Accumulation of advanced glycation end products (AGEs) on nucleotides, lipids, and peptides/proteins are an inevitable component of the aging process in all eukaryotic organisms, including humans. To date, a substantial body of evidence shows that AGEs and their functionally compromised adducts are linked to and perhaps responsible for changes seen during aging and for the development of many age-related morbidities. However, much remains to be learned about the biology of AGE formation, causal nature of these associations, and whether new interventions might be developed that will prevent or reduce the negative impact of AGEs-related damage. To facilitate achieving these latter ends, we show how invertebrate models, notably Drosophila melanogaster and Caenorhabditis elegans, can be used to explore AGE-related pathways in depth and to identify and assess drugs that will mitigate against the detrimental effects of AGE-adduct development.

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High density lipoproteins (HDL) structure and function studies are needed to better understand the heterogeneous nature of the HDL particle, and its interaction with associated proteins such as apolipoprotein A-1 (ApoA-1), paraoxonase 1 (PON1) and the environment. Our study assesses the effects of acute inflammation on PON1 and HDL subclasses in post-surgical colorectal cancer patients. PON1 was measured kinetically through its arylesterase and lactonase activity and HDL sub-classes were measured using Quantimetrix Lipoprint® System. White blood cells (WBC) counts, c-reactive protein (CRP) and serum amyloid A (SAA) levels were also analyzed using standard techniques. Our findings show that baseline PON1 activity is lower in colorectal cancer patients and significant reductions are observed in the acute inflammatory state post-surgery. PON1 changes are also inversely related to inflammatory markers such as SAA and CRP. In addition, our preliminary findings show that small and intermediate HDL decreases post-op Day 1. In conclusion, our study demonstrates the effects of chronic and acute inflammation on PON1. Specifically, PON1 arylesterase and lactonase activity is lower in states of chronic inflammation and further decreased in the acute inflammatory state. Additionally, in our limited sample size, while changes in PON1 and HDL subclasses may be variable in the acute inflammatory period, small HDL decreased with a loss of PON1 activity in the subacute phase.

Objective: To investigate the link between dietary sugar consumption and two separate pathogenetic mechanisms associated with metabolic syndrome: de novo lipogenesis (DNL) and non-enzymatic glycation. Design and participants: We assessed changes in serum D-lactate (the detoxification endproduct of methylglyoxal) concentration in response to nine days of isocaloric fructose restriction in 20 children with obesity and metabolic syndrome, and examined correlations with changes in DNL, liver fat, insulin sensitivity and other metrics of hepatic metabolism. Interventions: Nine days of dietary sugar restriction, with substitution of equal amounts of refined starch. Main Outcome Measures: On day 0 and 10, children had lab evaluation of D-lactate levels and other analytes, and underwent oral glucose tolerance testing, magnetic resonance spectroscopy to quantify fat depots, and 13 C-acetate incorporation into triglyceride to measure DNL. Results: D-lactate was associated with baseline liver fat fraction (p<0.001) and visceral adipose tissue (p<0.001), but not with subcutaneous adipose tissue. At baseline, D-lactate was positively correlated with DNL-AUC (p=0.003), liver fat fraction (p=0.02), triglyceride (p=0.004) and triglyceride to HDL ratio (p=0.002). After nine days of isocaloric fructose restriction, serum Dlactate levels reduced by 50% (p<0.0001), and changes in D-lactate correlated with both changes in DNL-AUC, and measures of insulin sensitivity. Conclusion: Baseline correlation of D-lactate with DNL and measures of insulin sensitivity; and reduction in D-lactate following nine days of isocaloric fructose restriction suggest that DNL and non-enzymatic glycation are functionally linked via intermediary glycolysis in the pathogenesis