nucleic acids—a basis for disease transmission and spread. Alternatively, exosomes derived from normal human neural stem cells also have been shown to attenuate inflammation and improve cognition in models of brains that have been damaged by radiation therapy [e.g., treatment-associated “brain fog” (113)].

Better animal models of human neurological disease are being studied, and studies are beginning to focus on the use of patient-specific mouse avatars for brain and other solid tumors and hematologic cancers and neurodegenerative diseases using established cancer stem cell isolation and expansion protocols. We were the first to our knowledge to describe solid tumor cancer stem or progenitor cell populations in primary cell culture and xenografted avatar mice, first in models of glioma (32, 83, 114) and then in osteosarcoma (33, 115) and prostate and colon cancers (100, 116). Studies are emerging in hematologic cancers and co-grafting patient-specific immune and target organ systems into immunocompromised mice along with orthotopic grafting of their tumors (e.g., for glioma) (80, 117) to create better models for screening radiation, biological, nutrient, and chemotherapies. For example, polymolecular botanical compounds (i.e., combinations of bioactive organic chemicals; Figure 1) include a first-generation compound referred to as Epidiferphane, which in initial studies has exhibited anti-inflammatory activity in a variety of degenerative and neoplastic disease models in which normal neurogenesis does not seem to be deterred while targeting disease-initiating cells (B Reynolds, C Louviere, B Griffith, H Futch, C Skinner, J McGuiness, L Deleyrolle, unpublished results, 2017).

Central to our approach was the application of multiple therapeutic agents that target a variety of pathways and mechanisms responsible for uncontrolled proliferation in brain cancer. Because of the heterogeneous nature of most solid-tissue cancers, targeting single pathways or mechanisms allows the selection pressure to evoke escape strategies (e.g., the ability to resist chemical, biological, or radiological therapies) at both the cell and population levels. The result of this targeting is the development of resistance through selection and dependence on alternative mechanisms to support continuous cellular growth. A solution is the application of multiple agents that target >1 pathway; however, this can be complicated by additive toxicity when >1 chemotherapy or biotherapy is used. A strategy to address this challenge is to use individual agents that have low toxicity and a broad safety profile. Many natural products fit this description. As described above, each of the natural products we have studied targets multiple signaling pathways that regulate tumor cell survival and proliferation. When combined, a variety of independent mechanisms that support tumor growth can be safely targeted (horizontal inhibition), and even individual pathways can be targeted at multiple points (vertical inhibition). The result is a continued selection pressure placed on the tumor population that dampens or delays the emergence of resistance. Polymolecular botanical drug-like compounds can be used as combinatorial anticancer and antidegenerative disease treatments; in these diseases chronic inflammation is a major contributing factor, involving the use of 3 natural products delivered as dietary supplements. This experimental therapeutic approach has demonstrated efficacy in altering tumor cell proliferation, reducing tumor progression, extending lifespan with no reported toxicity, and sensitizing tumor cells to conventional treatment. At the same time, such combination food-drug therapy approaches seem in preliminary studies to support beneficial cell genesis (e.g., neurogenesis) while dampening the propensity for such cells to undergo neoplastic transformation.

A study demonstrates the coexistence of cancer stem cell populations that can be dissected from human tissue, investigated, and profiled in vitro to predict intratumoral primary drug-response patterns before recurrent growth occurs in situ (114). This is relevant to personalized medicine and neuroregenerative nutrition in that the heterogeneity of tumor-initiating and recurring populations of cells that can be analyzed for such polyclonal dynamics will afford the opportunity to stratify patients based on types of residual brain cancer cells that can contribute to metastatic disease. Precision medicine and nutrition approaches as presented here together offer a reasonable approach to slowing or even deterring progression and recurrence of diseases that are typified by such extremely heterogeneous disease phenotypes and courses. Patient- and disease-specific avatars also can include new in vitro assays that are amenable to high content screening and that should include a patient’s immune cells, at-risk cells (i.e., disease associated or at risk for causing disease progression), and use of novel biosubstrates and microfluidics (118). In brain and other cancer avatar studies, one can use a variety of emerging and established technologies for subclonal analysis (clonal evolution) (119, 120) of tumor-initiating, tumor-propagating, and residual cells that contribute to genetic diversion of progression and recurrence as well as differences in response to therapy in patients with brain tumors and other cancers, and most likely also in the avatars.

