Brian Kennedy

Distinguished Professor of Biochemistry and Physiology

Affiliations

Professor, Departments of Biochemistry and Physiology, Yong Loo Lin School of Medicine, NUS.
Director Centre for Healthy Ageing, Yong Loo Lin School of Medicine, NUS.
Professor, Buck Institute for Research on Ageing, Novato, CA, USA.
Adjunct Professor, Leonard Davis School of Gerontology, USC, Los Angeles, CA, USA.
Affiliate Faculty, Department of Biochemistry, University of Washington, Seattle, WA USA.

Education

Degree and Institution Year(s)
B.A. in Biochemistry and Mathematics, Northwestern University , Evanston , IL, USA 1985-1989
Ph.D. in Biology , Massachusetts Institute of Technology, Cambridge, MA, USA 1990-1996

Professional Experience

Title Year(s)
Postdoctoral Fellow, Massachusetts General Hospital Cancer Center, Charlestown, MA, USA 1996–2001
Assistant Professor, Department of Biochemistry, University of Washington, Seattle , WA , USA 2001–2007
Associate Professor, Department of Biochemistry, University of Washington, Seattle , WA , USA 2007–2010
Visiting Professor, Guangdong Medical College, Guangdong Provence, China 2009–2014
President and CEO, Buck Institute for Research on Ageing, Novato, CA 2010–2016
Parkway Pantai Visiting Professor, Yong Loo Lin School of Medicine, National University Singapore 2017–present

Research Interest

Research in the Kennedy lab is directed at understanding the biology of ageing and translating research discoveries into new ways of delaying, detecting, preventing and treating human ageing and associated diseases.

Current Research Projects

Several research strategies are employed to understand the biology of human ageing and to develop translational approaches. We use multiple model organisms and systems for these purposes, relying on non-vertebrates for discovery-based approaches to generate hypotheses regarding ageing mechanisms and studies in mammals to test hypotheses and to develop translational strategies. Specific projects include:

Systems biology strategies to understand ageing - Using the yeast Saccharomyces cerevisiae, we employ large-scale genetic and molecular approaches to define how pathways controlling ageing interact in a network. Recently, we published a full genome analysis of replicative ageing, the number of divisions one yeast mother cell can undergo. Surprisingly, it is relatively easy to extend replicative lifespan, as nearly 250 long-lived gene deletions were identified. Currently, we are generating an epistasis network to define how these genes interact, and combining this with detailed analysis of specific long-lived mutants. In addition, we have identified drugs that extend yeast lifespan and seek their mechanism of action. We are also active with the nematode C. elegans, using it primarily as a short-lived multicellular species in which to define which yeast ageing pathways are conserved.

Murine longevity and studies and disease models - Several approaches are employed to identify the mechanisms governing mammalian ageing. Primary focus is on the mTOR pathway, which is intimately linked to ageing. Reduced mTOR signalling, for instance by treatment with rapamycin, extends both lifespan and healthspan, the disease-free and functional period of life. We use genetic and pharmacologic strategies to modify mTOR activity, with the goal of determining in which tissues mTOR modulates ageing, the temporal nature of interventions and, importantly, the pathways downstream of mTOR that transmit age-related signals. Other lines of experimental investigation are aimed at understanding BCAA metabolism and disease and understanding how altered nuclear lamin function is linked to ageing and diseases.

Selected Publications (out of over 170 total)

  1. Liao, C.-Y., Anderson, S.S., Chicoine, N.H., Mayfield, J.R., Academia, E.C., Wilson, J.A., Pongkietisak, C., Thompson, M.A., Lagmay, E.P., Miller D.M., Hsu, Y.-M. McCormick, M.A., O’Leary, M.N., and Kennedy, B.K. 2016. Rapamycin reverses metabolic deficits in lamin A/C-deficient mice. Cell Rep. 17: 2542-2552. PMID: 27926859.

  2. Davis, S.S., O’Leary, M.N., Gutierrez, M.A., Nguyen, S.M., Mateen, S., Hsu, Y., Mitchell, K.P., Lopez, A.J., Vockley, G., Kennedy, B.K., and Ramanathan, A. 2016. Metformin inhibits branched chain amino acid (BCAA) derived ketoacidosis and promotes metabolic homeostasis in MSUD. Sci. Rep. 6: 28755. PMID: 27373929.

  3. Tsai, S., Rodriguez, A.A., Dastidar, S.G., Del Greco, E., Carr, K.L., Sitzmann, J.M., Academia, E.C., Viray, C.M., Martinez, L.L., Kaplowitz, B.S., Ashe, T.D., La Spada, A., and Kennedy, B.K. 2016. Increased 4E-BP1 expression protects against diet-induced obesity and insulin resistance in male mice. Cell Rep. 16: 1903-1914. PMID: 27498874.

