- BBSRB 173
B.S. University of Redlands
Ph.D. University of California, Los Angeles
Some people grow old yet show few signs of aging, while others show signs of aging long before they grow old. How can this be? We are trying to identify and understand the signal transduction pathways and cellular processes that control the rate of biological aging and lifespan. Our goal is to develop a way to lower the frequency, slow the progression or delay the onset of age-related diseases including cancer, neurodegeneration, arthritis, cardiovascular pathology and diabetes that diminish health in the elderly and cause the majority of human deaths.
More than eighty years ago researchers found that feeding rats 30-40% fewer calories significantly improved health and increased lifespan. These results were utterly surprising were mostly ignored for fifty years. However, over the past twenty-five years, studies using model organisms have reinforced the notion that nutrient restriction, implemented either by reducing total calories (caloric restriction) or total protein/amino acid intake (protein or amino acid restriction), improves health and increases lifespan. Small-scale studies in humans are beginning to show that nutrient restriction slows aging and promotes a younger more youthful physiological state. But more research is required to fully evaluate the anti-aging effects of nutrient restriction and determine if it ameliorates the aging process and improves health in the elderly.
The chief drawback of nutrient restriction results from the natural, evolved-desire of humans to eat. Consequently, most people are not capable of restricting food intake sufficiently and over a long enough period of time to realize the potential health benefits. Thus, there is an urgent need to develop alternatives because the rapid, worldwide increase in the elderly population is creating medical, social and economic stresses that need to be solved.
We use the common baker’s yeast Saccharomyces cerevisiae as a model eukaryote for studying lifespan because it’s lifespan is short and be analyzed by genetic and biochemical techniques. Furthermore, many genes involved in regulating lifespan were identified in this organism and it continues to yield new insights into the molecular mechanisms of aging and longevity. A surprising outcome of studies in model organisms is that similar processes and signaling pathways regulate lifespan in yeasts, worms, flies, and mice. Humans have many of these processes and signaling pathways, thus, there is a good reason to believe that studies with model organisms will produce alternative ways to mimic nutrient restriction and reduce the burdens presented by aging populations.
We have found that lowering the rate of sphingolipid synthesis in yeasts increases lifespan and does so by regulating processes and signaling pathways that overlap with those that are controlled by nutrient restriction (Adjacent figure - Huang et al., PLoS Genetics, 2012; Liu et al., Aging Cell, 2013). For our experiments, we use a drug (myriocin) to slow the rate of sphingolipid synthesis. Besides the results shown in the adjacent figure, we have recently found that myriocin is producing a unique form of protein restriction. Future research will seek to identify how the drug mimics the effects of protein restriction and enhance longevity.
Diagram summarizing the effects of myriocin treatment on gene transcription in log phase yeast cells during a chronological lifespan (CLS) assay. The signaling cascades influenced by myriocin treatment include Snf1 (homolog of mammalian AMPK), protein kinase A (PKA), target of rapamycin complex I (TORC1, homolog of mammalian TORC1), Sch9 (homolog of mammalian S6k1/2) and Pkh1/2 (homolog of mammalian PDK1). Information of Transcription Factors (TFs) can be found at SGD the Saccharomyces Genome Database (www.yeastgenome.org).