Transgenic rodent and xenografts are the gold standard animal models for studying genetic, molecular, cellular, and systems biology in translational and regenerative medicine. Conventional diagnosis and treatment of neurodegenerative disease consist of neurological evaluation, brain imaging, and, most recently, genomic screening with a list of at-risk mutations [e.g., leucine-rich repeat kinase 2 for PD that for idiopathic disease has led to diagnosis, usually by exclusion]. For that reason, any breakthroughs in understanding early prodromal disease onset and phenotypic expression would offer huge advantages toward applications of treatment protocols early (as opposed to late) in the course of disease. New preclinical models that better reflect human disease expression heterogeneity and behavior and that have been standardized for drug testing are needed to develop treatments that are more effective than the present disease-symptom treatment. The development of a more predictive PD model, for example, could not only benefit our understanding of disease progression and resistance to standard-of-care therapies but also provide a better metric to be used for clinical development for discriminating PD from other movement disorders with similar neurological phenotypes (e.g., progressive supranuclear palsy, multisystem atrophy, Lewy body disease); establishing a platform for earlier diagnosis of disease or risk for disease in a prodromal population; and, ultimately, culling poor performers for a particular new therapeutic drug regimen before they enter the costly and critical clinical testing phase. We, as well as others, routinely generate and characterize normal and diseased (e.g., cancer, PD) human stem or progenitor cell primary lines and use them for in vitro and in vivo bioassays, including xenograft models of disease with the ultimate goal of better modeling of disease origin, progression, and response to treatment (2, 32, 44, 69, 117, 121, 122). Disease-related stem and progenitor cells can be differentiated into at-risk neural cells, such as midbrain dopaminergic neurons in PD, and they afford a detailed analysis of the interactions of at-risk brain cells with patient-matched immune cells whose earliest relation leads to a better understanding of cell and molecular bases for disease progression and potential response to new therapies [e.g., those derived from paradigm-shifting studies on the importance of the microbiota and neuroinflammation (123) in addition to diet and lifestyle in regulating behavioral deficits in PD] and, ultimately, remission. In AD models in which the expressed β-amyloid and τ proteinopathies aim to represent a dementia avatar, there is growing evidence that abnormal protein propagation from cell to cell underlies disease spread that is in many ways reflective of the Braak stages, which exhibit both regional and phenotypical progressions (47, 124). This includes receptor-mediated endocytotic uptake of pathological proteins and nucleic acids by naïve cells and exosomal or microvesicular transcellular transfer that acts as a biomarker (95), and also drug- (96, 125, 126) and food drug–targetable conduits of disease and progression attenuation.

Conclusions

It is our strong belief that the use of in vitro (i.e., cell culture models with patient disease–related and immune cells) and in vivo (i.e., xenotransplanted at-risk and immune cells) avatars for monitoring the precise effects of standard-of-care and integrated medicine, including the use of functional foods reviewed here and gleaned from studies of age-related changes in cell and molecular expressions of particularly inflammatory neurodegenerative disease and cancer components, will have a profoundly positive effect on translating nutrition and dietary approach data to a large prodromal human population that presents with numerous pressing unmet medical needs during aging and longer lifespans. Figure 1 summarizes all of the discussed methods and approaches for studying the roles of diet and nutrient therapies (in combination with standard-of-care and emerging pharmacological therapies) in preventing and treating neurological disorders in which aging and chronic inflammation are major contributing factors to disease onset, progression or recurrence, and resistance to therapies, especially monotherapies. Tapping new varieties of potentially therapeutic plants that induce limited damage to cells and tissues, which subsequently induces disease-fighting and regenerative processes, holds great promise but requires rigorous scientific evaluations through use of the most sensitive bioassays. Future studies may be focused on examining roles for combining standard-of-care therapies for cancers and neurodegenerative and other diseases with selective combinations of phytotherapies and particular microbes that moderate inflammation as a practical means of accomplishing hormesis” (98).

Our goal was to introduce a variety of concepts with examples from the literature, including many intersecting fields of study, that support a notion that whole foods and particular nutrient components have the ability to affect regenerative units in the aging human brain. In brain aging, both degenerative and neoplastic diseases contain similar cell and molecular interactions that are amenable to attenuation through use of therapeutic dosing of food-drugs that target many of the biochemical pathways that are the focus of pharmaceutical development. Thus, diet and lifestyle and other approaches in integrated medicine seem well suited for concurrent, complementary therapies in combination with standard-of-care medicine. The need for sensitive and reliable bioassays, including both in vitro and in vivo avatars of a patient’s condition (e.g., immune status and all of his or her omics), should provide a subtle means of discovering which combinations of nutrient compounds hold promise for helping to prevent and treat some of our most challenging health issues. Finally, the incorporation of emerging fields such as neuroregenerative nutrition into protocols for maintaining cognitive prowess throughout the lifespan do, in the words of a perspective on roles for diet in neurodegenerative diseases such as multiple sclerosis, “let wellness-based treatments stand on an equal footing with their pharmaceutical counterparts” (127).