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Training Grant-
Biology of Aging

Tomas Prolla

Tomas A. Prolla

Ph.D., Yale University
Professor, Department of Genetics

Genetic Characterization of Mammalian DNA Repair Pathways

Our laboratory is interested in understanding the role of eucaryotic DNA repair pathways in cancer and aging. Our primary experimental approach is the use of gene targeting in embryonic stem (ES) cells to discover gene function and to generate mouse models of human diseases. Mice carrying engineered mutations will be a valuable tool in the design of new approaches to cancer treatment and prevention. Most of our current work involves the DNA mismatch repair genes Msh2, Mlh1, Pms2 and Pms1. Mutations in these genes in humans result in hereditary colon cancer, the most common human inherited cancer syndrome. We are also investigating specific functions of individual DNA mismatch repair proteins in the correction of DNA replication errors and additional roles of DNA mismatch proteins, such as cell cycle control in response to DNA damage, genetic recombination and resistance to chemotherapeutic drugs. Since DNA mismatch repair deficient mice display greatly elevated nuclear mutation rates, they provide an excellent model to study the consequences of the accumulation of mutations on aging parameters. We are also investigating the effect of specific DNA lesions in aging parameters, by generating mice deficient for a variety of DNA repair enzymes. Our goal is to determine the relevance of different DNA repair pathways to cancer and aging.

Another area that we have targeted is cancer chemoprevention, since this area of research will revolutionize the cancer field within the next decade. We are using Mlh1 deficient mice, which develop both intestinal tumors and lymphomas, to determine the role of promising compounds in cancer chemoprevention. The first compound that we have selected for our studies is the mineral selenium. Many epidemiological studies suggest that dietary selenium intake is inversely correlated with human carcinogenesis. Recently, a double-blind study using moderate doses of Se has demonstrated a significant reduction in human cancer incidence at several sites, including lung, prostate and intestine. Obviously, understanding the mechanism of action of Se in chemoprevention will have a strong impact in cancer research in general. Surprisingly, there is no clear evidence supporting a specific mechanism of action of selenium in cancer prevention. We are using the Mlh1 and Min mouse models of hereditary colon cancer in order to elucidate the role of selenium in a model system that is highly relevant to human cancer, and to search for mechanisms of action. Findings from these studies may allow the rational design of compounds that are even more powerful in achieving tumor suppression, having broad implications in the general area of cancer prevention. Additionally, we are studying how dietary selenium and Vitamin E status modulate oxidative damage to DNA and aging parameters in the mouse.

Representative Publications
Someya, S., Kujoth, G. C., Kim, M. J., Hacker, T. A., Vermulst, M., Weindruch, R., & Prolla, T. A. (2017). Effects of calorie restriction on the lifespan and healthspan of POLG mitochondrial mutator mice. PLoS One, 12(2), e0171159.
View publication via DOI: DOI:10.1371/journal.pone.0171159

Han, C., Linser, P., Park, H. J., Kim, M. J., White, K., Vann, J. M., ... Prolla, T. A. ... Someya, S. (2016). Sirt1 deficiency protects cochlear cells and delays the early onset of age-related hearing loss in C57BL/6 mice. Neurobiolog of Aging, 43, 58-71.
View publication via DOI: DOI:10.1016/j.neurobiolaging.2016.03.023

Safdar, A., Khrapko, K., Flynn, J. M., Saleem, A., De Lisio, M., Johnston, A. P., ... Prolla, T. A. ... Tarnopolsky, M. A. (2016). Exercise-induced mitochondrial p53 repairs mtDNA mutations in mutator mice. Skeletal Muscle, 6, 7.
View publication via DOI: DOI:10.1186/s13395-016-0075-9

Barger, J. L., Anderson, R. M., Newton, M. A., da Silva, C., Vann, J. A., Pugh, T. D., Someya, S., Prolla, T. A., & Weindruch, R (2015). A conserved transcriptional signature of delayed aging and reduced disease vulnerability is partially mediated by SIRT3. PLoS One, 10(4), e0120738.
View publication via DOI: DOI:10.1371/journal.pone.0120738

Li-Harms, X., Milasta, S., Lynch, J., Wright, C., Joshi, A., Iyengar, R., Neale, G., Wang, X., Wang, Y. D., Prolla, T. A., Thompson, J. E., Opferman, J. T., Green, D. R., Schuetz, J., & Kundu, M. (2015). Mito-protective autophagy is impaired in erythroid cells of aged mtDNA-mutator mice. Blood, 125(1), 162-174.
View publication via DOI: DOI:10.1182/blood-2014-07-586396