  4. Moskalev, A., Chernyagina, E., Tsvetkov, V., Fedintsev, A., Shaposhnikov, M., Krut’ko, V., Zhavoronkov, A. and Kennedy, B.K. 2016. Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic. Aging Cell, 15: 407-415. PMID: 26970234.

  5. McCormick, M.A., Delaney, J.R., Tsuchiya, M., Tsuchiyama, S., Shemorry, A., Sim, S., Chou, A.C.-Z., Ahmed, U., Carr, D., Murakami, C.J., Schleit, J., Sutphin, G.L., Wasko, B.M., Bennett, C.F., Wang, A.M., Olsen, B., Beyer, R.P., Bammler, T.K., Prunkard, D., Johnson, S.C., Pennypacker, J.K., An, E., Anies, A., Castanza, A.S., Choi, E., Dang, N., Enerio, S., Fletcher, M., Fox, L., Goswami, S., Higgins, S.A., Holmberg, M.A., Hu, D., Hui, J., Jelic, M., Jeong, K.-S., Johnston, E., Kerr, E.O., Kim, D., Kim, J., Kirkland, K., Klum, S., Kotireddy, S., Liao, E., Lim, M., Lin, M.S., Lo, W.C., Lockshon, D., Miller, H.A., Moller, R.M., Muller, B., Oakes, J., Pak, D.N., Peng, Z.J., Pham, K.M., Pollard, T.G., Pradeep, P., Pruett, D., Rai, D., Robison, B., Rodriguez, A.A., Ros, B., Sage, M., Singh, M.K., Smith, E.D., Snead, K., Solanky, A., Spector, B.L., Steffen, K.K., Tchao, B.N., Ting, M.K., Vander Wende, H., Wang, D., Welton, K.L., Westman, E.A., Brem, R.B., Liu, X.-G., Suh, Y., Zhou, Z., Kaeberlein, M. and Kennedy, B.K. 2015. A comprehensive analysis of replicative lifespan in 4,698 single-gene deletion strains uncovers novel mechanisms of aging. Cell. Metab. 22: 895-906. PMID: 26456335.

  6. Tsai, S., Sitzmann, J.M., Dastidar, S.G., Rodriguez, A.A., Vu, S.L., McDonald, C.E., Academia, E.C., O’Leary, M.N., Ashe, T.D., La Spada, A.R. and Kennedy B.K. 2015. Activated muscle 4E-BP1 signaling improves metabolic parameters during aging and obesity. J. Clin. Invest. 125: 2952-2964. PMID: 26121750.

  7. Broadhurst, S., Choi, I.Y., Wei, M., Cheng, C.W., Sedrakyan, S., Navarrete, G., Dubeau, L., Yap, L.P., Park, R., Vinciguerra, M., Di Biase, S., Mirzaei, H., Mirisola, M.G., Childress, P., Ji, L., Groshen, S., Penna, F., Odetti, P., Perin, L., Conti, P.S., Ikeno, Y., Kennedy, B.K., Cohen, P., Morgan, T.E., Dorff, T.B. and Longo, V.D. 2015. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab. 22: 86-99. PMID: 26094889.

  8. Schreiber, K.H., Ortiz, D., Academia, E.C., Anies, A.C., Liao, C.-Y. and Kennedy, B.K. 2015. Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506 binding proteins. Aging Cell, 14: 265-273. PMID: 25652038.

  9. He, C., Tsuchiyama, S.K., Nguyen, Q.T., Plyusnina, E.N., Terrill, S.R., Sahibzada, S., Patel, B., Faulkner, A.R., Shaposhnikov, M.V., Tian, R., Tsuchiya, M., Kaeberlein, M. Moskalev, A.A., Kennedy, B.K. and Polymenis, M. 2014. Enhanced longevity by ibuprofen, conserved in multiple species, occurs in yeast through inhibition of tryptophan import. PLoS Genet. E1004860. PMID: 25521617.

  10. Kennedy, B.K., Berger, S.L., Brunet, A., Campisi, J., Cuervo, A.M., Epel, E.S., Franceschi, C., Lithgow, G.J., Morimoto, R.I., Pessin, J.E., Rando, T.A., Richardson, A., Schadt, E.E., Wyss-Coray, T., and Sierra, F. 2014. Geroscience: linking aging to chronic disease. Cell, 159: 709-713. PMID: 25417146.

  11. Levine, M.E., Suarez, J.A., Brandhorst, S., Balasubramanian, P., Cheng, C.-W., Madia, F., Mirisola, M.G., Guevara-Aguirre, J., Wan, J., Passarino, G., Kennedy, B.K., Cohen, P., Crimmins, E., and Longo. V.D. 2014. Low protein intake is associated with a major reduction in IGF-1, cancer and overall mortality in the 65 and younger but not older population. Cell Metab. 19: 407-417. PMID: 24606898.