- Huang, X.;Leggas, M.;Dickson, R.C. "Drug synergy drives conserved pathways to increase fission yeast lifespan." PloS one 10, 3 (2015): e0121877. [PubMed Link] | [ Full text ]
- Huang, X.;Leggas, M.;Dickson, R.C. "Correction: Drug synergy drives conserved pathways to increase fission yeast lifespan." PloS one 10, 4 (2015): e0125857. [PubMed Link] | [ Full text ]
- Neimanis, I.;Gaebel, K.;Dickson, R.C.;Levy, R.;Goebel, C.;Zizzo, A.J.;Woods, A.;Corsini, J. "Committee on Utilization, Review, and Education common referral form." Canadian family physician Medecin de famille canadien 60, 10 (2014): 916. [PubMed Link] | [ Full text ]
- Huang, X.;Withers, B.R.;Dickson, R.C. "Sphingolipids and lifespan regulation." Biochimica et biophysica acta 1841, 5 (2014): 657-64. [PubMed Link] | [ Full text ]
- Liu, J.;Huang, X.;Withers, B.R.;Blalock, E.;Liu, K.;Dickson, R.C. "Reducing sphingolipid synthesis orchestrates global changes to extend yeast lifespan." Aging cell 12, 5 (2013): 833-41. [PubMed Link] | [ Full text ]
- Dickson, R.C. "Not all diclofenac is equal." CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 185, 8 (2013): 687. [PubMed Link] | [ Full text ]
- Huang, X.;Liu, J.;Withers, B.R.;Samide, A.J.;Leggas, M.;Dickson, R.C. "Reducing signs of aging and increasing lifespan by drug synergy." Aging cell 12, 4 (2013): 652-60. [PubMed Link] | [ Full text ]
- Lester, R.L.;Withers, B.R.;Schultz, M.A.;Dickson, R.C. "Iron, glucose and intrinsic factors alter sphingolipid composition as yeast cells enter stationary phase." Biochimica et biophysica acta 1831, 4 (2013): 726-36. [PubMed Link] | [ Full text ]
- Aguilar Madrid, G.;Beaudry, M.;Bell, W.;Bowes, D.;Brophy, J.;Burdorf, A.;Carlsten, C.;Castleman, B.;Chaturvedi, S.;Conti, M.E.;Corra, L.;Corrêa Filho, H.R.;Cranor, C.F.;Cullen, E.;Dalvie, A.;Dickson, R.C.;Digon, A.;Egilman, D.;Eisner Falvo, C.;Fischer, E.;Frank, A.L.;Frank, E.;Gee, D.;Giannasi, F.;Goldstein, B.D.;Greenberg, M.;Guidotti, T.L.;Harris, W.A.;Hindry, M.;Houlson, A.;Hu, H.;Huff, J.;Infante, P.F.;Thambyappa, J.;Juarez Perez, C.A.;Jeebhay, M.F.;Joshi, T.K.;Keith, M.;Keyserlingk, J.R.;Khatter, K.;King, D.;Kodeih, N.;Kristensen, J.;Kulsomboon, V.;Landrigan, P.J.;Lee, C.W.;Leigh, J.;Lemen, R.A.;Lippman, A.;London, L.;Matzopoulos, R.;McCulloch, J.;McDiarmid, M.A.;Mehrdad, R.;Mirabelli, D.;Moshammer, H.;Notebaert, É.;Nycz, Z.;Oberta, A.F.;O'Connor, J.;O'Neill, R.;Orris, P.;Ozonoff, D.;Paek, D.;Rickard, C.;Rodriguez, E.J.;Sass, J.;Sentes, K.E.;Simpson, I.M.;Soffritti, M.;Soskolne, C.L.;Sparling, S.P.;Spiegel, J.;Takahashi, K.;Takaro, T.K.;Terracini, B.;Thébaud-Mony, A.;Trosic, I.;Turcotte, F.;Vakil, C.;Van Der Walt, A.;Waterman, Y.R.;Watterson, A.;Wegman, D.H.;Welch, L.S.;Weiss, S.H.;Winston, R.;Yassi, A. "Statement in response to asbestos industry efforts to prevent a ban on asbestos in Pakistan: chrysotile asbestos use is not safe and must be banned." Archives of environmental & occupational health 68, 4 (2013): 243-9. [PubMed Link] | [ Full text ]
- Lee, Y.J.;Huang, X.;Kropat, J.;Henras, A.;Merchant, S.S.;Dickson, R.C.;Chanfreau, G.F. "Sphingolipid signaling mediates iron toxicity." Cell metabolism 16, 1 (2012): 90-6. [PubMed Link] | [ Full text ]
- Huang, X.;Liu, J.;Dickson, R.C. "Down-regulating sphingolipid synthesis increases yeast lifespan." PLoS genetics 8, 2 (2012): e1002493. [PubMed Link] | [ Full text ]
- Luo, G.;Costanzo, M.;Boone, C.;Dickson, R.C. "Nutrients and the Pkh1/2 and Pkc1 protein kinases control mRNA decay and P-body assembly in yeast." The Journal of biological chemistry 286, 11 (2011): 8759-70. [PubMed Link] | [ Full text ]
