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Ph.D. 2003, University of Texas Southwestern Medical Center (Integrative Biology) 728 CRB |
The Baur lab is interested in the basic mechanisms that lead to aging. Age is the most important risk factor for many of the diseases affecting Western society today, including cancer, cardiovascular disease, and neurodegenerative disorders. Although the causes of aging are not known, it can be delayed experimentally in rodents by decreasing energy intake in the absence of malnutrition (caloric restriction, CR). Elucidating the mechanism(s) by which CR extends lifespan is expected to yield insights into the causes of aging and to highlight new therapeutic approaches to the prevention and treatment of age-related disease. One current project in the lab uses a transgenic mouse approach (overexpression of Nampt) to mimic the changes in NAD+ metabolism that occur during CR. Changes in NAD+ metabolism are thought to be the driving force that activates SIRT1 and other sirtuins, but are likely to affect a host of other processes as well. Thus, Nampt-overexpression may be a more effective strategy to mimic the full effects of CR than previous approaches, such as SIRT1-overexpression or resveratrol (a SIRT1 activator). Another area of interest is the role of mitochondrial biogenesis in CR. Although it has been studied since the 1930s, CR was shown only recently to paradoxically increase the number of mitochondria in many tissues. The consequences of this increase on reactive oxygen species generation, stress resistance, and insulin sensitivity are not known and cannot easily be distinguished from other effects of CR in vivo. Fortunately, the increase in mitochondrial biogenesis can be recapitulated in cell culture using serum from CR animals. We plan to use this system to functionally characterize cells with increased mitochondrial content and to isolate the serum factor that mediates the effect.
Selected Publications: Pearson, K.J.*, Baur, J.A.*, Lewis, K.N., Peshkin, L., Price, N.L., Labinskyy, N., Swindell, W.R., Kamara, D., Minor, R.K., Perez, E., Jamieson, H.A., Zhang, Y., Dunn, S.R., Sharma, K., Pleshko, N., Woolett, L.A., Csiszar, A., Ikeno, Y., Le Couteur, D., Elliott, P.J., Becker, K.G., Navas, P., Ingram, D.K., Wolf, N.S., Ungvari, Z., Sinclair, D.A., and de Cabo, R. (2008) Resveratrol delays age-related deterioration and mimcis transcriptional aspects of dietary restriction without extending life span. Cell Metabolism 8(2):157-168. Yang, H., Yang, T., Baur, J.A., Perez, E., Matsui, T., Carmona, J.J., Lamming, D.W., Souza-Pinto, N.C., Bohr, V.A., Rosenzweig, A., de Cabo, R., Sauve, A.A., Sinclair, D.A. (2007) Mitochondrial NAD+ levels are regulated and promote cell survival via SIRT3 and SIRT4. Cell 130(6):1095-1107. Baur, J.A.*, Pearson, K.J.*, Price, N.L., Jamieson, H.A., Lerin, C., Kalra, A., Prabhu, V.V., Allard, J.S., Lopez-Lluch, G., Lewis, K., Pistell, P.J., Poosala, S., Becker, K.G., Boss, O., Gwinn, D., Wang, M., Ramaswamy, S., Fishbein, K.W., Spencer, R.G., Lakatta, E.G., Le Couteur, D., Shaw, R.J., Navas, P., Puigserver, P., Ingram, D.K., de Cabo, R., Sinclair, D.A. (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444(7177):337-342. * These authors contributed equally. Baur, J.A. and Sinclair, D.A. (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nature Reviews in Drug Discovery 5(6):337-342. |
