Aging, in the absence of disease processes, can be characterized as a gradual decline of various physiological functions that are associated with both cellular and organ damage likely related to age-related modifications of macromolecules, including protein, lipid and nucleic acid. Accurate and sensitive measurements of protein modifications, such as glycosylation and phosphorylation, are critical for us to understand the aging processes. In collaboration with Drs. Rong-fong Shen, Bronwen Martin and Stuart Maudsley at the NIA, we have previously optimized the pulsed Q collision-induced dissociation (PQD) method for identification of peptides with a labile functional group, such as phosphopeptides, in proteomic studies. That study was published in the Journal of the American Society for Mass Spectrometry (2011). We have further improved the PQD method and developed a target-based approach that allows repetitive data acquisitions across chromatographic peaks of peptide signals. This method generates multiple-point data, which significantly improve the reliability of protein quantification by isobaric tags for relative and absolute quantitation (iTRAQ) in proteomic studies. This work has been published in the Journal of Proteomics (2012). The improved proteomic approaches we have developed will be instrumental in the development of our ongoing studies of age-related molecular changes, especially those in protein expression and modifications, and their role in aging. Oxidative damage induced by reactive oxygen species (ROS) is considered to be one of the most critical causal factors in aging and aging-related diseases. The composition of dietary macronutrients plays a critical role in maintaining redox status and modulating lifespan in many organisms. To understand how ROS modulate dietary effects on lifespan, we initiated a study to determine the role of superoxide dismutase 1 (SOD1) in modulating lifespan response to diet in Drosophila. SOD1 is a major cytosolic enzyme responsible for scavenging superoxides. We found that both high sugar-low protein (HS-LP) diet and low sugar-low protein diet increased lifespan but not resistance to acute oxidative stress in wild-type flies when compared to a standard base diet. Paradoxically, we have found that a low sugar-high protein diet had an opposite effect on lifespan and stress resistance, reducing oxidative stress while also shortening lifespan. The HS-LP diet but not the low sugar-low protein diet increased oxidative damage. Consistent with this observation, sod1 knockdown blunted lifespan extension by the HS-LP diet but not the low-calorie diet. Our findings suggest that the effect of SOD1 in modulating lifespan depends on diet composition and our results also caution the use of antioxidants in aging interventions. This work has been published in Aging Cell (2012). Ongoing studies are being directed to further determine the molecular mechanisms underlying the interaction between SOD1 and macronutrients in aging, which will provide insight into the effects of nutrient imbalance in aging. Nutraceuticals made from fruits and vegetables have been shown to provide numerous health benefits, such as anti-cancer, anti-inflammation, anti-infection and even anti-aging effects, probably due to their high antioxidant capacities and various bioactivities. We previously reported that long-term cranberry consumption improves health of pancreatic cells in aging rats, which was published in the Journal of Gerontology Series A: Biological Sciences (2011). In collaboration with Dr. Yuqing Dong at Clemson University, we employed C. elegans as the model organism to further understand the molecular mechanisms underlying the beneficial effects of cranberry consumption. Specifically, we examined the effect of a cranberry extract on lifespan and healthspan in C. elegans. We found that cranberry supplementation increased lifespan in C. elegans. This lifespan extension was associated with increased tolerance to heat shock, but not to oxidative stress or ultraviolet irradiation. Our study further demonstrated that lifespan extension induced by cranberry requires components of the insulin/IGF signaling pathway, such as AGE-1 and DAF-16, and the osmotic stress response pathways, OSR-1 and UNC-43. These findings suggest that cranberry supplementation confers increased longevity and stress resistance through insulin-like and osmotic stress response pathways. This study was published in AGE (2012) and appears to be the first study revealing a prolongevity effect of cranberry in an organism. In the future, we will further investigate the effect of cranberry consumption in alleviating age-related decline in physiological functions, such as immune function, and the underlying mechanisms that may be involved. This line of research should provide important scientific guidance for human consumption of fruits and herbs in the diet to improve both healthspan and lifespan. Dietary restriction (DR) has been shown to reliably extend lifespan in numerous model organisms. Lifespan extension induced by DR is associated with increased resistance to stress and has been reported to reduce the risk for development of cancer, diabetes, and age-related diseases, such as Parkinson's and Alzheimer's disease. In collaboration with Donald Ingram at Louisiana State University, Mark Mattson and Rafael de Cabo at the NIA and Kwok-Fai So at the University of Hong Kong, we have demonstrated that the neuroprotective effect induced by DR was enhanced by reducing the level of corticosterone, a stress-induced hormone, by adrenalectomizing the DR rats. These findings were published in Neurobiology of Aging (2012) and should provide valuable guidance to improve the efficacy of aging interventions for promoting healthspan and lifespan in humans. In summary, we have developed analytic tools for accurate and reliable measurement of protein and protein modifications directly applicable to the investigation of molecular changes in aging. We have determined the role of a key ROS scavenging enzyme, SOD1, in modulating lifespan response to dietary macronutrients. In addition, we have demonstrated the effects of cranberry in promoting health in rats and extending lifespan in C. elegans. These studies are valuable for advancing the objectives of the Laboratory of Experimental Gerontology and the mission of the NIA to understand the basic biology of aging and develop efficient aging interventions for humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000365-08
Application #
8552384
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2012
Total Cost
$467,088
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Sun, Xiaoping; Wheeler, Charles T; Yolitz, Jason et al. (2014) A mitochondrial ATP synthase subunit interacts with TOR signaling to modulate protein homeostasis and lifespan in Drosophila. Cell Rep 8:1781-92
Sun, Yaning; Yolitz, Jason; Wang, Cecilia et al. (2013) Aging studies in Drosophila melanogaster. Methods Mol Biol 1048:77-93
De, Supriyo; Zhang, Yongqing; Wolkow, Catherine A et al. (2013) Genome-wide modeling of complex phenotypes in Caenorhabditis elegans and Drosophila melanogaster. BMC Genomics 14:580
Wilson, Mark; Mattson, Mark P; Zou, Sige (2013) Invertebrates as workhorses for aging and intervention studies. Ageing Res Rev 12:402-3
Yan, Bin; Li, Huai; Yang, Xinping et al. (2013) Unraveling regulatory programs for NF-kappaB, p53 and microRNAs in head and neck squamous cell carcinoma. PLoS One 8:e73656
Xu, Dongyi; Shen, Weiping; Guo, Rong et al. (2013) Top3β is an RNA topoisomerase that works with fragile X syndrome protein to promote synapse formation. Nat Neurosci 16:1238-47
Qiu, Guang; Spangler, Edward L; Wan, Ruiqian et al. (2012) Neuroprotection provided by dietary restriction in rats is further enhanced by reducing glucocortocoids. Neurobiol Aging 33:2398-410
Wu, Wells W; Wang, Guanghui; Insel, Paul A et al. (2012) Discovery- and target-based protein quantification using iTRAQ and pulsed Q collision induced dissociation (PQD). J Proteomics 75:2480-7
Guha, Sujay; Cao, Min; Kane, Ryan M et al. (2012) The longevity effect of cranberry extract in Caenorhabditis elegans is modulated by daf-16 and osr-1. Age (Dordr) :
Sun, Xiaoping; Komatsu, Toshimitsu; Lim, Jinhwan et al. (2012) Nutrient-dependent requirement for SOD1 in lifespan extension by protein restriction in Drosophila melanogaster. Aging Cell 11:783-93

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