研究领域
Animal lifespans range widely, from several days to over a century, yet the underlying reasons for these vast differences remain poorly understood. Many cell types are terminally differentiated in adult organisms, and in some instances these individual cells may endure for the entire adult lifespan. The goal of my research program is to gain a better understanding of the molecular mechanisms permitting these long-lived cells to maintain their functional integrity throughout the lifespan. Currently, we are using two types of experimental models to explore this. We use mice harbouring gene mutations that confer increases in maximal lifespan of up to 50% (e.g. the Snell dwarf mouse). We also employ a broadly comparative approach, using naturally short- and long-lived animal species to identify characteristics that have been selected during the evolution of increased lifespans.
We hypothesize that longevity is associated with one or more of the following cellular properties: (1) improved reactive oxygen species (ROS) metabolism. ROS are produced by mitochondria during normal respiration and, though ROS have important biological functions, they can initiate reactions leading to cell death. We study differences in the expression of antioxidant enzymes that neutralize the lethal effects of ROS. (2) improved ability to handle proteotoxic stress. Protein damage due to both endogenous and exogenous stressors interrupts normal cellular functions and activities leading, in the worse case scenario, to cell death. We study differences in proteasome activity, protein repair and heat shock protein expression that are associated with longevity. (3) improved ability to handle genotoxic stress. DNA damage from endogenous and exogenous agents threatens cell viability. The enhancement of longevity may be achievable by maintaining robust DNA protection and repair activities. We study DNA base excision repair activities, in the nucleus and mitochondria of animal cells, and how these relate to lifespan.
We are also studying the biological activities of phytoestrogens, such as resveratrol. This molecule, found in red wine and a variety of fruit and vegetables, interacts with cellular signaling pathways and enhances cellular stress resistance. We have identified the mitochondria and the mitochondrial matrix enzyme superoxide dismutase (MnSOD) as important targets of resveratrol and are studying the detailed molecular mechanisms by which resveratrol elicits the induction of MnSOD and developing ways to enhance resveratrol delivery in vivo.
Mitochondrial Network Analysis (MiNA)
Mitochondria exist in a dynamic balance of fusion/fission and biogenesis/mitophagy that determine the size and morphology of the ‘mitochondrial network’. Many of the mitochondrial phenomena we investigate exert effects on these processes and thus manifest as changes in mitochondrial network morphology. These morphological changes affect cell physiology and are therefore important to measure and understand. To facilitate this we developed the Mitochondrial Network Analysis (MiNA) toolset as a simple set of macros making use of existing ImageJ plug-ins that allows a semi-automated analysis of mitochondrial networks in cultured mammalian cells. The tool incorporates optional preprocessing steps to enhance image quality before converting the images to binary and producing a morphological skeleton for calculating several parameters that quantitatively capture the morphology of the mitochondrial network.
This link will direct you to the downloadable manual and toolset for using MiNA to study mitochondrial networks in cultured mammalian cells. https://github.com/ScienceToolkit/MiNA
The Comparative Cellular and Molecular Biology of Longevity Database
Vertebrate species maximum lifespans vary from several years to over two centuries, and this presents an opportunity to investigate the underlying biological traits that have co-evolved with longevity. We maintain a cell and tissue bank with brain, heart, liver, and kidney samples and skeletal muscle myoblasts from over 20 mammalian, avian and reptilian species. These collections provide a means to investigate the expression levels of various putative longevity traits in the context of longevity.
The Comparative Cellular and Molecular Biology of Longevity (CCMBL) database (http://genomics.brocku.ca/ccmbl/) contains the combined datasets from dozens of studies (including ours) in which cellular and molecular traits have been measured in the context of evolved species longevity. The purpose of the CCMBL database is simply to provide a convenient repository that brings together the accumulating wealth of species longevity data that is available but distributed widely in the scientific literature. We hope that this single-source collection of information will promote an integrative appreciation of the cellular and molecular biology of longevity by providing a broad comparative framework into which new data can be inserted as it becomes available.
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Stuart, J.A. and Robb, E.L. Bioactive Polyphenols from Wine Grapes. Springer Press, New Jeresey. 2013. 77 pp.
Stuart, J.A., Editor, Mitochondrial DNA: Methods and Protocols, 2nd edition. Volume 197 In: Methods in Molecular Biology, Human Press, Totowa, New Jersey. 2009.
Page, M.M. and Stuart, J.A. In vitro measurement of mitochondrial DNA base excision repair enzyme activities. In: Mitochondrial DNA: Methods and Protocols, 2nd edition. Methods in Molecular Biology Series, J.M. Walker, Human Press, Totowa, New Jersey. Published online June 2009.
Valente, A.J.F., Maddalena, L.A., Robb, E.L., Moradi, F., Stuart, J.A., 2017. A Simple ImageJ Macro Tool for Analyzing Mitochondrial Network Morphology in Mammalian Cell Culture. Acta Histochem, In Press.
