Polyphenols as an Effective Therapeutic Intervention Against Cognitive Decline During Normal and Pathological Brain Aging.
TL;DR: A combined intervention of polyphenols along with regular physical exercise provides cognitive benefits for the aging brain and holds promising venues for preclinical and clinical studies in formulating neuro-nutraceuticals as functional foods for a healthy brain.
Abstract: Research in animals and humans has indicated that polyphenols can delay the age-related decline in learning, memory and neurodegenerative diseases. Among the polyphenols, berry phenolics have extensive beneficial effects because of their antioxidant and anti-inflammatory properties. Long-term consumption of grapes results in accumulation of polyphenols in the brain, which modulates cell-signalling pathways and neutralises the redox imbalance in the aging brain. Here we review the in vivo and in vitro evidence for considering grape-derived polyphenolics, the flavonoids- catechins, epicatechin, anthocyanidin, and quercetin, and non-flavonoids-gallic acid and resveratrol, as effective dietary sources to facilitate cognition in adults and lessen the decline in the old and pathogenic states, Alzheimer's and Parkinson's disease. Furthermore, a combined intervention of polyphenols along with regular physical exercise provides cognitive benefits for the aging brain and holds promising venues for preclinical and clinical studies in formulating neuro-nutraceuticals as functional foods for a healthy brain.
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01 Feb 2014
TL;DR: Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent deacylases that have traditionally been linked with calorie restriction and aging in mammals.
Abstract: Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent deacylases that have traditionally been linked with calorie restriction and aging in mammals. These proteins also play an important role in maintaining neuronal health during aging. During neuronal development, the SIR2 ortholog SIRT1 is structurally important, promoting axonal elongation, neurite outgrowth, and dendritic branching. This sirtuin also plays a role in memory formation by modulating synaptic plasticity. Hypothalamic functions that affect feeding behavior, endocrine function, and circadian rhythmicity are all regulated by SIRT1. Finally, SIRT1 plays protective roles in several neurodegenerative diseases including Alzheimer's, Parkinson's, and motor neuron diseases, which may relate to its functions in metabolism, stress resistance, and genomic stability. Drugs that activate SIRT1 may offer a promising approach to treat these disorders.
238 citations
TL;DR: In this article, a phytosomal formulation (in olive pomace oil) of the natural flavonoid luteolin was used to mitigate brain fog in patients undergoing or following chemotherapy for cancer (chemofog or chemobrain), as well in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or mast cell activation syndrome (MCAS).
Abstract: COVID-19 leads to severe respiratory problems, but also to long-COVID syndrome associated primarily with cognitive dysfunction and fatigue. Long-COVID syndrome symptoms, especially brain fog, are similar to those experienced by patients undertaking or following chemotherapy for cancer (chemofog or chemobrain), as well in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or mast cell activation syndrome (MCAS). The pathogenesis of brain fog in these illnesses is presently unknown but may involve neuroinflammation via mast cells stimulated by pathogenic and stress stimuli to release mediators that activate microglia and lead to inflammation in the hypothalamus. These processes could be mitigated by phytosomal formulation (in olive pomace oil) of the natural flavonoid luteolin.
81 citations
TL;DR: Whether dietary polyphenols and micro-ecology favorably interact to promote multiple physiological functions on human organism is clearly documents.
Abstract: Lifestyle factors, especially diet and nutrition, are currently regarded as essential avenues to decrease modern-day cardiometabolic disorders (CMD), including obesity, metabolic syndrome, type 2 diabetes, and atherosclerosis. Many groups around the world attribute these trends, at least partially, to bioactive plant polyphenols given their anti-oxidant and anti-inflammatory actions. In fact, polyphenols can prevent or reverse the progression of disease processes through many distinct mechanisms. In particular, the crosstalk between polyphenols and gut microbiota, recently unveiled thanks to DNA-based tools and next generation sequencing, unravelled the central regulatory role of dietary polyphenols and their intestinal micro-ecology metabolites on the host energy metabolism and related illnesses. The objectives of this review are to: (1) provide an understanding of classification, structure, and bioavailability of dietary polyphenols; (2) underline their metabolism by gut microbiota; (3) highlight their prebiotic effects on microflora; (4) discuss the multifaceted roles of their metabolites in CMD while shedding light on the mechanisms of action; and (5) underscore their ability to initiate host epigenetic regulation. In sum, the review clearly documents whether dietary polyphenols and micro-ecology favorably interact to promote multiple physiological functions on human organism.
64 citations
TL;DR: In this article , the authors investigated the neurotoxic effects of spike proteins in the brain and proposed a vaccine to mitigate spike protein-related detrimental effects to the brain, possibly via use of small natural molecules, especially the flavonoids luteolin and quercetin.
