BBS Faculty Member - Vadim Gladyshev

Vadim Gladyshev

Department of Medicine
Division of Genetics

Brigham & Women's Hospital
New Research Building Room 435C
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: 617-525-5122
Fax: 617-525-4147
Email: vgladyshev@rics.bwh.harvard.edu
Visit my lab page here.



Mice live 3 years, dogs 15 years and humans 100 years. How does Nature change the lifespan of species? We are trying to uncover the molecular basis for natural changes in longevity by identifying adaptations in long-lived mammals and examining longevity-associated processes across all mammals. We recently sequenced and analyzed the genomes of the naked mole rat and the Brandt’s bat, as well as a number other mammals with exceptional lifespan, and uncovered some of the adaptations that contribute to their long lifespans. We also identified general gene expression and metabolic changes that associate with longer life. We suggest that inducing these longevity patterns may allow the increase of the lifespan of any mammal.

For the past couple of years, we have had an active research program on the mechanisms of aging. The causes of aging are not known, but this is a key question in biology. Delaying the aging process may allow the delay in the onset of all diseases of aging, such as cancer, diabetes and Alzheimer’s disease. We suggested that imperfectness of biological processes leads to inevitable damage accumulation causing aging. We are now characterizing properties of cumulative damage and its impact on the aging process. We also examine cancer as a disease of aging. Further understanding of the mechanisms by which organisms produce damage, deal with it and how these processes themselves deteriorate is crucial to an understanding of the aging process.

We are also trying to understand the mechanisms of redox regulation of cellular processes. Little is known on what the specific targets of reactive oxygen species are and how oxidant and antioxidant signals are transmitted in the cell. To understand mechanisms of redox control and its role in aging and cancer, we need to know identities and functions of participants in the redox process. Thus, we are developing bioinformatics approaches and carrying out genome sequencing, proteomics and functional genomics studies, which are followed with in vitro and in vivo tests of the identified targets. We are particularly interested in the redox control that involves specific and stochastic oxidation of cysteine and methionine residues in proteins. For example, we developed methods for the identification of catalytic redox active cysteines and reported that proteins can be regulated by reversible stereospecific site-specific methionine oxidation, a novel regulatory posttranslational modification.

In mammals, major redox systems are dependent on the trace element selenium, which is an essential component of various redox enzymes in thioredoxin, glutathione and methionine sulfoxide reduction pathways. Selenium is present in proteins in the form of the 21st amino acid, selenocysteine, encoded by UGA codon. Selenocysteine can be viewed as a redox “supercysteine” because it is used as the catalytic residue in oxidoreductases. Because UGA is also a stop signal, selenoprotein genes are typically misannotated in sequence databases. To overcome this problem, we identify these genes by genome-wide searches for structural and thermodynamic properties of specific RNA structures and independently by searches for selenocysteine/cysteine pairs in homologous sequences. Subsequently, we characterize functions, regulation and specific targets of selenoproteins and other oxidoreductases to gain a system-wide view on selenium metabolism and redox regulation of cellular processes.

We hope that our studies will provide a better understanding of the aging process and redox control in physiological and pathophysiological states, and will lead to new therapeutic and disease-preventive agents.



Last Update: 6/19/2014



Publications

For a complete listing of publications click here.

 


 

Fomenko DE, Xing W, Adair BM, Thomas DJ, Gladyshev VN. (2007) High-throughput identification of catalytic redox-active cysteine residues. Science 315, 387-389.

Turanov AA, Lobanov AV, Fomenko DE, Morrison HG, Sogin ML, Klobutcher LA, Hatfield DL,
Gladyshev VN. (2009) Genetic code supports targeted insertion of two amino acids by one codon. Science 323, 259-261.

Kim EB, Fang X, Fushan AA, Huang Z, Lobanov AV, Han L, Marino SM, Sun X, Turanov AA, Yang P, Yim SH, Zhao X, Kasaikina MV, Stoletzki N, Peng C, Polak P, Xiong Z, Kiezun A, Zhu Y, Chen Y, Kryukov GV, Zhang Q, Peshkin L, Yang L, Bronson RT, Buffenstein R, Wang B, Han C, Li Q, Chen L, Zhao W, Sunyaev SR, Park TJ, Zhang G, Wang J,
Gladyshev VN. (2011) Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature 479, 223-227.

Lee BC, Péterfi Z, Hoffmann FW, Moore RE, Kaya A, Avanesov A, Tarrago L, Zhou Y, Weerapana E, Fomenko DE, Hoffmann PR,
Gladyshev VN. (2013) MsrB1 and MICALs Regulate Actin Assembly and Macrophage Function via Reversible Stereoselective Methionine Oxidation. Mol. Cell 51, 397-404.

Avanesov AS, Ma S, Pierce KA, Yim SH, Lee BC, Clish CB,
Gladyshev VN. (2014) Age- and diet-associated metabolome remodeling characterizes the aging process driven by damage accumulation. eLife 3, e02077.



© 2013 by the President and Fellows of Harvard College