Resveratrol Supplementation Confers Neuroprotection in Cortical Brain Tissue of Nonhuman Primates Fed a High-Fat/Sucrose Diet

Previous studies have shown positive effects of long-term resveratrol (RSV) supplementation in preventing pancreatic beta cell dysfunction, arterial stiffening and metabolic decline induced by high-fat/high-sugar (HFS) diet in nonhuman primates. Here, the analysis was extended to examine whether RSV may reduce dietary stress toxicity in the cerebral cortex of the same cohort of treated animals. Middle-aged male rhesus monkeys were fed for 2 years with HFS alone or combined with RSV, after which whole-genome microarray analysis of cerebral cortex tissue was carried out along with ELISA, immunofluorescence, and biochemical analyses to examine markers of vascular health and inflammation in the cerebral cortices. A number of genes and pathways that were differentially modulated in these dietary interventions indicated an exacerbation of neuroinflammation (e.g., oxidative stress markers, apoptosis, NF-κB activation) in HFS-fed animals and protection by RSV treatment. The decreased expression of mitochondrial aldehyde dehydrogenase 2, dysregulation in endothelial nitric oxide synthase, and reduced capillary density induced by HFS stress were rescued by RSV supplementation. Our results suggest that long-term RSV treatment confers neuroprotection against cerebral vascular dysfunction during nutrient stress

Blood Leukocyte Dna Methylation Predicts Risk of Future Myocardial infarction and Coronary Heart Disease

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD

DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases.

BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10-7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10-4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10-5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10-3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10-5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation

