Mitochondrial Aldehyde Dehydrogenase 2 (ALDH2) Protects against Binge Alcohol-Mediated Gut and Brain Injury.

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) metabolizes acetaldehyde to acetate. People with ALDH2 deficiency and Aldh2-knockout (KO) mice are more susceptible to alcohol-induced tissue damage. However, the underlying mechanisms behind ALDH2-related gut-associated brain damage remain unclear. Age-matched young female Aldh2-KO and C57BL/6J wild-type (WT) mice were gavaged with binge alcohol (4 g/kg/dose, three doses) or dextrose (control) at 12 h intervals. Tissues and sera were collected 1 h after the last ethanol dose and evaluated by histological and biochemical analyses of the gut and hippocampus and their extracts. For the mechanistic study, mouse neuroblast Neuro2A cells were exposed to ethanol with or without an Aldh2 inhibitor (Daidzin). Binge alcohol decreased intestinal tight/adherens junction proteins but increased oxidative stress-mediated post-translational modifications (PTMs) and enterocyte apoptosis, leading to elevated gut leakiness and endotoxemia in Aldh2-KO mice compared to corresponding WT mice. Alcohol-exposed Aldh2-KO mice also showed higher levels of hippocampal brain injury, oxidative stress-related PTMs, and neuronal apoptosis than the WT mice. Additionally, alcohol exposure reduced Neuro2A cell viability with elevated oxidative stress-related PTMs and apoptosis, all of which were exacerbated by Aldh2 inhibition. Our results show for the first time that ALDH2 plays a protective role in binge alcohol-induced brain injury partly through the gut-brain axis, suggesting that ALDH2 is a potential target for attenuating alcohol-induced tissue injury.

Non-invasive tests for alcohol-associated liver disease.

Alcohol consumption is a global phenomenon and a major contributor to alcohol-associated liver disease (ALD). Detecting individuals at risk of ALD has been challenging, with only a small fraction of patients being identified at early stages compared to other chronic liver diseases. In response to this challenge, non-invasive tests (NITs) have become essential tools for the detection of ALD, offering opportunities for early identification and intervention to mitigate the disease burden. Noninvasive alcohol consumption biomarkers are crucial in estimating individuals' recent alcohol intake, providing valuable insights into their drinking patterns. Various NITs have been investigated for the initial screening of asymptomatic individuals at risk of ALD, as well as for identifying specific stages of the disease. These NITs are applied in 2 main clinical scenarios: population-based stratification for identifying and predicting liver-related symptoms and diagnosing and prognosticating compensated cirrhosis or advanced chronic liver disease in secondary or tertiary care settings. Moreover, NITs play a significant role in the prognostic assessment of patients with various manifestations of ALD, including alcohol-associated hepatitis (AH), decompensated cirrhosis, and metabolic-associated and ALD. These tests guide appropriate treatment decisions and predict outcomes. In this review, various NITs for the early detection and monitoring of alcohol consumption were discussed. Additionally, the evaluation of NITs for screening and predicting ALD and liver complications was addressed comprehensively. Future perspectives of NITs for ALD were explored, alongside a thorough discussion of the opportunities and challenges associated with NITs for ALD screening.

Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction.

This review provides an update on recent findings from basic, translational, and clinical studies on the molecular mechanisms of mitochondrial dysfunction and apoptosis of hepatocytes in multiple liver diseases, including but not limited to alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and drug-induced liver injury (DILI). While the ethanol-inducible cytochrome P450-2E1 (CYP2E1) is mainly responsible for oxidizing binge alcohol via the microsomal ethanol oxidizing system, it is also responsible for metabolizing many xenobiotics, including pollutants, chemicals, drugs, and specific diets abundant in n-6 fatty acids, into toxic metabolites in many organs, including the liver, causing pathological insults through organelles such as mitochondria and endoplasmic reticula. Oxidative imbalances (oxidative stress) in mitochondria promote the covalent modifications of lipids, proteins, and nucleic acids through enzymatic and non-enzymatic mechanisms. Excessive changes stimulate various post-translational modifications (PTMs) of mitochondrial proteins, transcription factors, and histones. Increased PTMs of mitochondrial proteins inactivate many enzymes involved in the reduction of oxidative species, fatty acid metabolism, and mitophagy pathways, leading to mitochondrial dysfunction, energy depletion, and apoptosis. Unique from other organelles, mitochondria control many signaling cascades involved in bioenergetics (fat metabolism), inflammation, and apoptosis/necrosis of hepatocytes. When mitochondrial homeostasis is shifted, these pathways become altered or shut down, likely contributing to the death of hepatocytes with activation of inflammation and hepatic stellate cells, causing liver fibrosis and cirrhosis. This review will encapsulate how mitochondrial dysfunction contributes to hepatocyte apoptosis in several types of liver diseases in order to provide recommendations for targeted therapeutics.

