|
Molecular
Biology of Aging
We
have initiated genome-wide screens to identify yeast genes that
regulate aging. Having identified these genes, we are attempting to
determine the level of conservation of aging pathways among different
eukaryotic aging model systems (worms and mice) by testing the
longevity phenotypes of their orthologs. These large scale studies are
made possible by a grant from the Ellison Medical Foundation and in
collaboration with a number of scientists at the University of
Washington, including Stan Fields, Matt Kaeberlein, Warren Ladiges,
George Martin, Peter Rabinovitch, and Jim Thomas. See http://www.pathology.washington.edu/research/bioage/ellison/
for more information.
We
also seek to identify the molecular pathways that coordinate yeast
longevity. Ultimately we hope to understand all major aging pathways in
yeast and to determine whether they are acting similarly in mammals. Of
particular interest are the pathways which are required for life span
extension by calorie restriction. Calorie restriction (CR) is the only
intervention known to increase life-span in yeast, worms, flies, and
mammals, but the molecular mechanism for this phenomenon remains
mysterious. By understanding calorie restriction in yeast, we hope to
develop hypothesis that can be tested in multicellular eukaryotes
including mammals.
Selected Publications
Kaeberlein M, Powers RW III, Steffen KK, Westman EA, Hu D, Dang N, Kerr EO, Kirkland KT, Fields S, Kennedy BK (2005). Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193-6.
Kaeberlein M, Hu D, Kerr EO, Tsuchiya M, Westman EA, Dang N, Fields S, Kennedy BK (2005). Increased life span due to calorie restriction in respiratory-deficient yeast. PLoS Genet. 1, e69 [epub ahead of print].
Kennedy BK (2005). The enigmatic role of Sir2 in aging. Cell 123, 548-50.
Kudlow BA, Jameson SA, and Kennedy BK. HIV protease inhibitors block adipocyte differentiation independently of lamin A/C. AIDS 19: 1565-1573.
Barbie DA, Conlan LA, and Kennedy BK. 2005. Nuclear tumor suppressors in space and time. Trends Cell Biol. 15: 378-385.
Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman EA, Caldwell S, Napper A, Curtis R, DiStefano PS, Fields S, Bedalov A, and Kennedy BK (2005) Substrate specific activation of sirtuins by resveratrol. J. Biol. Chem. 280:17039-17045.
Smith
ED, Kudlow BA, Frock RL and Kennedy BK (2005) A-type nuclear lamins, progerias and other degenerative disorders. Mech. Ageing Dev. 126: 447-460.
Kaeberlein, M, Kirkland KT, Fields S, and Kennedy BK (2005) Genes determining yeast replicative life span in a long-lived genetic
background. Mech. Ageing Dev. 126: 491-504.
Huang S, Kennedy BK, and Oshima, J. 2005. LMNA mutations in progeroid syndromes. Novartis Found. Symp. 264:197-202.
Kaeberlein M and Kennedy BK (2005) Large-scale identification in yeast of conserved ageing genes. Mech. Ageing Dev. 126: 17-21.
Johnson BR, Nitta R, Frock RL, Mounkes L, Barbie DA, Stewart C,
Harlow E, and Kennedy BK (2004) A-type lamins regulate
retinoblastoma protein function by promoting subnuclear localization
and preventing proteasomal degradation. Proc. Natl. Acad. Sci., USA
101: 9677-9682.
Kaeberlein M, Kirkland KT, Fields S, and Kennedy BK (2004) Sir2-independent life span extension by calorie restriction in yeast.
PLoS Biology 2: 1381-1387.
Barbie DA, Kudlow BA, Frock R, Zhao J, Johnson BR, Dyson N,
Harlow E and Kennedy BK (2004) Nuclear reorganization of mammalian
DNA synthesis prior to cell cycle exit. Mol. Cell. Biol. 24: 595-607.
Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvold O, Shafeghati Y, Botha EG, Garg A, Hanson NB, Martin GM, Mian IS,
Kennedy BK, and Oshima, J (2003) LMNA mutations in atypical Werner's
syndrome. Lancet 362: 440-445.
Kennedy BK (2002) Mammalian transcription factors in yeast: strangers in a
familiar land. Nat. Rev. Mol. Cell Biol. 3: 41-49.
Kennedy BK, Barbie DA, Classon M, Dyson N, and Harlow E. 2000.
Nuclear organization of DNA replication in primary mammalian cells.
Genes Dev. 14: 2855-68.
|