Functional Genomic Study of Aging and Aging Interventions

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Aging is characterized as a gradual decline of various physiological functions and is associated with numerous damage and modifications to 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. To this end, we have collaborated with several laboratories in and outside of the National Institute on Aging (NIA) to develop quantitative tools valuable for aging research. In collaboration with Dr. Dongmao Zhang at the Mississippi State University, we published two quantification methods. One is to use an acid cleavable surface enhanced Raman spectroscopy (SERS) tag to quantify the levels of protein and protein modifications. Our method significantly improves the sensitivity and accuracy of fluorescence based protein detection. This work was published in The Analyst (2011). The other method is to detect carbohydrates using a Rhodamine B derivative as the Surface Enhancement Raman Spectroscopy (SERS) tag. The latter method can be utilized to measure protein glycosylation in aging, which remains quite elusive. This work has been published in Analytical Chemistry (2010). In collaboration with Drs. Rong-fong Shen, Bronwen Martin and Stuart Maudsley at the NIA, we have systematically evaluated the pulsed Q collision induced dissociation (PQD) method for peptide identification in proteomic studies. The PQD method is often employed to facilitate detection of low-mass reporter ions in peptide quantification using an LTQ mass spectrometer. Optimization of the PQD method is particularly valuable for identification of peptides with a labile functional group, such as phosphopeptides, in proteomic studies. This work has been accepted for publication in Journal of the American Society for Mass Spectrometry (2011, in press). To understand basic biological processes in aging, we have identified and characterized a fly gene highly homologous to the mammalian gene Aven. Mammalian Aven is a regulator of the DNA-damage response and G2/M cell cycle progression, and is linked to several types of cancer, such as acute myeloid leukemia. We have found that Drosophila Aven (dAven) is required for normal cell cycle progression in fly fat tissue. This work has been published in Cell Cycle (2011). Future studies will be directed to understand the role of dAven in DNA damage response, which should reveal information that may be relevant to cancer and aging. Taken together, our findings from this study along with analytical tools described above provide a foundation for us to further investigate molecular changes in the aging processes and consequences of these alterations on lifespan and health span. Many botanicals, including fruits and vegetables, are ideal for promoting longevity and health span due to their high antioxidant capacities and numerous bioactivities. However, few botanicals are actually known to possess prolongevity properties. The effective ways to implementing aging interventions remain poorly understood. We have previously demonstrated that supplementation of a fruit extract mixed with cranberry and oregano extracts can promote longevity and reproductive capacity in the Mexican fruit fly. To further investigate the health benefits of cranberry, we have evaluated the effect of long-term cranberry consumption on age-related changes in rat pancreas. We have found that a long-term cranberry consumption protects against an age-related decline in basal insulin release, improves β-cell glucose responsiveness and maintains functional β-cell mass in normal aging rats. Our findings suggest that cranberry consumption can be beneficial for diabetic patients. This work has been published in Journal of Gerontology Serial A: Biological Sciences (2011). To further understand the molecular mechanisms of lifespan regulation by fruits and herbs, we have employed Drosophila melanogaster as the model system. We have determined the effect of nectarine, a globally consumed fruit, on lifespan and health span in Drosophila melanogaster. Our findings suggest that nectarine promotes longevity and health span at least partly through modulating glucose metabolism and reducing oxidative damage. This work provides the first evidence showing the prolongevity effect of nectarine and has been published in Free Radical Biology & Medicine (2011). These findings encourage us to further investigate health benefits of various botanical extracts and the underlying mechanisms related to aging. This will also provide scientific guidance to consumption of fruits and herbs. In summary, we have developed analytic tools for accurate and reliable measurements of protein and protein modifications applicable for investigating molecular changes in aging. In addition, we have demonstrated the effects of two botanical extracts, cranberry and nectarine extracts, in promoting health and longevity in rats and flies, respectively. These studies should prove valuable to advance the objective of the Laboratory of Experimental Gerontology and the mission of the NIA to understand basic biology of aging and develop effect aging interventions. This project should provide insight into basic biology of human aging and facilitate developing effective aging intervention strategies for humans.