Ellagic Acid Prevented Dextran-Sodium-Sulfate-Induced Colitis, Liver, and Brain Injury through Gut Microbiome Changes.

Inflammatory bowel disease (IBD) affects millions of people worldwide and is considered a significant risk factor for colorectal cancer. Recent in vivo and in vitro studies reported that ellagic acid (EA) exhibits important antioxidant and anti-inflammatory properties. In this study, we investigated the preventive effects of EA against dextran sulfate sodium (DSS)-induced acute colitis, liver, and brain injury in mice through the gut-liver-brain axis. Acute colitis, liver, and brain injury were induced by treatment with 5% (w/v) DSS in the drinking water for 7 days. Freshly prepared EA (60 mg/kg/day) was orally administered, while control (CON) group mice were treated similarly by daily oral administrations with a vehicle (water). All the mice were euthanized 24 h after the final treatment with EA. The blood, liver, colon, and brain samples were collected for further histological and biochemical analyses. Co-treatment with a physiologically relevant dose (60 mg/kg/day) of EA for 7 days significantly reduced the DSS-induced gut barrier dysfunction; endotoxemia; and inflammatory gut, liver, and brain injury in mice by modulating gut microbiota composition and inhibiting the elevated oxidative and nitrative stress marker proteins. Our results further demonstrated that the preventive effect of EA on the DSS-induced IBD mouse model was mediated by blocking the NF-κB and mitogen-activated protein kinase (MAPK) pathway. Therefore, EA co-treatment significantly attenuated the pro-inflammatory and oxidative stress markers by suppressing the activation of NF-κB/MAPK pathways in gut, liver, and brain injury. These results suggest that EA, effective in attenuating IBD in a mouse model, deserves further consideration as a potential therapeutic for the treatment of inflammatory diseases.

Post-translational modifications of histone and non-histone proteins in epigenetic regulation and translational applications in alcohol-associated liver disease: Challenges and research opportunities.

Epigenetic regulation is a process that takes place through adaptive cellular pathways influenced by environmental factors and metabolic changes to modulate gene activity with heritable phenotypic variations without altering the DNA sequences of many target genes. Epigenetic regulation can be facilitated by diverse mechanisms: many different types of post-translational modifications (PTMs) of histone and non-histone nuclear proteins, DNA methylation, altered levels of noncoding RNAs, incorporation of histone variants, nucleosomal positioning, chromatin remodeling, etc. These factors modulate chromatin structure and stability with or without the involvement of metabolic products, depending on the cellular context of target cells or environmental stimuli, such as intake of alcohol (ethanol) or Western-style high-fat diets. Alterations of epigenetics have been actively studied, since they are frequently associated with multiple disease states. Consequently, explorations of epigenetic regulation have recently shed light on the pathogenesis and progression of alcohol-associated disorders. In this review, we highlight the roles of various types of PTMs, including less-characterized modifications of nuclear histone and non-histone proteins, in the epigenetic regulation of alcohol-associated liver disease (ALD) and other disorders. We also describe challenges in characterizing specific PTMs and suggest future opportunities for basic and translational research to prevent or treat ALD and many other disease states.

Therapeutic strategies of small molecules in the microbiota-gut-brain axis for alcohol use disorder.

The microbiota-gut-brain axis (MGBA) is important in maintaining the structure and function of the central nervous system (CNS) and is regulated by the CNS environment and signals from the peripheral tissues. However, the mechanism and function of the MGBA in alcohol use disorder (AUD) are still not completely understood. In this review, we investigate the underlying mechanisms involved in the onset of AUD and/or associated neuronal deficits and create a foundation for better treatment (and prevention) strategies. We summarize recent reports focusing on the alteration of the MGBA in AUD. Importantly, we highlight the properties of small-molecule short-chain fatty acids (SCFAs), neurotransmitters, hormones, and peptides in the MGBA and discusses their usage as therapeutic agents against AUD.