Dittenhafer-Reed, K. E., Richards, A. L., Fan, J., Smallegan, M. J., Fotuhi Siahpirani, A., Kemmerer, Z. A., Prolla, T. A., Roy, S., Coon, J. J., & Denu, J. M. (2015). SIRT3 mediates multi-tissue coupling for metabolic fuel switching. Cell Metabolism, 21(4), 637-646.
View publication via DOI: DOI:10.1016/j.cmet.2015.03.007

Orogo, A. M., Gonzalez, E. R., Kubli, D. A., Baptista, I. L., Ong, S. B., Prolla, T. A., Sussman, M. A., Murphy, A. N., & Gustafsson, A. B. (2015). Accumulation of mitochondrial DNA mutations disrupts cardiac progenitor cell function and reduces survival. Journal of Biological Chemistry, 290(36), 22061-22075.
View publication via DOI: DOI:10.1074/jbc.M115.649657

Safdar, A., Khrapko, K., Flynn, J. M., Saleem, A., De Lisio, M., Johnston, A. P., ... Prolla, T. A., & Tarnopolsky, M. A. (2015). Exercise-induced mitochondrial p53 repairs mtDNA mutations in mutator mice. Skeletal Muscle, 6, 7.
View publication via DOI: DOI:10.1186/s13395-016-0075-9

Taylor, S. D., Ericson, N. G., Burton, J. N., Prolla, T. A., Silber, J. R., Shendure, J., & Bielas, J. H. (2014). Targeted enrichment and high-resolution digital profiling of mitochondrial DNA deletions in human brain. Cell, 13(1), 29-38.
View publication via DOI: DOI:10.1111/acel.12146

Dai, Y., Clark, J., Zheng, K., Kujoth, G. C., Prolla, T. A., & Simon, D. K. (2014). Somatic mitochondrial DNA mutations do not increase neuronal vulnerability to MPTP in young POLG mutator mice. Neurotoxicology and Teratology, 46, 62-67.
View publication via DOI: DOI:10.1016/j.ntt.2014.10.004

Fuke, S., Kametani, M., Yamada, K., Kasahara, T., Kubota-Sakashita, M., Kujoth, G. C., Prolla, T. A., Hitoshi, S., & Kato, T. (2014). Heterozygous polg mutation causes motor dysfunction due to mtDNA deletions. Annals of Clinical and Translational Neurology, 1(11), 909-920.
View publication via DOI: DOI:10.1002/acn3.133

Hsu, K. T., Yu, X. M., Audhya, A. W., Jaume, J. C., Lloyd, R. V., Miyamoto, S., Prolla, T. A., & Chen, H. (2014). Increased mtDNA mutations with aging promotes amyloid accumulation and brain atrophy in the APP/Ld transgenic mouse model of Alzheimer's disease. Molecular Neurodegeneration, 9, 16.
View publication via DOI: DOI:10.1186/1750-1326-9-16

Prolla, T. A., & Denu, J. M. (2014). NAD+ deficiency in age-related mitochondrial dysfunction. Cell Metabolism, 19(2), 178-180.
View publication via DOI: DOI:10.1016/j.cmet.2014.01.005

Hebert, A.S., Dittenhafer-Reed, K.E., Yu, W., Bailey, D.J., Selen, E.S., Boersma, M.D., ... Pagliarini, D.J., Prolla, T.A., ... Coon, J.J. (2013). Calorie Restriction and SIRT3 Trigger Global Reprogramming of the Mitochondrial Protein Acetylome. Molecular Cell, 49(1), 186-99.
View publication via DOI: DOI:10.1016/j.molcel.2012.10.024

Collino, S., Martin, F.-P., Montoliu, I., Barger, J., DaSilva, L., Prolla, T., Weindruch, R., Kochhar, S. (2013). Transcriptomics and metabonomics identify essential metabolic signatures in caloric restriction regulation across multiple mouse strains. Metabolites, 3(4), 881-911.
View publication via DOI: DOI:10.3390/metabo3040881

Joseph, A. M., Adhihetty, P. J., Wawrzyniak, N. R., Wohlgemuth, S. E., Picca, A., Kujoth, G. C., . . . Prolla, T. A., & Leeuwenburgh, C. (2013). Dysregulation of mitochondrial quality control processes contribute to sarcopenia in a mouse model of premature aging. PLoS One, 8(7), e69327.
View publication via DOI: DOI:10.1371/journal.pone.0069327

Dai, Y., Kiselak, T., Clark, J., Clore, E., Zheng, K., Cheng, A., . . . Prolla, T. Am., . . . Simon, D. K. (2013). Behavioral and metabolic characterization of heterozygous and homozygous polg mutator mice. Mitochondrion, 13(4), 282-291.
View publication via DOI: DOI:10.1016/j.mito.2013.03.006

