The effect of resveratrol on lifespan depends on both gender and dietary nutrient composition in Drosophila melanogaster.

Resveratrol, a polyphenolic compound, has been shown to extend lifespan in different organisms. Emerging evidence suggests that the prolongevity effect of resveratrol depends on dietary composition. However, the mechanisms underlying the interaction of resveratrol and dietary nutrients in modulating lifespan remain elusive. Here, we investigated the effect of resveratrol on lifespan of Drosophila melanogaster fed diets differing in the concentrations of sugar, yeast extract, and palmitic acid representing carbohydrate, protein, and fat, respectively. Resveratrol at up to 200 µM in diets did not affect lifespan of wild-type female flies fed a standard, restricted or high sugar-low protein diet, but extended lifespan of females fed a low sugar-high protein diet. Resveratrol at 400 µM extended lifespan of females fed a high-fat diet. Lifespan extension by resveratrol was associated with downregulation of genes in aging-related pathways, including antioxidant peroxiredoxins, insulin-like peptides involved in insulin-like signaling and several downstream genes in Jun-kinase signaling involved in oxidative stress response. Furthermore, resveratrol increased lifespan of superoxide dismutase 1 (sod1) knockdown mutant females fed a standard or high-fat diet. No lifespan extension by resveratrol was observed in wild-type and sod1 knockdown males under the culture conditions in this study. Our results suggest that the gender-specific prolongevity effect of resveratrol is influenced by dietary composition and resveratrol promotes the survival of flies by modulating genetic pathways that can reduce cellular damage. This study reveals the context-dependent effect of resveratrol on lifespan and suggests the importance of dietary nutrients in implementation of effective aging interventions using dietary supplements.

Preserved learning and memory following 5-fluorouracil and cyclophosphamide treatment in rats.

Some patients experience enduring cognitive impairment after cancer treatment, a condition termed "chemofog". Animal models allow assessment of chemotherapy effects on learning and memory per se, independent of changes due to cancer itself or associated health consequences such as depression. The present study examined the long-term learning and memory effects of a chemotherapy cocktail used widely in the treatment of breast cancer, consisting of 5-fluorouracil (5FU) and cyclophosphamide (CYP). Eighty 5-month old male F344 rats received contextual and cued fear conditioning before treatment with saline, or a low or high dose drug cocktail (50mg/kg CYP and 75 mg/kg 5FU, or 75 mg/kg CYP and 120 mg/kg 5FU, i.p., respectively) every 30 days for 2 months. After a 2-month, no-drug recovery, both long-term retention and new task acquisition in the water maze and 14-unit T-maze were assessed. Neither dose of the CYP/5FU cocktail impaired retrograde fear memory despite marked toxicity documented by enduring weight loss and 50% mortality at the higher dose. Acquisition in the water maze and Stone maze was also normal relative to controls in rats treated with CYP/5FU. The results contribute to a growing literature suggesting that learning and memory mediated by the hippocampus can be relatively resistant to chemotherapy. Future investigation may need to focus on assessments of processing speed, executive function and attention, and the possible interactive contribution of cancer itself and aging to the post-treatment development of cognitive impairment.

Blueberry polyphenols attenuate kainic acid-induced decrements in cognition and alter inflammatory gene expression in rat hippocampus.

Cognitive impairment in age-related neurodegenerative diseases such as Alzheimer's disease may be partly due to long-term exposure and increased susceptibility to inflammatory insults. In the current study, we investigated whether polyphenols in blueberries can reduce the deleterious effects of inflammation induced by central administration of kainic acid by altering the expression of genes associated with inflammation. To this end, 4-month-old male Fischer-344 (F344) rats were fed a control, 0.015% piroxicam (an NSAID) or 2% blueberry diet for 8 weeks before either Ringer's buffer or kainic acid was bilaterally micro-infused into the hippocampus. Two weeks later, following behavioral evaluation, the rats were killed and total RNA from the hippocampus was extracted and used in real-time quantitative RT-PCR (qRT-PCR) to analyze the expression of inflammation-related genes. Kainic acid had deleterious effects on cognitive behavior as kainic acid-injected rats on the control diet exhibited increased latencies to find a hidden platform in the Morris water maze compared to Ringer's buffer-injected rats and utilized non-spatial strategies during probe trials. The blueberry diet, and to a lesser degree the piroxicam diet, was able to improve cognitive performance. Immunohistochemical analyses of OX-6 expression revealed that kainic acid produced an inflammatory response by increasing the OX-6 positive areas in the hippocampus of kainic acid-injected rats. Kainic acid up-regulated the expression of the inflammatory cytokines IL-1beta and TNF-alpha, the neurotrophic factor IGF-1, and the transcription factor NF-kappaB. Blueberry and piroxicam supplementations were found to attenuate the kainic acid-induced increase in the expression of IL-1beta, TNF-alpha, and NF-kappaB, while only blueberry was able to augment the increased IGF-1 expression. These results indicate that blueberry polyphenols attenuate learning impairments following neurotoxic insult and exert anti-inflammatory actions, perhaps via alteration of gene expression.

A blueberry-enriched diet provides cellular protection against oxidative stress and reduces a kainate-induced learning impairment in rats.

Young male Fischer-344 rats were fed a diet containing 2% blueberry (BB) extract or control diet for at least 8 weeks and then received bilateral hippocampal injections of kainic acid (KA 200 ng/0.5 microl) or phosphate buffered saline (PBS). One week later rats were trained in one-way active footshock avoidance in a straight runway followed the next day by training in a footshock motivated 14-unit T-maze with documented sensitivity to hippocampal glutamatergic manipulations. Based on analyses of several performance variables, KA-treated rats exhibited clearly impaired learning performance; however, the BB diet significantly reduced this impairment. Supporting the behavioral findings, stereological assessment of CA1 pyramidal neurons documented greater neuronal loss in KA-treated controls compared to KA-treated rats on the BB diet. In an in vitro experiment, FaO cells grown in medium supplemented with serum from BB-fed rats had enhanced viability after exposure to hydrogen peroxide. These findings suggest that BB supplementation may protect against neurodegeneration and cognitive impairment mediated by excitotoxicity and oxidative stress.