Abstract: SARS-CoV-2 infects cells via its spike protein binding to its surface receptor on target cells and results in acute symptoms involving especially the lungs known as COVID-19. However, increasing evidence indicates that many patients develop a chronic condition characterized by fatigue and neuropsychiatric symptoms, termed long-COVID. Most of the vaccines produced so far for COVID-19 direct mammalian cells via either mRNA or an adenovirus vector to express the spike protein, or administer recombinant spike protein, which is recognized by the immune system leading to the production of neutralizing antibodies. Recent publications provide new findings that may help decipher the pathogenesis of long-COVID. One paper reported perivascular inflammation in brains of deceased patients with COVID-19, while others showed that the spike protein could damage the endothelium in an animal model, that it could disrupt an in vitro model of the blood-brain barrier (BBB), and that it can cross the BBB resulting in perivascular inflammation. Moreover, the spike protein appears to share antigenic epitopes with human molecular chaperons resulting in autoimmunity and can activate toll-like receptors (TLRs), leading to release of inflammatory cytokines. Moreover, some antibodies produced against the spike protein may not be neutralizing, but may change its conformation rendering it more likely to bind to its receptor. As a result, one wonders whether the spike protein entering the brain or being expressed by brain cells could activate microglia, alone or together with inflammatory cytokines, since protective antibodies could not cross the BBB, leading to neuro-inflammation and contributing to long-COVID. Hence, there is urgent need to better understand the neurotoxic effects of the spike protein and to consider possible interventions to mitigate spike protein-related detrimental effects to the brain, possibly via use of small natural molecules, especially the flavonoids luteolin and quercetin.
53 citations
TL;DR: In this paper, the effects of these phytochemicals (either pure forms or polyphenolic-food) are reviewed and summarized according to affected cellular signaling pathways, and the effectiveness of the anti-aging preventive action of nutritional interventions based on diets rich in poly-phenolic food, such as the diets of the Blue zones, are discussed.
Abstract: Aging and, particularly, the onset of age-related diseases are associated with tissue dysfunction and macromolecular damage, some of which can be attributed to accumulation of oxidative damage. Recently, growing interest has emerged on the beneficial effects of plant-based diets for the prevention of chronic diseases including obesity, diabetes, and cardiovascular disease. Several studies collectively suggests that the intake of polyphenols and their major food sources may exert beneficial effects on improving insulin resistance and related diabetes risk factors, such as inflammation and oxidative stress. They are the most abundant antioxidants in the diet, and their intake has been associated with a reduced aging in humans. Polyphenolic intake has been shown to be effective at ameliorating several age-related phenotypes, including oxidative stress, inflammation, impaired proteostasis, and cellular senescence, both in vitro and in vivo. In this paper, effects of these phytochemicals (either pure forms or polyphenolic-food) are reviewed and summarized according to affected cellular signaling pathways. Finally, the effectiveness of the anti-aging preventive action of nutritional interventions based on diets rich in polyphenolic food, such as the diets of the Blue zones, are discussed.
34 citations
References
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TL;DR: It is suggested that hippocampus undergoes structural and biochemical changes with normal aging and that these changes may represent an important component of age-related deterioration in hippocampus-dependent cognition.
Abstract: Aging is often accompanied by learning and memory problems, many of which resemble deficits associated with hippocampal damage. Studies of aging in nonhuman animals have demonstrated hippocampus-related memory decline, and point to a possible locus for impairments associated with normal and pathological aging in humans. Two well-characterized hippocampus-dependent tasks in nonhuman animal literature are the Morris water task (MWT) and the transverse patterning discrimination task (TPDT). We employed the virtual MWT and the TPDT to assess hippocampus-dependent cognition in humans. Magnetic resonance imaging and proton magnetic resonance spectroscopy were employed to measure hippocampal volume and neurochemistry respectively. Age-related deficits were observed in performance on both hippocampus-dependent tasks. This pattern of impairment was accompanied by decreased hippocampal NAA/Cre ratios and volume, both of which imply neuronal loss and/or decrease in neuronal density. Collectively, our results suggest that hippocampus undergoes structural and biochemical changes with normal aging and that these changes may represent an important component of age-related deterioration in hippocampusdependent cognition.
422 citations
TL;DR: The authors showed that resveratrol, a natural polyphenol associated with anti-inflammatory effects and currently in clinical trials for AD, prevented the activation of macrophages and microglial BV-2 cells treated with TLR4 ligand, lipopolysaccharide (LPS).
