Ph.D. Molecular and Cell Biology, University of California at Berkeley, 2003
One of the most fundamental questions in biology is how we age. The past decade has witnessed a significant revision of a traditional view that aging is simply a random and passive process that is solely driven by entropy. In fact, the aging process is regulated genetically and lifespan can be extended by single gene mutations. Our research aims to understand signal transduction that regulates the aging process and explore therapeutic targets to slow aging. The most intriguing aspect of pharmaceutical intervention that targets the aging pathways is that, instead of targeting a specific disease, it has the potential of ameliorating a wide array of seemingly unrelated diseases associated with aging, such as cancer, tissue degeneration, metabolic syndrome and immune dysfunction.
Calorie restriction (CR) is the most effective dietary intervention to extend lifespan in a wide spectrum of species. In mammals, this dietary regiment also prevents diseases of aging. One important concept that emerges from aging research is that, while degenerative changes associated with aging are complex and difficult to integrate, the molecular mechanism of CR comprises regulated pathways amenable to study and provides an entry point to decipher how we age. The molecular mechanisms underlying these biological processes are currently being studied using systemic genome-wide screens, cell culture studies, and genetics.
Sirtuins are a highly conserved protein family with unique NAD+-dependent protein deacetylase activity. Sirtuins are the prime candidates for the mediators of CR response, because they may sense the availability of nutrients via the concentration of NAD+, a major metabolite in the cell, and elicit profound CR response by deacetylating a variety of downstream targets. Many protein targets of sirtuins have been identified, which turn out to be the key regulators of diverse biological pathways associated with CR response, such as stress resistance, glucose and fat metabolism. Increased dose of sirtuins extend lifespan in model organisms. In mammals, there are seven sirtuins, SIRT1 -7, which are expressed in different tissues with different cellular localizations. The molecular pathways regulated by sirtuins and their physiological relevance in metabolic regulation, aging, stem cell maintenance and tissue homeostasis, and disease progression are under investigation.
The functional studies of sirtuins will have direct pharmaceutical implications. Small molecule SIRT1 activators are currently in clinical trials for metabolic diseases associated with aging, in which the function of SIRT1 has been intensively investigated. Our studies open up the possibility of using sirtuin activators as potential pharmaceutical interventions for other diseases of aging. Understanding how sirtuins regulate various biological pathways at the molecular level will provide the basis for testing the drugs.
Most Recent Publications
Shin, J., Zhang, D., and Chen, D. (2011) Reversible acetylation of metabolic enzymes celebration: SIRT2 and p300 join the party. Molecular Cell. 43(1):3-5.
Qiu, X*., Brown, K*. (* equal contribution), Hirschey, M., Verdin, E., and Chen, D. (2010) Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metabolism. 12: 662-667..
Baur JA, Chen D., Chini EN, Chua K, Cohen HY, de Cabo R, Deng C, Dimmeler S, Gius D, Guarente LP, Helfand SL, Imai S, Itoh H, Kadowaki T, Koya D, Leeuwenburgh C, McBurney M, Nabeshima Y, Neri C, Oberdoerffer P, Pestell RG, Rogina B, Sadoshima J, Sartorelli V, Serrano M, Sinclair DA, Steegborn C, Tatar M, Tissenbaum HA, Tong Q, Tsubota K, Vaquero A, Verdin E. (2010). Dietary restriction: standing up for sirtuins. Science. 329(5995):1012-3.
Nakahata, Y., Kaluzova, M., Grimaldi, B., Sahar, S., Kiravama, J., Chen, D., Brunet, A., Guarente., L, and Sassone-Corsi, P. The NAD-dependent Deacetylase SIRT1 Operates with CLOCK in Regulating Chromatin Remodeling and Circadian Control. (2008) Cell. 134(2):329-40.
Liu, Y.*, Dentin, R*., Chen, D.* (* equal contribution), Ravnskjaer, K., Cole, P., Olefsky, J., Yates, J., Guarente, L. and Montminy, M. SIRT1-modulated gluconeogenesis via deacetylation of TORC2. (2008) Nature. In press.
Chen, D., Bruno, J., Easlon, E., Lin, SJ., Alt, F. and Guarente, L. Tissue-specific regulation of SIRT1 by calorie restriction. (2008) Genes & Dev. 22(13): 1753-57.
Chen, D., and Guarente, L. (2007) Sir2: A potential target for calorie restriction mimetics. Review. Trends Mol. Med. 13(2): 64-71.
Chen, D., Steele, A., Lindquist, S., and Guarente, L. (2005) Increase in activity during calorie restriction requires Sirt1. Science. 310:1641.
Chen, D., and Zhou, Q. (2004) Caspase-cleavage of BimEL triggers a positive feedback amplification of apoptotic signaling. Proc. Natl. Acad. Sci. USA. 101(5): 1235-40.
Chen, D., Wang, M., Zhou, S., and Zhou, Q. (2002) HIV-1 Tat targets microtubules to induce apoptosis, a process promoted by the pro-apoptotic Bcl-2 relative Bim. EMBO J. 21(24):6801-10.
O’Keeffe, B., Fong, Y., Chen, D., Zhou, S., and Zhou, Q. (2000) Requirement for a kinase-specific chaperone pathway in the production of a Cdk9/cyclin T1 heterodimer responsible for P-TEFb-mediated Tat stimulation of HIV-1 transcription. J. Biol. Chem., 275, 279-287.
Chen, D., and Zhou, Q. (1999) Tat activates HIV-1 transcriptional elongation independent of TFIIH kinase. Mol. Cell. Bio. 19, 2863-2871.
Chen, D., Fong, Y., and Zhou, Q. (1999) Specific interaction of Tat with the human but not rodent P-TEFb complex mediates the species-specific Tat activation of HIV-1 transcription. Proc. Natl. Acad. Sci. USA. 96, 2728-2733.
Luo, K., Stroschein, S. L., Wang, W., Chen, D., Martens, E., Zhou, S., and Zhou, Q. (1999) The Ski oncoprotein interacts with the Smad proteins to repress TGF signaling. Genes & Dev. 13, 2196-2206.
Zhou, Q., Chen, D., Pierstorff, E., and Luo, K. (1998) Transcription elongation factor P-TEFb mediates Tat activation of HIV-1 transcription at multiple stages. EMBO J. 17, 3681-3691.