One of the most fundamental questions in biology is how we age. The past decades have 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 molecular and cellular mechanisms that regulate the aging process and explore therapeutic targets to slow aging and even reverse aging-associated degeneration. 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.
1. Calorie Restriction and Oxidative Stress
Calorie restriction (CR) extends lifespan in numerous species. In mammals, this dietary regimen ameliorates a wide spectrum of diseases. One major focus is to understand how CR reduces oxidative stress, a major contributor to numerous human diseases and aging. The central hypothesis is that, instead of passively slowing metabolism, CR triggers an active defense program involving a cascade of molecular regulators to reduce oxidative stress. Supporting this hypothesis is our recent finding that CR activates SIRT3, a nutrient sensor, to reduce oxidative stress (Qiu et al. Cell Metabolism, 2010). Mechanistically, we found that SIRT3 reduces oxidative stress by deacetylating and activating SOD2, a key antioxidant in the mitochondria. Importantly, the physiological relevance of SIRT3, e.g. prevention of hearing loss and cancer, is dependent on its function to reduce oxidative stress.
2. Stem Cell Aging and Tissue Maintenance
The ability of stem cells to self-renew and repair damaged tissues decreases with age, which may underlie much of the aging-associated degeneration in mammals. The second major focus is to use hematopoietic stem cells (HSCs) as a model to understand the molecular bases of stem cell aging. We found that SIRT3 is highly enriched in HSCs, where it regulates the oxidative stress response. Importantly, SIRT3 expression declines with age, and SIRT3 overexpression rescues the functional defects of aged HSCs (Brown et al. Cell Reports, 2013). In contrast to the traditional view that reactive oxygen species (ROS) levels increase with age through a random and passive process, our findings suggest that it is a regulated process and that the effect of ROS on aging is acute and reversible. Taking advantage of a defined system, our studies provided the first evidence that aging-associated degeneration can be reversed by a sirtuin.
We have also identified a novel branch of mitochondrial unfolded protein response that is mediated by the interaction between SIRT7 and NRF1 and is coupled to energy metabolism and cell proliferation (Mohrin et al. Science, 2015). We found that this regulatory program is essential for HSC maintenance and its deregulation contributes to HSC aging.
3. Metabolic Diseases
The third major research focus investigates how overnutrition and aging perturb metabolic homeostasis, leading to the development of obesity and increased risk of numerous human diseases, such as cardiovascular disease, hypertension, cancer, and type 2 diabetes. We found that SIRT7 functions at chromatin to suppress ER stress and prevent the development of fatty liver disease (Shin, et al. Cell Reports, 2013). SIRT7 is induced upon ER stress and is stabilized at the promoters of ribosomal proteins through its interaction with the transcription factor Myc to silence gene expression and to relieve ER stress. This protective program is perturbed by aging or overnutrition, and SIRT7 can be targeted to restore metabolic homeostasis in animals with metabolic disorders.
Luo, H., Chiang, H., Louw, M., Susanto, A, and Chen, D. (2017) Nutrient Sensing and the Oxidative Stress Response. Trends in Endocrinology & Metabolism. 28(6):449-460.
Mohrin, M.*, Shin, J.*, Liu, Y.*, Brown, K.*, Luo, H., Xi, Y., Haynes, C., and Chen, D. (2015) A Mitochondrial UPR-mediated Metabolic Checkpoint Regulates Hematopoietic Stem Cell Aging. Science 347 (6228): 1374-77.
See also Perspective, Science. (2015) 347 (6228): 1319-20.
See also Nature Reviews Molecular Cell Biology. (2015) 16 (5): 266-7.
See also Leading Edge, Cell. (2015) 161 (6): 1235-7.
Xi, Y. and Chen, D. (2014). Partitioning the Circadian Clock. Science. 345(6201): 1122-3.
Shin, J.*, He, M.*, Liu, Y.*, Paredes, S.*, Villanova, L., Brown, K., Qiu, X., Nabavi, N., Mohrin, M., Wojnoonski, K., Li, P., Cheng, H., Murphy, A., Valenzuela, D., Luo, H., Kapahi, P., Krauss, R., Mostoslavsky, R., Yancopoulos, G., Alt, F., Chua, K., and Chen, D. (2013) SIRT7 Represses Myc Activity to Suppress ER Stress and Prevent Fatty Liver Disease. Cell Reports 5(3):654-665.
Brown, K.*, Xie, S.*, Qiu, X., Mohrin, M., Shin, J., Liu, Y., Zhang, D., Scadden, D., Chen, D. (2013) SIRT3 reverses aging-associated degeneration. Cell Reports 3(2):319-27.
See also Editors’ choice, Science. (2013) 339: 884.
See also Cell Reports Best of 2013.
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.
Nakahata, Y., Kaluzova, M., Grimaldi, B., Sahar, S., Hirayama, J., Chen, D., Brunet, A., Guarente., L, and Sassone-Corsi, P. (2008) The NAD-dependent Deacetylase SIRT1 Modulates CLOCK-Mediated Chromatin Remodeling and Circadian Control. 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. (2008) SIRT1-modulated gluconeogenesis via deacetylation of TORC2. Nature. 456(7219): 269-73.
Chen, D., Bruno, J., Easlon, E., Lin, SJ., Alt, F. and Guarente, L. (2008) Tissue-specific regulation of SIRT1 by calorie restriction. Genes & Dev. 22(13): 1753-57.
Chen, D., and Guarente, L. (2007) Sir2: A potential target for calorie restriction mimetics. Trends in Molecular Medicine. 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. PMID: 16339438
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. PMID: 14732682
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. PMID: 12486001
Chen, D., and Zhou, Q. (1999) Tat activates HIV-1 transcriptional elongation independent of TFIIH kinase. Mol. Cell. Bio. 19, 2863-2871. PMID: 10082552
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. PMID: 10077579