Biological aging is one of the greatest enigmas of the life sciences. While the aging process is ubiquitous in nature, maximum lifespans for different organisms vary widely from a day for the mayfly, to over one thousand years for the bristlecone pine. For model organisms such as yeast, worms, and flies, both lifespan and the onset of age-associated phenotypic changes can be altered experimentally in the laboratory. For mammals such as humans, aging is marked by a complex series of declines in physiological function, and an increase in the incidence of diseases such as cancer, Alzheimer’s, and diabetes.
The goal of the Hubbard lab is to identify pharmacological agents to prevent and treat age-related diseases, and promote longevity. To accomplish this objective, we develop biochemical assays to report on the activity of central longevity pathways, and decompose specific aspects of age-related disease into in vitro systems. Using high-throughput small molecule screening and macromolecular protein engineering and evolution, we then attempt to identify agents that can perturb these systems. Positive hits are investigated in vivo for potential therapeutic value, and as tools to garner further insight into the mechanisms underlying age-related disease.
Current projects include:
1) Discovering compounds that prevent binding of SIRT1, a conserved longevity enzyme, to its endogenous inhibitor, DBC1
2) Studying the biochemistry of enzymes that mediate mitochondrial protein acetylation
3) Investigating the metal binding modes of amyloid-beta peptide, and evolving biologically active variants with altered cation preference
Van Meter M, Simon M, Tombline G, May A, Morello TD, Hubbard BP, Bredbenner K, Park R, Sinclair DA, Bohr VA, Gorbunova V and Seluanov A. (2016) JNK Phosphorylates SIRT6 to Stimulate DNA Double-Strand Break Repair in Response to Oxidative Stress by Recruiting PARP1 to DNA Breaks. Cell Rep 16(10):2641-50. PMID: 27508560.
Dai H, Ellis JL, Sinclair DA and Hubbard BP. (2016) Synthesis and Assay of SIRT1-Activating Compounds. Methods Enzymol 574:213-44. PMID: 27423864.
Hubbard BP, Badran AH, Zuris JA, Guilinger JP, Davis KM, Chen L, Tsai SQ, Sander JD, Joung JK, Liu DR. (2015) Continuous directed evolution of DNA-binding proteins to improve TALEN specificity. Nat Methods 12(10):939-42. PMID: 26258293.
Bhullar KS and Hubbard BP. (2015) Lifespan and healthspan extension by resveratrol. Biochim Biophys Acta 1852(6):1209-18. PMID: 25640851.
Hubbard BP and Sinclair DA. (2014) Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends in Pharmacological Sciences 35(3): 146-154. PMID: 24439680.
Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA. (2013) Declining NAD (+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155(7): 1624-1638. PMID: 24360282.
Biason-Lauber A, Böni-Schnetzler M, Hubbard BP, Bouzakri K, Brunner A, Cavelti-Weder C, Keller C, Meyer-Böni M, Meier DT, Brorsson C, Timper K, Leibowitz G, Patrignani A, Bruggmann R, Boily G, Zulewski H, Geier A, Cermak JM, Elliott P, Ellis JL, Westphal C, Knobel U, Eloranta JJ, Kerr-Conte J, Pattou F, Konrad D, Matter CM, Fontana A, Rogler G, Schlapbach R, Regairaz C, Carballido JM, Glaser B, McBurney MW, Pociot F, Sinclair DA, Donath MY. (2013) Identification of a SIRT1 mutation in a family with type 1 diabetes. Cell metabolism 17(3): 448-455. PMID: 23473037.
Hubbard BP, Gomes AP, Dai H, Li J, Case AW, Considine T, Riera TV, Lee JE, E SY, Lamming DW, Pentelute BL, Schuman ER, Stevens LA, Ling AJ, Armour SM, Michan S, Zhao H, Jiang Y, Sweitzer SM, Blum CA, Disch JS, Ng PY, Howitz KT, Rolo AP, Hamuro Y, Moss J, Perni RB, Ellis JL, Vlasuk GP, Sinclair DA. (2013) Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339(6124): 1216-1219. PMID: 23471411.
Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, Agarwal B, Ye L, Ramadori G, Teodoro JS, Hubbard BP, Varela AT, Davis JG, Varamini B, Hafner A, Moaddel R, Rolo AP, Coppari R, Palmeira CM, de Cabo R, Baur JA, Sinclair DA. (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell metabolism 15(5): 675-690. PMID: 22560220.