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Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging

Science
15 Jul 2005
Vol 309, Issue 5733
pp. 481-484

Abstract

Mutations in mitochondrial DNA (mtDNA) accumulate in tissues of mammalian species and have been hypothesized to contribute to aging. We show that mice expressing a proofreading-deficient version of the mitochondrial DNA polymerase g (POLG) accumulate mtDNA mutations and display features of accelerated aging. Accumulation of mtDNA mutations was not associated with increased markers of oxidative stress or a defect in cellular proliferation, but was correlated with the induction of apoptotic markers, particularly in tissues characterized by rapid cellular turnover. The levels of apoptotic markers were also found to increase during aging in normal mice. Thus, accumulation of mtDNA mutations that promote apoptosis may be a central mechanism driving mammalian aging.

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We thank J. Warren for stem cell injections, S. Kinoshita for histological processing, and D. Carlson for support in mouse colony management. Supported by NIH grants AG021905 (T.A.P.), AG18922 (R.W.), AG17994 (C.L.), AG21042 (C.L.), DK48831, GM15431, and RR00095 (J.D.M.), and AG16694 (J.M.S.); by NIH training grants T32 AG00213 (G.C.K.) and T32 GM07601 (W.A.J.); and by American Heart Association predoctoral fellowship 0415166B (A.H.). R.W. and T.A.P. are founders and members of the board of LifeGen Technologies, a company focused on nutritional genomics, including the impact of nutrients and caloric restriction on the aging process.

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Information & Authors

Information

Published In

Science
Volume 309 | Issue 5733
15 July 2005

Submission history

Received: 11 March 2005
Accepted: 25 May 2005
Published in print: 15 July 2005

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Notes

Supporting Online Material
www.sciencemag.org/cgi/content/full/309/5733/481/DC1
Materials and Methods
Figs. S1 to S10

Authors

Affiliations

G. C. Kujoth
Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, WI 53706, USA.
A. Hiona
Department of Aging and Geriatric Research, College of Medicine, Institute on Aging, Biochemistry of Aging Laboratory, University of Florida, Gainesville, FL 32610-0107, USA.
T. D. Pugh
Department of Medicine and Veterans Administration Hospital, University of Wisconsin, Madison, WI 53705-2286, USA.
S. Someya
Department of Applied Biological Chemistry, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
K. Panzer
Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, WI 53706, USA.
S. E. Wohlgemuth
Department of Aging and Geriatric Research, College of Medicine, Institute on Aging, Biochemistry of Aging Laboratory, University of Florida, Gainesville, FL 32610-0107, USA.
T. Hofer
Department of Aging and Geriatric Research, College of Medicine, Institute on Aging, Biochemistry of Aging Laboratory, University of Florida, Gainesville, FL 32610-0107, USA.
A. Y. Seo
Department of Aging and Geriatric Research, College of Medicine, Institute on Aging, Biochemistry of Aging Laboratory, University of Florida, Gainesville, FL 32610-0107, USA.
R. Sullivan
Waisman Center, University of Wisconsin, Madison, WI 53705-2280, USA.
W. A. Jobling
Department of Molecular Biology, Cell Biology and Biochemistry and Center for Genomics and Proteomics, Brown University, Providence, RI 02912, USA.
J. D. Morrow
Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
H. Van Remmen
Department of Cellular and Structural Biology and Barshop Institute on Longevity and Aging Studies, University of Texas Health Center at San Antonio, San Antonio, TX 78284, USA.
J. M. Sedivy
Department of Molecular Biology, Cell Biology and Biochemistry and Center for Genomics and Proteomics, Brown University, Providence, RI 02912, USA.
T. Yamasoba
Department of Otolaryngology, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
M. Tanokura
Department of Applied Biological Chemistry, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
R. Weindruch
Department of Medicine and Veterans Administration Hospital, University of Wisconsin, Madison, WI 53705-2286, USA.
C. Leeuwenburgh
Department of Aging and Geriatric Research, College of Medicine, Institute on Aging, Biochemistry of Aging Laboratory, University of Florida, Gainesville, FL 32610-0107, USA.
T. A. Prolla* [email protected]
Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, WI 53706, USA.

Notes

*
To whom correspondence should be addressed. E-mail: [email protected]

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