ALDH2 deficiency increases susceptibility to binge alcohol-induced gut leakiness, endotoxemia, and acute liver injury in mice through the gut-liver axis.

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is the major enzyme responsible for metabolizing toxic acetaldehyde to acetate and acts as a protective or defensive protein against various disease states associated with alcohol use disorder (AUD), including alcohol-related liver disease (ARLD). We hypothesized that Aldh2-knockout (KO) mice are more susceptible to binge alcohol-mediated liver injury than wild-type (WT) mice through increased oxidative stress, gut leakiness and endotoxemia. Therefore, this study aimed to investigate the protective role of ALDH2 in binge alcohol-induced gut permeability, endotoxemia, and acute inflammatory liver injury by exposing Aldh2-KO or WT mice to a single oral dose of binge alcohol 3.5, 4.0, or 5.0 g/kg. Our findings showed for the first time that ALDH2 deficiency in Aldh2-KO mice increases their sensitivity to binge alcohol-induced oxidative and nitrative stress, enterocyte apoptosis, and nitration of gut tight junction (TJ) and adherent junction (AJ) proteins, leading to their degradation. These resulted in gut leakiness and endotoxemia in Aldh2-KO mice after exposure to a single dose of ethanol even at 3.5 g/kg, while no changes were observed in the corresponding WT mice. The elevated serum endotoxin (lipopolysaccharide, LPS) and bacterial translocation contributed to systemic inflammation, hepatocyte apoptosis, and subsequently acute liver injury through the gut-liver axis. Treatment with Daidzin, an ALDH2 inhibitor, exacerbated ethanol-induced cell permeability and reduced TJ/AJ proteins in T84 human colon cells. These changes were reversed by Alda-1, an ALDH2 activator. Furthermore, CRISPR/Cas9-mediated knockout of ALDH2 in T84 cells increased alcohol-mediated cell damage and paracellular permeability. All these findings demonstrate the critical role of ALDH2 in alcohol-induced epithelial barrier dysfunction and suggest that ALDH2 deficiency or gene mutation in humans is a risk factor for alcohol-mediated gut and liver injury, and that ALDH2 could be an important therapeutic target against alcohol-associated tissue or organ damage.

Melatonin Prevents Alcohol- and Metabolic Dysfunction- Associated Steatotic Liver Disease by Mitigating Gut Dysbiosis, Intestinal Barrier Dysfunction, and Endotoxemia.

Melatonin (MT) has often been used to support good sleep quality, especially during the COVID-19 pandemic, as many have suffered from stress-related disrupted sleep patterns. It is less known that MT is an antioxidant, anti-inflammatory compound, and modulator of gut barrier dysfunction, which plays a significant role in many disease states. Furthermore, MT is produced at 400-500 times greater concentrations in intestinal enterochromaffin cells, supporting the role of MT in maintaining the functions of the intestines and gut-organ axes. Given this information, the focus of this article is to review the functions of MT and the molecular mechanisms by which it prevents alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), including its metabolism and interactions with mitochondria to exert its antioxidant and anti-inflammatory activities in the gut-liver axis. We detail various mechanisms by which MT acts as an antioxidant, anti-inflammatory compound, and modulator of intestinal barrier function to prevent the progression of ALD and MASLD via the gut-liver axis, with a focus on how these conditions are modeled in animal studies. Using the mechanisms of MT prevention and animal studies described, we suggest behavioral modifications and several exogenous sources of MT, including food and supplements. Further clinical research should be performed to develop the field of MT in preventing the progression of liver diseases via the gut-liver axis, so we mention a few considerations regarding MT supplementation in the context of clinical trials in order to advance this field of research.

Role of Endogenous Lipopolysaccharides in Neurological Disorders.