The aging brain and nutrition

Old age is the greatest risk factor for most neurodegenerative diseases. During recent decades, there have been major advances in understanding the biology of aging, and the development of nutritional interventions that delay aging including calorie restriction (CR) and intermittent fasting (IF), and chemicals that influence pathways linking nutrition and aging processes. CR influences brain aging in many animal models and recent findings suggest that dietary interventions can influence brain health and dementia in older humans. The role of individual macronutrients in brain aging also has been studied, with conflicting results about the effects of dietary protein, branch-chained amino acids, and carbohydrates. Chapter 1 is a general introduction which reviews these concepts and highlights the need for future research in macronutrient composition intake and cognitive health. Additionally, evaluation of behaviour and cognition in rodent models underpins mechanistic and interventional studies of brain aging and neurodegenerative diseases, especially dementia. Commonly used tests include the Morris water maze, Barnes maze, Novel object recognition, fear conditioning, radial arm water maze and Y maze. These tests each reflect some aspects of human memory including episodic memory, recognition memory, semantic memory, spatial memory and emotional memory. Although most interventional studies in rodent models of dementia have focused on pharmacological agents, there are an increasing number of studies that have evaluated nutritional interventions including caloric restriction, intermittent fasting and manipulation of macronutrients. Chapter 2 outlines the most commonly used behavioural tests used in the context of nutritional studies and their main mechanistic underpinnings. Calorie restriction (CR) is one of the most robust interventions to improve brain health, increase memory, and delay the onset of neurodegenerative disease in mice. It was recently reported that low-protein, high carbohydrate (LPHC) diets provided ad libitum (i.e. without CR) extended life and improved cardiometabolic health in mice, but it is not known whether LPHC diets would also be beneficial for brain health. Therefore, one of the primary purposes of the data and research in Chapter 3 is to explore the roles of low-protein, high-carbohydrate diets on brain aging and neurobiology in male and female mice and compare those diets to traditional 20% CR. Here, male and female mice subjected to 20% CR or provided with ad libitum access from weaning to one of three LPHC diets (%P:%C 5:75, 10:70, 15:65), or to a standard rearing diet (19:61). As expected, LPHC (notably 5% protein) and CR diets were both associated with improvements in glucose and insulin metabolism. Overall patterns of total gene expression in hippocampus differed between LPHC and CR diets, although there were similarities with respect to specific genes known to be associated with longevity, CR, cytokines and dendrite morphogenesis. There were also similarities between LPHC and CR in protein expression and activation of SIRT1, MTOR and PGC1α, however the effects varied by sex. CR and LPHC (5% protein) diets were associated with increased dendritic spine densities in dentate gyrus neurons, and although the results were modest and primarily seen in middle age, both diets led to improvements in performance in the Barnes Maze and Novel Object Recognition tests. The diets differed in their effects on hippocampus biology and varied by sex. However, several of the main findings provide the first evidence that ad-libitum LPHC diets confer similar benefits to traditional 20% CR by improving key neurobiological and histological markers of hippocampus health, while simultaneously improving memory on two cognitive-behavioural tasks. Furthermore, there is a link between increased branch-chain amino acid (BCAA) consumption and adverse health outcomes. However, the relationship between BCAA consumption and brain health is not yet known. Therefore, the data in Chapter 4 continues with the topic of nutrition, brain health and underlying cognitive processes, but focuses on BCAA consumption and mouse brain health. There is evidence to suggest that circulating branch-chain amino acids (BCAA) are partly responsible for adverse cardiometabolic effects in mice, partly by increasing hepatic mechanistic target of rapamycin (MTOR) activation. While it is generally accepted that increased dietary BCAA consumption results in adverse metabolic health outcomes in mice, there is a lack of knowledge of whether the result would be similar for brain health. To this end, this study investigated the effects of 4 isocaloric ad-libitum diets ranging in BCAA content (20%, 50%, 100%, or 200%) on markers of hippocampus health and cognitive function in mice. Biochemical analyses including nutrient sensing pathway protein expression, markers of hippocampus function and inflammation, total hippocampus RNA analysis, and cognitive behavioural memory tasks were performed. The results of the current study reveal that dietary BCAA consumption influences hippocampus biology and memory in mice. Elevated dietary BCAA intake may be harmful to hippocampus health; consequently, reducing BCAA consumption may mitigate some of those harmful effects. Chapter 5 explores the role of Sirtuin 1 (SIRT1) in the formation of fear conditioning memory in the hippocampus. SIRT1 is a NAD+-dependent enzyme that has important roles in many biological processes involved in aging, including cell growth and repair, inflammation, and energy regulation. SIRT1 is also implicated in brain health and may be important in the preservation of memory processes that deteriorate during aging. Here, the role was investigated of brain-associated SIRT1 expression in the acquisition of fear memory and anxiety related behaviour in mice at 45 and 65 weeks of age. Mice with brain-specific knock-out or overexpression of Sirt1 were assessed on a fear conditioning paradigm and elevated plus maze test to determine the role of SIRT1 in fear memory acquisition and anxiety related behaviour. While there were no differences among groups in anxiety related behaviour, mice lacking brain SIRT1 could not learn the fear conditioning paradigm during training, context, or cue phases. The results of the study indicate that SIRT1 expression in the brain is critical for the formation of fear memory in male mice but not anxiety related behaviour. Chapter 6 is a conclusion and general discussion. Given the growing recognition of the role of aging biology in dementia, these analyses and studies may provide a new approach for dietary interventions that optimize aging brain health and prevent dementia in older people. Dietary interventions have been shown to influence various behavioural tests and underlying neurobiology in rodents indicating that nutrition can influence brain aging and possibly prevent or reduce neurodegeneration in humans. Given the growing recognition of the role of aging biology in dementia, these analyses and studies may provide a new approach for dietary interventions that optimize aging brain health and prevent dementia in older people. Dietary interventions have been shown to influence various behavioural tests and underlying neurobiology in rodents indicating that nutrition can influence brain aging and possibly prevent or reduce neurodegeneration in humans

Resveratrol supplementation: Where are we now and where should we go?

