Ph.D., Yale University, 1994
Postdoctoral Research: Baylor College of Medicine
Address: 3430 Genetics/Biotech
Department: Genetics and Medical Genetics
DNA repair, cancer and the aging process
Human and Mammalian
research program is focused on understanding the molecular basis of the aging
process and its retardation by caloric restriction. Our studies have uncovered a central role for
mitochondria and energy metabolism in both aging and its retardation by caloric
use the mouse as model system and most of our studies are based on the
construction of mouse models of accelerated or retarded aging. We generate
these models through the use of gene targeting in ES cells, as well as transgenic
animal construction. An example of such work from our Laboratory is a widely
used model of age-related mitochondrial dysfunction, mice deficient in the
exonuclease domain of the mitochondrial
DNA polymerase gamma (PolgD257A).
We have previously used DNA microarrays to shown that caloric restriction leads to a “metabolic reprogramming” at the transcriptional level. Our more recent studies have focused on the role of the sirtuin SIRT3 in mediating the beneficial effects of caloric restriction in aging, including such metabolic reprogramming. SIRT3 is a NAD+ dependent deacetylase located in the mitochondrial matrix that induces metabolic shifts in response to caloric restriction. Such metabolic shifts appear to increase oxidative stress resistance and prevent an increase in age-related apoptosis. We are investigating if this metabolic adaptation underlies the beneficial effects of caloric restriction in age-related diseases as well as age-related physiological declines. The long-term goal of our studies is to identify critical pathways in aging and find either natural or synthetic compounds that modulate such pathways in a favorable manner.
Dillon LM, Williams SL, Hida A, Peacock JD, Prolla TA, Lincoln J, Moraes CT. Increased
mitochondrial biogenesis in muscle improves aging phenotypes in the mtDNA
mutator mouse. Hum Mol Genet.21:2288-97, 2012.
Hiona A, Sanz A, Kujoth GC, Pamplona R, Seo AY, Hofer T, Someya S, Miyakawa T, Nakayama C, Samhan-Arias AK, Servais S, Barger JL, Portero-Otín M, Tanokura M, Prolla TA, Leeuwenburgh C. Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice. PLoS One. 7;5(7):e11468, 2010.
Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, Tanokura M, Denu JM, Prolla TA. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell;143:802-12, 2010.
Someya S, Xu J, Kondo K, Ding D, Salvi RJ, Yamasoba T, Rabinovitch PS, Weindruch R, Leeuwenburgh C, Tanokura M, Prolla TA. Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis. Proc. Natl. Acad. Sci. USA. 106:19432-7, 2009.
Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science. 309:481-4, 2005.