Lipopolysaccharide (LPS) is a cell-wall immunostimulatory endotoxin component of Gram-negative bacteria. A growing body of evidence reveals that alterations in the bacterial composition of the intestinal microbiota (gut dysbiosis) disrupt host immune homeostasis and the intestinal barrier function. Microbial dysbiosis leads to a proinflammatory milieu and systemic endotoxemia, which contribute to the development of neurodegenerative diseases and metabolic disorders. Two important pathophysiological hallmarks of neurodegenerative diseases (NDDs) are oxidative/nitrative stress and inflammation, which can be initiated by elevated intestinal permeability, with increased abundance of pathobionts. These changes lead to excessive release of LPS and other bacterial products into blood, which in turn induce chronic systemic inflammation, which damages the blood-brain barrier (BBB). An impaired BBB allows the translocation of potentially harmful bacterial products, including LPS, and activated neutrophils/leucocytes into the brain, which results in neuroinflammation and apoptosis. Chronic neuroinflammation causes neuronal damage and synaptic loss, leading to memory impairment. LPS-induced inflammation causes inappropriate activation of microglia, astrocytes, and dendritic cells. Consequently, these alterations negatively affect mitochondrial function and lead to increases in oxidative/nitrative stress and neuronal senescence. These cellular changes in the brain give rise to specific clinical symptoms, such as impairment of locomotor function, muscle weakness, paralysis, learning deficits, and dementia. This review summarizes the contributing role of LPS in the development of neuroinflammation and neuronal cell death in various neurodegenerative diseases.

Mechanistic Insights into the Link between Gut Dysbiosis and Major Depression: An Extensive Review.

Depression is a highly common mental disorder, which is often multifactorial with sex, genetic, environmental, and/or psychological causes. Recent advancements in biomedical research have demonstrated a clear correlation between gut dysbiosis (GD) or gut microbial dysbiosis and the development of anxiety or depressive behaviors. The gut microbiome communicates with the brain through the neural, immune, and metabolic pathways, either directly (via vagal nerves) or indirectly (via gut- and microbial-derived metabolites as well as gut hormones and endocrine peptides, including peptide YY, pancreatic polypeptide, neuropeptide Y, cholecystokinin, corticotropin-releasing factor, glucagon-like peptide, oxytocin, and ghrelin). Maintaining healthy gut microbiota (GM) is now being recognized as important for brain health through the use of probiotics, prebiotics, synbiotics, fecal microbial transplantation (FMT), etc. A few approaches exert antidepressant effects via restoring GM and hypothalamus-pituitary-adrenal (HPA) axis functions. In this review, we have summarized the etiopathogenic link between gut dysbiosis and depression with preclinical and clinical evidence. In addition, we have collated information on the recent therapies and supplements, such as probiotics, prebiotics, short-chain fatty acids, and vitamin B12, omega-3 fatty acids, etc., which target the gut-brain axis (GBA) for the effective management of depressive behavior and anxiety.

The Influence of Gut Dysbiosis in the Pathogenesis and Management of Ischemic Stroke.

Recent research on the gut microbiome has revealed the influence of gut microbiota (GM) on ischemic stroke pathogenesis and treatment outcomes. Alterations in the diversity, abundance, and functions of the gut microbiome, termed gut dysbiosis, results in dysregulated gut-brain signaling, which induces intestinal barrier changes, endotoxemia, systemic inflammation, and infection, affecting post-stroke outcomes. Gut-brain interactions are bidirectional, and the signals from the gut to the brain are mediated by microbially derived metabolites, such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs); bacterial components, such as lipopolysaccharide (LPS); immune cells, such as T helper cells; and bacterial translocation via hormonal, immune, and neural pathways. Ischemic stroke affects gut microbial composition via neural and hypothalamic-pituitary-adrenal (HPA) pathways, which can contribute to post-stroke outcomes. Experimental and clinical studies have demonstrated that the restoration of the gut microbiome usually improves stroke treatment outcomes by regulating metabolic, immune, and inflammatory responses via the gut-brain axis (GBA). Therefore, restoring healthy microbial ecology in the gut may be a key therapeutic target for the effective management and treatment of ischemic stroke.

Mitochondria-Endoplasmic Reticulum Crosstalk in Parkinson's Disease: The Role of Brain Renin Angiotensin System Components.