Robb, E.L., Moradi, F., Maddalena, L.A., Valente, A., Fonseca, J., Stuart, J.A., 2017 Resveratrol stimulates mitochondrial fusion by a mechanism requiring mitofusin-2. Biochem Biophys Res Commun, In Press.
Maddalena, L.A, Ghelfi, M., Atkinson, J., Stuart, J.A., 2017. The mitochondria-targeted imidazole substituted oleic acid 'TPP-IOA' affects mitochondrial bioenergetics and its protective efficacy in cells is influenced by cellular dependence on aerobic metabolism. Biochim Biophys Acta. 1858:73-85.
Yalagala, R.S., Mazinani, S.A., Maddalena, L.A., Stuart, J.A., Yan, F., Yan, H. 2016. Microwave-assisted syntheses of BODIPY-sugar conjugates through click chemistry and conjugate assembly into liposomes. Carbohydr Res. 2016 Apr 7;424:15-20.
Stuart, J.A., Maddalena, L.A., Merilovich, M., and Robb, E.L., 2014. A Midlife Crisis for the Mitochondrial Free Radical Theory of Aging. Healthspan and Longevity. 3(1):4.
Robb, E.L, Christoff, C.A., Maddalena, L.A., and Stuart, J.A., 2014. Mitochondrial reactive oxygen species in animal cells: relevance to aging and normal physiology. Can. J. Zool. 92(7): 603-613.
Page, M.M., Sinclair, A., Robb, E.L., Stuart, J.A., Withers, D.J., Selman, C., 2014 Fibroblasts derived from long-lived insulin receptor substrate 1 null mice are not resistant to multiple forms of stress. Aging Cell 13(5), 962-964.
Robb, E.L. and Stuart, J.A., 2014. The stilbenes resveratrol, pterostilbene and piceid affect growth and stress resistance in mammalian cells via a mechanism requiring estrogen receptor beta and the induction of Mn-superoxide dismutase. Phytochemistry, 98,164-173.
Robb, E.L. and Stuart, J.A., 2014. Multiple phytoestrogens inhibit cell growth and confer cytoprotection by inducing manganese superoxide dismutase expression. Phytother. Res. 28,120-131.
Stuart, J.A., Liang, P., Luo, X., Page, M.M., Gallagher, E.J., Christoff, C.A. and Robb, E.L., 2013. A Comparative Cellular and Molecular Biology of Longevity Database. Age. 35,1937-1947.
Robb, E.L., Maddalena, L.A., Dunlop, V.A., Foster, T. and Stuart, J.A., 2012. Absence of metabolic rate allometry in an ex vivo model of mammalian skeletal muscle. Comp. Biochem. Physiol. 162,157-162.
Page, M.M. and Stuart, J.A., 2012. Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan. Age. 34(5), 1195-1209.
Kronenberg, G., Gertz, K., Overall, R.W., Harms, C., Klein, J., Page, M.M., Stuart, J.A., Endres, M., 2011. Folate deficiency increases mtDNA and D-1 mtDNA deletion in aged brain of mice lacking uracil-DNA glycosylase. Exptl. Neurol. 228(2), 253-258.
Salway, K.D., Gallagher, E.J. and Stuart, J.A., 2011. Longer-lived mammals and birds have higher levels of heat shock proteins. Mech. Age. Devel. 132(6-7), 287-297.
Skandalis, D.A., Stuart, J.A. and Tattersall, G.J., 2011. Responses of Drosophila melanogaster to atypical oxygen atmospheres. J. Insect Physiol. 57(4), 444-451.
Robb, E.L. and Stuart, J.A., 2011. Resveratrol interacts with estrogen receptor-β to inhibit cell replicative growth and enhance stress resistance by upregulating mitochondrial superoxide dismutase. Free Radic. Biol. Med. 50(7), 821-831.
Stuart, J.A. and Page, M.M., 2010. Plasma [IGF-1] is negatively correlated with body mass in a comparison of 36 mammalian species. Mech. Age. Devel. 131, 591-598.
Salway, K.D. and Stuart, J.A., 2010. Antioxidant enzymes and oxidative damage biomarkers in heart and selected other tissues of estivating and arousing land snails (Achatina fulica). Comp. Biochem. Physiol. 157, 229-36.
Salway, K.D., Page, M. M., Faure, P.A., Burness, G. and Stuart, J.A., 2010. Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species. AGE. Published online Jun 22.
Robb. E.L. and Stuart, J.A., 2010. trans-Resveratrol as a neuroprotectant. Molecules 15, 1196-1212.
Page, M.M., Robb, E.L., Salway, K.D., and Stuart, J.A., 2010. Mitochondrial redox metabolism: aging, longevity and dietary effects. Mech. Ageing and Devel. 131, 242-252.
Page, M.M., Richardson, J., Wiens, B.E., Tiedtke, E., Peters, C.W., Faure, P.A., Burness, G. and Stuart, J.A., 2010. Antioxidant enzyme activities are not broadly correlated with longevity in 14 endotherm species. AGE. 32, 255-270.
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