Ahlqvist, K. J., Hamalainen, R. H., Yatsuga, S., Uutela, M., Terzioglu, M., Gotz, A., ... Prolla, T., Trifunovic, A., & Suomalainen, A. (2012). Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. Cell Metabolism, 15(1), 100-109.
View publication via DOI: DOI:10.1016/j.cmet.2011.11.012

Barger, J. L., Kayo, T., Pugh, T. D., Vann, J. A., Power, R., Dawson, K., ... Prolla, T. A. (2012). Gene expression profiling reveals differential effects of sodium selenite, selenomethionine, and yeast-derived selenium in the mouse. Genes Nutr, 7(2), 155-165.
View publication via DOI: DOI:10.1007/s12263-011-0243-9

Dillon, L. M., Hida, A., Garcia, S., Prolla, T. A., & Moraes, C. T. (2012). Long-term bezafibrate treatment improves skin and spleen phenotypes of the mtDNA mutator mouse. PLoS ONE, 7(9), e44335.
View publication via DOI: DOI:10.1371/journal.pone.0044335

Dillon, L. M., Williams, S. L., Hida, A., Peacock, J. D., Prolla, T. A., Lincoln, J., & Moraes, C. T. (2012). Increased mitochondrial biogenesis in muscle improves aging phenotypes in the mtDNA mutator mouse. Human Molecular Genetics, 21(10), 2288-2297.
View publication via DOI: DOI:10.1093/hmg/dds049

Fox, R. G., Magness, S., Kujoth, G. C., Prolla, T. A., & Maeda, N. (2012). Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption. American Journal of Physiology. Gastrointestinal and Liver Physiology, 302(9), G914-924.
View publication via DOI: DOI:10.1152/ajpgi.00402.2011

Hallows, W.C., Yu, W., Smith, B.C., Devires, M.K., Ellinger, J., Someya, S., Shortreed, M., Prolla, T.A. ... Denu, JM. (2011). Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Molecular Cell, 41(2), 139-149.
View publication via DOI: DOI:10.1016/j.molcel.2011.01.002

Fox, R., Kim, H. S., Reddick, R. L., Kujoth, G. C., Prolla, T. A., Tsutsumi, S., . . . Maeda, N. (2011). Mitochondrial DNA polymerase editing mutation, PolgD257A, reduces the diabetic phenotype of akita male mice by suppressing appetite. Proceedings of the National Academy of Sciences of the United States of America, 108(21), 8779-8784.
View publication via DOI: DOI:10.1073/pnas.1106344108

Safdar, A., Bourgeois, J. M., Ogborn, D. I., Little, J. P., Hettinga, B. P., Akhtar, M., ... Prolla, T. A., & Tarnopolsky, M. A. (2011). Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proceedings of the National Academy of Sciences of the United States of America, 108(10), 4135-4140.
View publication via DOI: DOI:10.1073/pnas.1019581108

Someya, S., Tanokura, M., Weindruch, R., Prolla, T.A., & Yamasoba, T. (2010). Effects of caloric restriction on age-related hearing loss in rodents and rhesus monkeys. Current Aging Science, 3(1), 20-25.
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Hiona, A., Sanz, A., Kujoth, GC., Pamplona, R., Seo, AY., Hofer, T., Someya, S., Miyagawa, T., Nakayama, C., Samhan-Arias, AK., Servais, S., Portero-Otin, M., Tanokura, M., Prolla, T.A., & Leeuwenburgh, C. (2010). Mitochondrial DNA mutations induce mitochondrial dysfunction, supression of nuclear encoded mitochondrial genes, apoptosis and sarcopenia in skeletal muscle. PLoS One 5, e11468.

Someya, S., & Prolla, T.A. (2010). Mitochondrial oxidative damage and apoptosis in age-related hearing loss. Mechanisms of Ageing and Development, 131, 480-486.
View publication via DOI: DOI:10.1016/j.mad.2010.04.006

Someya, S., Prolla, T.A., & Tanokura, M. (2010). Effects of functional antioxidants on age-related hearing loss. In D. Bagchi, F. C. Lau, & D. K. Ghosh (Eds.), Biotechnology in functional foods and nutraceuticals (pp. 113-124). CRC Press.

