There is substantial interest in the role of plant secondary metabolites as protective dietary agents. In particular, the involvement of flavonoids and related compounds has become a major topic in human nutrition research. Evidence from epidemiological and human intervention studies is emerging regarding the protective effects of various (poly)phenol-rich foods against several chronic diseases, including neurodegeneration, cancer and cardiovascular diseases. In recent years, the use of HPLC-MS for the analysis of flavonoids and related compounds in foods and biological samples has significantly enhanced our understanding of (poly)phenol bioavailability. These advancements have also led to improvements in the available food composition and metabolomic databases, and consequently in the development of biomarkers of (poly)phenol intake to use in epidemiological studies. Efforts to create adequate standardised materials and well-matched controls to use in randomised controlled trials have also improved the quality of the available data. In vitro investigations using physiologically achievable concentrations of (poly)phenol metabolites and catabolites with appropriate model test systems have provided new and interesting insights on potential mechanisms of actions. This article will summarise recent findings on the bioavailability and biological activity of (poly)phenols, focusing on the epidemiological and clinical evidence of beneficial effects of flavonoids and related compounds on urinary tract infections, cognitive function and age-related cognitive decline, cancer and cardiovascular disease.

It is widely accepted that caloric restriction (CR) without malnutrition delays the onset of aging and extends lifespan in diverse animal models including yeast, worms, flies and laboratory rodents. The mechanism underlying this phenomenon is still unknown. We have hypothesized that a reprogramming of energy metabolism is a key event in the mechanism of CR (Anderson and Weindruch, Interdiscip. Topics in Gerontol. 2007). Data will be presented from studies of mice on CR, which lend support to this hypothesis. Effects of long-term CR (but not short-term CR) on gene expression in white adipose tissue (WAT) are overt. In mice and monkeys, a chronic 30% reduction in energy intake yields approximately a 70% decrease in adiposity. In mouse epididymal WAT, long-term CR causes overt shifts in the gene expression profile: CR increased the expression of genes involved in energy metabolism (Higami et al. FASEB J, 2004) while it down regulates the expression of more than 50 pro-inflammatory genes (Higami et al. J. Nutr., 2006). Whether aging retardation occurs in primates on CR is unknown. We have been investigating this issue in rhesus monkeys subjected to CR since 1989 and will discuss the current status of this project. A new finding from this project is that CR reduces the rate of age-associated muscle loss (sarcopenia) in monkeys (Colman et al., J. Gerontol., 2008).

The 4-(dimethylamino)cinnamaldehyde (DMAC) assay is currently used to quantify proanthocyanidin (PAC) content in cranberry products. However, this method suffers from issues of accuracy and precision in the analysis and comparison of PAC levels across a broad range of cranberry products. Current use of procyanidin A2 as a standard leads to an underestimation of PACs content in certain cranberry products, especially those containing higher molecular weight PACs. To begin to address the issue of accuracy, a method for the production of a cranberry PAC standard, derived from an extraction of cranberry (c-PAC) press cake, was developed and evaluated. Use of the c-PAC standard to quantify PAC content in cranberry samples resulted in values that were 2.2 times higher than those determined by procyanidin A2. Increased accuracy is critical for estimating PAC content in relationship to research on authenticity, efficacy, and bioactivity, especially in designing clinical trials for determination of putative health benefits.

Aging is often perceived as a degenerative process caused by random accrual of cellular damage over time. In spite of this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles from almost any tissue of the body. Since such pan-tissue epigenetic clocks have been successfully developed for several different species, it is difficult to ignore the likelihood that a defined and shared mechanism instead, underlies the aging process. To address this, we generated 10,000 methylation arrays, each profiling up to 37,000 cytosines in highly-conserved stretches of DNA, from over 59 tissue-types derived from 128 mammalian species. From these, we identified and characterized specific cytosines, whose methylation levels change with age across mammalian species. Genes associated with these cytosines are greatly enriched in mammalian developmental processes and implicated in age-associated diseases. From the methylation profiles of these age-related cytosines, we successfully constructed three highly accurate universal mammalian clocks for eutherians, and one universal clock for marsupials. The universal clocks for eutherians are similarly accurate for estimating ages (r>0.96) of any mammalian species and tissue with a single mathematical formula. Collectively, these new observations support the notion that aging is indeed evolutionarily conserved and coupled to developmental processes across all mammalian species - a notion that was long-debated without the benefit of this new and compelling evidence.