Abstract: Activation of microglia, the resident macrophages of the brain, around the amyloid plaques is a key hallmark of Alzheimer's disease (AD). Recent evidence in mouse models indicates that microglia are required for the neurodegenerative process of AD. Amyloid-β (Aβ) peptides, the core components of the amyloid plaques, can trigger microglial activation by interacting with several Toll-like receptors (TLRs), including TLR4. In this study, we show that resveratrol, a natural polyphenol associated with anti-inflammatory effects and currently in clinical trials for AD, prevented the activation of murine RAW 264.7 macrophages and microglial BV-2 cells treated with the TLR4 ligand, lipopolysaccharide (LPS). Resveratrol preferentially inhibited nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation upon LPS stimulation by interfering with IKK and IκB phosphorylation, an effect that potently reduced the transcriptional stimulation of several NF-κB target genes, including tumor necrosis factor-α and interleukin-6. Consequently, downstream phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3 upon LPS stimulation was also inhibited by resveratrol. We found that resveratrol acted upstream in the activation cascade by interfering with TLR4 oligomerization upon receptor stimulation. Resveratrol treatment also prevented the pro-inflammatory effect of fibrillar Aβ on macrophages by potently inhibiting the effect of Aβ on IκB phosphorylation, activation of STAT1 and STAT3, and on tumor necrosis factor-α and interleukin-6 secretion. Importantly, orally administered resveratrol in a mouse model of cerebral amyloid deposition lowered microglial activation associated with cortical amyloid plaque formation. Together this work provides strong evidence that resveratrol has in vitro and in vivo anti-inflammatory effects against Aβ-triggered microglial activation. Further studies in cell culture systems showed that resveratrol acted via a mechanism involving the TLR4/NF-κB/STAT signaling cascade.
355 citations
TL;DR: Initial evidence is provided that supplementary resveratrol improves memory performance in association with improved glucose metabolism and increased hippocampal FC in older adults, offering the basis for novel strategies to maintain brain health during aging.
Abstract: Dietary habits such as caloric restriction or nutrients that mimic these effects may exert beneficial effects on brain aging. The plant-derived polyphenol resveratrol has been shown to increase memory performance in primates; however, interventional studies in older humans are lacking. Here, we tested whether supplementation of resveratrol would enhance memory performance in older adults and addressed potential mechanisms underlying this effect. Twenty-three healthy overweight older individuals that successfully completed 26 weeks of resveratrol intake (200 mg/d) were pairwise matched to 23 participants that received placebo (total n = 46, 18 females, 50-75 years). Before and after the intervention/control period, subjects underwent memory tasks and neuroimaging to assess volume, microstructure, and functional connectivity (FC) of the hippocampus, a key region implicated in memory functions. In addition, anthropometry, glucose and lipid metabolism, inflammation, neurotrophic factors, and vascular parameters were assayed. We observed a significant effect of resveratrol on retention of words over 30 min compared with placebo (p = 0.038). In addition, resveratrol led to significant increases in hippocampal FC, decreases in glycated hemoglobin (HbA1c) and body fat, and increases in leptin compared with placebo (all p < 0.05). Increases in FC between the left posterior hippocampus and the medial prefrontal cortex correlated with increases in retention scores and with decreases in HbA1c (all p < 0.05). This study provides initial evidence that supplementary resveratrol improves memory performance in association with improved glucose metabolism and increased hippocampal FC in older adults. Our findings offer the basis for novel strategies to maintain brain health during aging.
354 citations
TL;DR: It is found that a naturally derived grape seed polyphenolic extract can significantly inhibit amyloid β-protein aggregation into high-molecular-weight oligomers in vitro and suggests that grape seed-derived polyphenolics may be useful agents to prevent or treat AD.
Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive impairments in memory and cognition. Extracellular accumulation of soluble high-molecular-weight (HMW) Abeta oligomers has been proposed to be largely responsible for AD dementia and memory deficits in the Tg2576 mice, a model of AD. In this study, we found that a naturally derived grape seed polyphenolic extract can significantly inhibit amyloid beta-protein aggregation into high-molecular-weight oligomers in vitro. When orally administered to Tg2576 mice, this polyphenolic preparation significantly attenuates AD-type cognitive deterioration coincidentally with reduced HMW soluble oligomeric Abeta in the brain. Our study suggests that grape seed-derived polyphenolics may be useful agents to prevent or treat AD.
347 citations
TL;DR: This review highlights the literature surrounding this topic on the prominently studied and documented polyphenols as pertaining to cardiovascular health and aging.
Abstract: Numerous studies have demonstrated the importance of naturally occurring dietary polyphenols in promoting cardiovascular health and emphasized the significant role these compounds play in limiting the effects of cellular aging. Polyphenols such as resveratrol, epigallocatechin gallate (EGCG), and curcumin have been acknowledged for having beneficial effects on cardiovascular health, while some have also been shown to be protective in aging. This review highlights the literature surrounding this topic on the prominently studied and documented polyphenols as pertaining to cardiovascular health and aging.
346 citations