This work has been supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII.Pre-clinical findings have provided mounting evidence that resveratrol, a dietary polyphenol, may confer health benefits and protect against a variety of medical conditions and age-related complications. However, there is no consistent evidence of an increased protection against metabolic disorders and other ailments when comparing studies in laboratory animals and humans. A number of extraneous and potential confounding variables can affect the outcome of clinical research. To date, most of the studies that have investigated the effect of resveratrol administration on patient outcomes have been limited by their sample sizes. In this review, we will survey the latest advances regarding the timing, dosage, formulation, bioavailability, toxicity of resveratrol, and resveratrol–drug interactions in human studies. Moreover, the present report focuses on the actions of resveratrol treatment in combating diseases, such as cancer, diabetes, neurodegeneration, cardiovascular disease, and other age-related ailments.Depto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasTRUEpu

Sex Specific Differences in Response to Calorie Restriction in Skeletal Muscle of Young Rats

Calorie restriction (CR), defined as a reduction of the total calorie intake of 30% to 60% without malnutrition, is the only nutritional strategy that has been shown to extend lifespan, prevent or delay the onset of age-associated diseases, and delay the functional decline in a wide range of species. However, little is known about the effects of CR when started early in life. We sought to analyze the effects of CR in the skeletal muscle of young Wistar rats. For this, 3-month-old male and female rats were subjected to 40% CR or fed ad libitum for 3 months. Gastrocnemius muscles were used to extract RNA and total protein. Western blot and RT-qPCR were performed to evaluate the expression of key markers/pathways modulated by CR and affected by aging. CR decreased body and skeletal muscle weight in both sexes. No differences were found in most senescence, antioxidant, and nutrient sensing pathways analyzed. However, we found a sexual dimorphism in markers of oxidative stress, inflammation, apoptosis, and mitochondrial function in response to CR. Our data show that young female rats treated with CR exhibit similar expression patterns of key genes/pathways associated with healthy aging when compared to old animals treated with CR, while in male rats these effects are reduced. Additional studies are needed to understand how early or later life CR exerts positive effects on healthspan and lifespan

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

Abstract Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer’s disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. In this study, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-κB and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old (aged 19 months) wildtype mice, and in rTg4510 tau pathology mice (aged 2 months). We found that 4 weeks of NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and rTg4510 mice. These effects of NF-κB/NLRP3-targeting Nanoligomers were also associated with reduced glial cell activation and pathology, favorable changes in transcriptome signatures of glia-associated inflammation (reduced) and neuronal health (increased), and positive systemic effects. Collectively, our results provide a basis for future translational studies targeting both NF-κB and NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegeneration

Comparing the Effects of Low-Protein and High-Carbohydrate Diets and Caloric Restriction on Brain Aging in Mice

Summary: Calorie restriction (CR) increases lifespan and improves brain health in mice. Ad libitum low-protein, high-carbohydrate (LPHC) diets also extend lifespan, but it is not known whether they are beneficial for brain health. We compared hippocampus biology and memory in mice subjected to 20% CR or provided ad libitum access to one of three LPHC diets or to a control diet. Patterns of RNA expression in the hippocampus of 15-month-old mice were similar between mice fed CR and LPHC diets when we looked at genes associated with longevity, cytokines, and dendrite morphogenesis. Nutrient-sensing proteins, including SIRT1, mTOR, and PGC1α, were also influenced by diet; however, the effects varied by sex. CR and LPHC diets were associated with increased dendritic spines in dentate gyrus neurons. Mice fed CR and LPHC diets had modest improvements in the Barnes maze and novel object recognition. LPHC diets recapitulate some of the benefits of CR on brain aging. : Calorie restriction (CR) and ad libitum low-protein, high-carbohydrate (LPHC) diets improve cardiometabolic health in mice. Wahl et al. show that, like healthspan, CR and LPHC diets positively affect hippocampus biology in mice by influencing hippocampus gene expression, nutrient-sensing pathways, dendritic morphology, and cognition. Keywords: calorie restriction, cognitive function, protein restriction, brain aging, hippocampus, cardiometabolic healt