Emerging pathogen Candida auris causes nosocomial outbreaks of lifethreatening invasive candidiasis. It is unclear how this species colonizes skin and spreads in health care facilities. Here, we analyzed C. auris growth in synthetic sweat medium designed to mimic axillary skin conditions. We show that C. auris demonstrates a high capacity for biofilm formation in this milieu, well beyond that observed for the most commonly isolated Candida sp., Candida albicans. The C. auris biofilms persist in environmental conditions expected in the hospital setting. To model C. auris skin colonization, we designed an ex vivo porcine skin model. We show that C. auris proliferates on porcine skin in multilayer biofilms. This capacity to thrive in skin niche conditions helps explain the propensity of C. auris to colonize skin, persist on medical devices, and rapidly spread in hospitals. These studies provide clinically relevant tools to further characterize this important growth modality. IMPORTANCE The emerging fungal pathogen Candida auris causes invasive infections and is spreading in hospitals worldwide. Why this species exhibits the capacity to transfer efficiently among patients is unknown. Our findings reveal that C. auris forms high-burden biofilms in conditions mimicking sweat on the skin surface. These adherent biofilm communities persist in environmental conditions expected in the hospital setting. Using a pig skin model, we show that C. auris also forms high-burden biofilm structures on the skin surface. Identification of this mode of growth sheds light on how this recently described pathogen persists in hospital settings and spreads among patients.

Gut colonization by extra-intestinal pathogenic Escherichia coli (ExPEC) increases the risk of subsequent infections, including urinary tract infection and septicemia. Previous work suggests that cranberry proanthocyanidins (PAC) interact with bacterial surface factors, altering bacterial interaction with host cells. Methods were developed to determine if ratios of "A-type" to "B-type" interflavan bonds in PAC affect ExPEC agglutination and invasion of enterocytes. In cranberries, 94.5% of PAC contain one or more "A-type" bonds, whereas in apples, 88.3% of PAC contain exclusively "B-type" bonds. Results show that cranberry "A-type" PAC have greater bioactivity than apple "B-type" PAC for increasing ExPEC agglutination and decreasing ExPEC epithelial cell invasion.

The long-term health benefits of caloric restriction (CR) are well known but the associated molecular mechanisms are poorly understood despite increasing knowledge of transcriptional and related metabolic changes. We report new metabolic insights into long-term CR in nonhuman primates revealed by the holistic inspection of plasma 1H-NMR spectroscopic metabolic and lipoprotein profiles. The results revealed attenuation of aging-dependant alterations of lipoprotein and energy metabolism by CR, noted by relative increase in HDL and reduction in VLDL levels. Metabonomic analysis also revealed animals exhibiting distinct metabolic trajectories from aging that correlated with higher insulin sensitivity. The plasma profiles of insulin-sensitive animals were marked by higher levels of gluconate and acetate suggesting a CR-modulated increase in metabolic flux through the pentose phosphate pathway. The metabonomic findings, particularly those that parallel improved insulin sensitivity, are consistent with diminished adiposity in CR monkeys despite aging. The metabolic profile and the associated pathways are compatible with our previous findings that CR-induced gene transcriptional changes in tissue suggest the critical regulation of peroxisome proliferator-activated receptors as a key mechanism. The metabolic phenotyping provided in this study can be used to define a reference molecular profile of CR-associated health benefits and longevity in symbiotic superorganisms and man.

PN without enteral nutrition impairs innate mucosal immune function. Tissue expression of Paneth cell antimicrobial proteins decreases associated with compositional shifts to the microbiome, decreased bactericidal activity of mucosal secretions and greater susceptibility of to enteroinvasion by E coli. These changes may explain in-part the increased risk of infection in parenterally fed patients.