Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, WI 53706, USA.
Department of Aging and Geriatric Research, College of Medicine, Institute on Aging, Biochemistry of Aging Laboratory, University of Florida, Gainesville, FL 32610-0107, USA.
Department of Medicine and Veterans Administration Hospital, University of Wisconsin, Madison, WI 53705-2286, USA.
Department of Applied Biological Chemistry, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
Waisman Center, University of Wisconsin, Madison, WI 53705-2280, USA.
Department of Molecular Biology, Cell Biology and Biochemistry and Center for Genomics and Proteomics, Brown University, Providence, RI 02912, USA.
Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
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.
Department of Otolaryngology, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
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.