Someya, S., Yu, W., Hallows, W.C., Xu, J., Vann, J.M., Leeuwenburgh, C., Tanokura, M., Denu, J.M. & Prolla, T.A. (2010). Mitochondrial Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell, 143, 802-812.
View publication via DOI: DOI:10.1016/j.cell.2010.10.002

Someya, S., Xu, J., Kondo, K., Ding, D., Salvi, R.J., Yamasoba, T., Rabinovitch, P.S., Weindruch, R., Leeuwenburgh, C., Tanokura, M., & Prolla, T.A. (2009). Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis. Proceedings of the National Academy of Sciences, 106(46), 19432-19437.
View publication via DOI: DOI:10.1073/pnas.0908786106

Park, S.K., Kim, K., Page, G.P., Allison, D.B., Weindruch, R., & Prolla, T.A. (2009). Gene expression profiling of aging in multiple mouse strains: Identification of aging biomarkers and impact of dietary antioxidants. Aging Cell, 8(4), 484-495.
View publication via DOI: DOI:10.1111/j.1474-9726.2009.00496.x

Anderson, R.M., Barger, J.L., Edwards, M.G., Braun, K.H., O'Connor, C.E., Prolla, T.A., & Weindruch, R. (2008). Dynamic regulation of PGC-1alpha localization and turnover implicates mitochondrial adaptation in longevity and the stress response. Aging Cell, 7, 10.
View publication via DOI: DOI:10.1111/j.1474-9726.2007.00357.x

Barger, J.L., Kayo, T., Pugh, T.D., Prolla, T.A., & Weindruch, R. (2008). Short-term consumption of a resveratrol-containing nutraceutical mixture mimics gene expression of long-term caloric restriction in mouse heart. Experimental Gerontology, 43(9), 859-86.
View publication via DOI: DOI:10.1016/j.exger.2008.06.013

Someya, S., Yamasoba, T., Kujoth, G.C., Pugh, T.D., Weindruch, R., Tanokura, M., & Prolla, T.A. (2008). The role of mtDNA mutations in the pathogenesis of age-related hearing loss in mice carrying a mutator DNA polymerase gamma. Neurobiology of Aging, 29(7), 1080-109.
View publication via DOI: DOI:10.1016/j.neurobiolaging.2007.01.014

Park, S.K., Page, G.P., Kim, K., Allison, D.B., Meydani, M., Weindruch, R., & Prolla, T.A. (2008). Alpha- and gamma-tocopherol prevent age-related transcriptional alterations in the heart and brain of mice. Journal of Nutrition, 138(6), 1010-1018.

Barger, J.L., Kayo, T., Vann, J.M., Arias, E.B., Wang, J., Hacker, T.A., Wang, Y., Raederstorff, D., Morrow, J.D., Leeuwenburgh, C., Allison, D.B., Saupe, K.W., Cartee, G.D., Weindruch, R., & Prolla, T.A. (2008). A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE, 3(6), e2264.
View publication via DOI: DOI:10.1371/journal.pone.0002264

Edwards, M.G., Anderson, R.M., Yuan, M., Kendziorski, C., Weindruch, R., & Prolla, T.A. (2007). Gene expression profiling of aging reveals activation of a p53-mediated transcriptional program. BMC Genomics, 8, 80.
View publication via DOI: DOI:10.1186/1471-2164-8-80

Someya, S., Yamasoba, T., Prolla, TA., & Tanokura, M. (2007). Genes encoding mitochondrial respiratory chain components are profoundly down-regulated with aging in the cochlea of DBA/2J mice. Brain Research, 26, 26-33.

Someya, S., Yamasoba, T., Weindruch, R., Prolla, T.A., & Tanokura, M. (2007). Caloric restriction suppresses apoptotic cell death in the mammalian cochlea and leads to prevention of presbycusis. Neurobiology of Aging, 28, 1613-1622.
View publication via DOI: DOI:10.1016/j.neurobiolaging.2006.06.024

Yamasoba, T., Someya, S., Yamada, C., Weindruch, R., Prolla, TA., & Tanokura, M. (2007). Role of mitochondrial dysfunction and mitochondrial DNA mutations in age-related hearing loss. Hearing Research, 26, 185-193.
View publication via DOI: DOI:10.1016/j.heares.2006.06.004

Lee, C.K., Allison, D.B., Brand, J., Weindruch, R., & Prolla, T.A. (2002). Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts. Proc. Natl. Acad. Sci. USA, 99, 14988-14993.
View publication via DOI: DOI:10.1073/pnas.232308999

Kayo, T., Allison, D.B., Weindruch, R., & Prolla, T.A. (2001). Influences of aging and caloric restriction on the transcriptional profile of skeletal muscle from rhesus monkeys. Proc. Natl. Acad. Sci. USA, 98, 5093-5098.
View publication via DOI: DOI:10.1073/pnas.081061898

Lee, C.K., Weindruch, R., & Prolla, T.A. (2000). Gene expression profile of the aging brain in mice. Nat. Genet., 25, 294-297.
View publication via DOI: DOI:10.1038/77046

Lee, C.K., Klopp, R.G., Weindruch, R., & Prolla, T.A. (1999). Gene expression profile of aging and its retardation by caloric restriction. Science, 285, 1390-1393.
View publication via DOI: DOI:10.1126/science.285.5432.1390

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