The past few decades have seen an increased emphasis on the involvement of the mitochondrial-associated membrane (MAM) in various neurodegenerative diseases, particularly in Parkinson's disease (PD) and Alzheimer's disease (AD). In PD, alterations in mitochondria, endoplasmic reticulum (ER), and MAM functions affect the secretion and metabolism of proteins, causing an imbalance in calcium homeostasis and oxidative stress. These changes lead to alterations in the translocation of the MAM components, such as IP3R, VDAC, and MFN1 and 2, and consequently disrupt calcium homeostasis and cause misfolded proteins with impaired autophagy, distorted mitochondrial dynamics, and cell death. Various reports indicate the detrimental involvement of the brain renin-angiotensin system (RAS) in oxidative stress, neuroinflammation, and apoptosis in various neurodegenerative diseases. In this review, we attempted to update the reports (using various search engines, such as PubMed, SCOPUS, Elsevier, and Springer Nature) demonstrating the pathogenic interactions between the various proteins present in mitochondria, ER, and MAM with respect to Parkinson's disease. We also made an attempt to speculate the possible involvement of RAS and its components, i.e., AT1 and AT2 receptors, angiotensinogen, in this crosstalk and PD pathology. The review also collates and provides updated information on the role of MAM in calcium signaling, oxidative stress, neuroinflammation, and apoptosis in PD.

Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury.

Advanced glycation end products (AGEs) are potentially harmful and heterogeneous molecules derived from nonenzymatic glycation. The pathological implications of AGEs are ascribed to their ability to promote oxidative stress, inflammation, and apoptosis. Recent studies in basic and translational research have revealed the contributing roles of AGEs in the development and progression of various aging-related pathological conditions, such as diabetes, cardiovascular complications, gut microbiome-associated illnesses, liver or neurodegenerative diseases, and cancer. Excessive chronic and/or acute binge consumption of alcohol (ethanol), a widely consumed addictive substance, is known to cause more than 200 diseases, including alcohol use disorder (addiction), alcoholic liver disease, and brain damage. However, despite the considerable amount of research in this area, the underlying molecular mechanisms by which alcohol abuse causes cellular toxicity and organ damage remain to be further characterized. In this review, we first briefly describe the properties of AGEs: their formation, accumulation, and receptor interactions. We then focus on the causative functions of AGEs that impact various aging-related diseases. We also highlight the biological connection of AGE-alcohol-adduct formations to alcohol-mediated tissue injury. Finally, we describe the potential translational research opportunities for treatment of various AGE- and/or alcohol-related adduct-associated disorders according to the mechanistic insights presented.

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases.

With aging, the nervous system gradually undergoes degeneration. Increased oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and cell death are considered to be common pathophysiological mechanisms of various neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), organophosphate-induced delayed neuropathy (OPIDN), and amyotrophic lateral sclerosis (ALS). Autophagy is a cellular basic metabolic process that degrades the aggregated or misfolded proteins and abnormal organelles in cells. The abnormal regulation of neuronal autophagy is accompanied by the accumulation and deposition of irregular proteins, leading to changes in neuron homeostasis and neurodegeneration. Autophagy exhibits both a protective mechanism and a damage pathway related to programmed cell death. Because of its "double-edged sword", autophagy plays an important role in neurological damage and NDDs including AD, PD, HD, OPIDN, and ALS. Melatonin is a neuroendocrine hormone mainly synthesized in the pineal gland and exhibits a wide range of biological functions, such as sleep control, regulating circadian rhythm, immune enhancement, metabolism regulation, antioxidant, anti-aging, and anti-tumor effects. It can prevent cell death, reduce inflammation, block calcium channels, etc. In this review, we briefly discuss the neuroprotective role of melatonin against various NDDs via regulating autophagy, which could be a new field for future translational research and clinical studies to discover preventive or therapeutic agents for many NDDs.

Gamma-oryzanol Prevents LPS-induced Brain Inflammation and Cognitive Impairment in Adult Mice.