  12. O’Leary, M.N., Schreiber, K.H., Zhang, Y., Duc, A.-C.E., Rao, S., Hale, J.S., Academia, E., Shah, S.R., Morton, J.F., Holstein, C.A., Martin, D.B., Kaeberlein, M., Ladiges, W.C., Fink, P.J., MacKay, V.L., Wiest, D.L., and Kennedy, B.K. 2013. The ribosomal protein Rpl22 controls ribosome composition by directly repressing expression of its own paralog, Rpl22L1. PLoS Genet. 9: e1003708. PMID: 23990801.

  13. Liu, B., Ghosh, S., Yang, X., Zheng, H., Liu, X., Wang, Z., Jin, G., Zheng, B., Kennedy, B.K., Suh, Y., Kaeberlein, M., Tryggvason, K., and Zhou, Z. 2012. Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria. Cell Metab. 16: 738-750. PMID: 23020224.

  14. Ramos, F., Chen, S.C., Garelick, M.G., Dai, D.-F., Liao, C.-Y., Schreiber, K.H., MacKay, V.L., An, E.H., Strong, R., Ladiges, W.C., Kaeberlein, M. and Kennedy, B.K. 2012. Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function and extends survival. Sci. Transl. Med. 4: 144ra103. PMID: 22837538.

  15. Dang, W., Steffen, K.K., Perry, R., Dorsey, J. Johnson, F.B., Shilatifard, A., Kaeberlein, M. Kennedy, B.K., and Berger, S.L. 2009. Histone H4 lysine-16 acetylation regulates cellular lifespan. Nature 459, 802-807.

  16. Kudlow, B.A., Stanfel, M.N., Burtner, C.R., Johnston, E.D., and Kennedy, B.K. 2008. Suppression of proliferative defects associated with processing-defective lamin A mutants by hTERT or inactivation of p53. Mol. Biol. Cell 19: 5238-5248.

  17. Smith, E.D., Tsuchiya, M., Fox, L.A., Dang, N., Hu, D., Kerr, E.O., Johnston, E.D., Tchao, B.N., Pak, D.N., Welton, K.L., Promislow, D.E.L., Thomas, J.H., Kaeberlein, M. and Kennedy B.K. 2008. Quantitative evidence for conserved longevity pathways between divergent eukaryotic species. Genome Res. 18: 564-570.

  18. Steffen, K.K., MacKay, V.L., Kerr, E.O., Tsuchiya, M., Hu, D., Fox, L.A., Dang, N., Johnston, E.D., Oakes, J.A., Tchao, B.N., Pak, D.N., Fields, S., Kennedy B.K. and Kaeberlein, M. 2008. Yeast lifespan extension by depletion of 60S ribosomal subunits is mediated by Gcn4. Cell 133: 292-302.

  19. Frock, R.L., Kudlow, B.A., Evans, A.M., Jameson, S.A., Hauschka, S.D. and Kennedy, B.K. 2006. Lamin A/C and emerin are critical for skeletal muscle satellite cell differentiation. Genes Dev. 20: 486-500.

  20. Powers, R.W. III, Kaeberlein, M., Caldwell, S.D., Kennedy, B.K., and Fields, S. 2006. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 20: 174-184.

  21. Kaeberlein, M., Powers, R.W. III, Steffen, K.K., Westman, E.A., Hu, D., Dang, N., Kerr, E.O., Kirkland, K.T., Fields, S., and Kennedy, B.K. 2005. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310: 1193-1196.

  22. Kaeberlein, M., McDonagh, T., Heltweg, B., Hixon, J., Westman E.A., Caldwell, S., Napper, A., Curtis, R., DiStefano, P.S., Fields, S. Bedalov, A. and Kennedy, B.K. 2005. Substrate specific activation of sirtuins by resveratrol. J. Biol. Chem. 280:17039-17045.

  23. Kaeberlein, M., Kirkland, K.T., Fields, S., and Kennedy, B.K. 2004. Sir2-independent life span extension by calorie restriction in yeast. PLoS Biology 2: 1381-1387.

  24. Kennedy, B.K., Gotta, M., Sinclair, D.A., Mills, K., McNabb, D.S., Murthy, M., Pak, S.M., Laroche, T., Gasser, S.M., and L. Guarente. 1997. Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in S. cerevisiae. Cell 89: 381-391.

  25. Kennedy, B.K., Austriaco, N.R. Jr., Zhang, J., and L. Guarente. 1995. Mutation in the silencing gene SIR4 can delay aging in Saccharomyces cerevisiae. Cell 80: 485-496.