- Dickson, R.C. "Roles for sphingolipids in Saccharomyces cerevisiae." Advances in experimental medicine and biology 688, (2010): 217-31. [PubMed Link] |
- Dickson, R.C. "Thematic review series: sphingolipids. New insights into sphingolipid metabolism and function in budding yeast." Journal of lipid research 49, 5 (2008): 909-21. [PubMed Link] | [ Full text ]
- Dickson, R.C. "More chores for TOR: de novo ceramide synthesis." Cell metabolism 7, 2 (2008): 99-100. [PubMed Link] | [ Full text ]
- Luo, G.;Gruhler, A.;Liu, Y.;Jensen, O.N.;Dickson, R.C. "The sphingolipid long-chain base-Pkh1/2-Ypk1/2 signaling pathway regulates eisosome assembly and turnover." The Journal of biological chemistry 283, 16 (2008): 10433-44. [PubMed Link] | [ Full text ]
- Brace, J.L.;Lester, R.L.;Dickson, R.C.;Rudin, C.M. "SVF1 regulates cell survival by affecting sphingolipid metabolism in Saccharomyces cerevisiae." Genetics 175, 1 (2007): 65-76. [PubMed Link] | [ Full text ]
- Dickson, R.C.;Sumanasekera, C.;Lester, R.L. "Functions and metabolism of sphingolipids in Saccharomyces cerevisiae." Progress in lipid research 45, 6 (2006): 447-65. [PubMed Link] | [ Full text ]
- Valachovic, M.;Bareither, B.M.;Shah Alam Bhuiyan, M.;Eckstein, J.;Barbuch, R.;Balderes, D.;Wilcox, L.;Sturley, S.L.;Dickson, R.C.;Bard, M. "Cumulative mutations affecting sterol biosynthesis in the yeast Saccharomyces cerevisiae result in synthetic lethality that is suppressed by alterations in sphingolipid profiles." Genetics 173, 4 (2006): 1893-908. [PubMed Link] | [ Full text ]
- Liu, K.;Zhang, X.;Sumanasekera, C.;Lester, R.L.;Dickson, R.C. "Signalling functions for sphingolipid long-chain bases in Saccharomyces cerevisiae." Biochemical Society transactions 33, Pt 5 (2005): 1170-3. [PubMed Link] | [ Full text ]
- Zink, S.;Mehlgarten, C.;Kitamoto, H.K.;Nagase, J.;Jablonowski, D.;Dickson, R.C.;Stark, M.J.;Schaffrath, R. "Mannosyl-diinositolphospho-ceramide, the major yeast plasma membrane sphingolipid, governs toxicity of Kluyveromyces lactis zymocin." Eukaryotic cell 4, 5 (2005): 879-89. [PubMed Link] | [ Full text ]
- Liu, K.;Zhang, X.;Lester, R.L.;Dickson, R.C. "The sphingoid long chain base phytosphingosine activates AGC-type protein kinases in Saccharomyces cerevisiae including Ypk1, Ypk2, and Sch9." The Journal of biological chemistry 280, 24 (2005): 22679-87. [PubMed Link] | [ Full text ]
- Zhang, X.;Lester, R.L.;Dickson, R.C. "Pil1p and Lsp1p negatively regulate the 3-phosphoinositide-dependent protein kinase-like kinase Pkh1p and downstream signaling pathways Pkc1p and Ypk1p." The Journal of biological chemistry 279, 21 (2004): 22030-8. [PubMed Link] | [ Full text ]
- Hearn, J.D.;Lester, R.L.;Dickson, R.C. "The uracil transporter Fur4p associates with lipid rafts." The Journal of biological chemistry 278, 6 (2003): 3679-86. [PubMed Link] | [ Full text ]
- Chung, J.H.;Lester, R.L.;Dickson, R.C. "Sphingolipid requirement for generation of a functional v1 component of the vacuolar ATPase." The Journal of biological chemistry 278, 31 (2003): 28872-81. [PubMed Link] | [ Full text ]
- Ferguson-Yankey, S.R.;Skrzypek, M.S.;Lester, R.L.;Dickson, R.C. "Mutant analysis reveals complex regulation of sphingolipid long chain base phosphates and long chain bases during heat stress in yeast." Yeast (Chichester, England) 19, 7 (2002): 573-86. [PubMed Link] | [ Full text ]
- Dickson, R.C.;Lester, R.L. "Sphingolipid functions in Saccharomyces cerevisiae." Biochimica et biophysica acta 1583, 1 (2002): 13-25. [PubMed Link] | [ Full text ]
- Hait, N.C.;Fujita, K.;Lester, R.L.;Dickson, R.C. "Lcb4p sphingoid base kinase localizes to the Golgi and late endosomes." FEBS letters 532, 1-2 (2002): 97-102. [PubMed Link] | [ Full text ]