BACKGROUND: Rice (Oryza sativa L.) is the main food source for more than half of humankind. Rice is rich in phytochemicals and antioxidants with several biological activities; among these compounds, the presence of γ-oryzanol is noteworthy. The present study aims to explore the effects of γ-oryzanol on cognitive performance in a mouse model of neuroinflammation and cognitive alterations. METHODS: Mice received 100 mg/kg γ-oryzanol (ORY) or vehicle once daily for 21 consecutive days and were then exposed to an inflammatory stimulus elicited by lipopolysaccharide (LPS). A novel object recognition test and mRNA expression of antioxidant and neuroinflammatory markers in the hippocampus were evaluated. RESULTS: ORY treatment was able to improve cognitive performance during the neuroinflammatory response. Furthermore, phase II antioxidant enzymes such as heme oxygenase-1 (HO-1) and NADPH-dehydrogenase-quinone-1 (NQO1) were upregulated in the hippocampi of ORY and ORY+LPS mice. Lastly, γ-oryzanol showed a strong anti-inflammatory action by downregulating inflammatory genes after LPS treatment. CONCLUSION: These results suggest that chronic consumption of γ-oryzanol can revert the LPS-induced cognitive and memory impairments by promoting hippocampal antioxidant and anti-inflammatory molecular responses.

γ-Oryzanol Improves Cognitive Function and Modulates Hippocampal Proteome in Mice.

Rice (Oryza sativa L.) is the richest source of γ-oryzanol, a compound endowed with antioxidant and anti-inflammatory properties. γ-Oryzanol has been demonstrated to cross the blood-brain barrier in intact form and exert beneficial effects on brain function. This study aimed to clarify the effects of γ-oryzanol in the hippocampus in terms of cognitive function and protein expression. Adult mice were administered with γ-oryzanol 100 mg/kg or vehicle (control) once a day for 21 consecutive days following which cognitive behavior and hippocampal proteome were investigated. Cognitive tests using novel object recognition and Y-maze showed that long-term consumption of γ-oryzanol improves cognitive function in mice. To investigate the hippocampal proteome modulated by γ-oryzanol, 2D-difference gel electrophoresis (2D-DIGE) was performed. Interestingly, we found that γ-oryzanol modulates quantitative changes of proteins involved in synaptic plasticity and neuronal trafficking, neuroprotection and antioxidant activity, and mitochondria and energy metabolism. These findings suggested γ-oryzanol as a natural compound able to maintain and reinforce brain function. Although more intensive studies are needed, we propose γ-oryzanol as a putative dietary phytochemical for preserving brain reserve, the ability to tolerate age-related changes, thereby preventing clinical symptoms or signs of neurodegenerative diseases.

Redox Homeostasis and Natural Dietary Compounds: Focusing on Antioxidants of Rice (Oryza sativa L.).

Redox homeostasis may be defined as the dynamic equilibrium between electrophiles and nucleophiles to maintain the optimum redox steady state. This mechanism involves complex reactions, including nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, activated by oxidative stress in order to restore the redox balance. The ability to maintain the optimal redox homeostasis is fundamental for preserving physiological functions and preventing phenotypic shift toward pathological conditions. Here, we reviewed mechanisms involved in redox homeostasis and how certain natural compounds regulate the nucleophilic tone. In addition, we focused on the antioxidant properties of rice and particularly on its bioactive compound, γ-oryzanol. It is well known that γ-oryzanol exerts a variety of beneficial effects mediated by its antioxidant properties. Recently, γ-oryzanol was also found as a Nrf2 inducer, resulting in nucleophilic tone regulation and making rice a para-hormetic food.

Nutrition and AGE-ing: Focusing on Alzheimer's Disease.

Recently, the role of food and nutrition in preventing or delaying chronic disability in the elderly population has received great attention. Thanks to their ability to influence biochemical and biological processes, bioactive nutrients are considered modifiable factors capable of preserving a healthy brain status. A diet rich in vitamins and polyphenols and poor in saturated fatty acids has been recommended. In the prospective of a healthy diet, cooking methods should be also considered. In fact, cooking procedures can modify the original dietary content, contributing not only to the loss of healthy nutrients, but also to the formation of toxins, including advanced glycation end products (AGEs). These harmful compounds are adsorbed at intestinal levels and can contribute to the ageing process. The accumulation of AGEs in ageing ("AGE-ing") is further involved in the exacerbation of neurodegenerative and many other chronic diseases. In this review, we discuss food's dual role as both source of bioactive nutrients and reservoir for potential toxic compounds-paying particular attention to the importance of proper nutrition in preventing/delaying Alzheimer's disease. In addition, we focus on the importance of a good education in processing food in order to benefit from the nutritional properties of an optimal diet.