Van Remmen H. Reduced mitochondrial ROS, enhanced antioxidant defense, and distinct age-related changes in oxidative damage in muscles of long-lived Peromyscus leucopus. Am J Physiol Regul Integr Comp Physiol 304: R343-R355, 2013. First published January 16, 2013 doi:10.1152/ajpregu.00139.2012.-Comparing biological processes in closely related species with divergent life spans is a powerful approach to study mechanisms of aging. The oxidative stress hypothesis of aging predicts that longer-lived species would have lower reactive oxygen species (ROS) generation and/or an increased antioxidant capacity, resulting in reduced oxidative damage with age than in shorter-lived species. In this study, we measured ROS generation in the young adult animals of the long-lived white-footed mouse, Peromyscus leucopus (maximal life span potential, MLSP ϭ 8 yr) and the common laboratory mouse, Mus musculus (C57BL/6J strain; MLSP ϭ 3.5 yr). Consistent with the hypothesis, our results show that skeletal muscle mitochondria from adult P. leucopus produce less ROS (superoxide and hydrogen peroxide) compared with M. musculus. Additionally, P. leucopus has an increase in the activity of antioxidant enzymes superoxide dismutase 1, catalase, and glutathione peroxidase 1 at young age. P. leucopus compared with M. musculus display low levels of lipid peroxidation (isoprostanes) throughout life; however, P. leucopus although having elevated protein carbonyls at a young age, the accrual of protein oxidation with age is minimal in contrast to the linear increase in M. musculus. Altogether, the results from young animals are in agreement with the predictions of the oxidative stress hypothesis of aging with the exception of protein carbonyls. Nonetheless, the age-dependent increase in protein carbonyls is more pronounced in short-lived M. musculus, which supports enhanced protein homeostasis in longlived P. leucopus. Peromyscus leucopus; mitochondria; reactive oxygen species; skeletal muscle; oxidative damage; comparative biology of aging MAMMALIAN LIFE SPAN RANGES a hundred-fold, and comparative studies on long-lived animals can offer insights into key cellular mechanism(s) that may contribute to successful aging and longevity. The white-footed mouse, Peromyscus leucopus (Rodentia: Cricetidae), is one of the most common rodent species residing in North America. Both P. leucopus and the commonly used laboratory mouse, Mus musculus, belong to the superfamily Muridae and closely resemble each other in both body size and physical appearance. Yet P. leucopus can live more than 8 yr in captivity (35, 54), while the C57BL/6J strain of M. musculus lives up to 3.5 yr under standard laboratory conditions (Jax.org).In comparative aging studies, it is important to account for the effect of body size on species longevity, and it is calculated using the longevity quotient (LQ), which is the ratio of observed maximum life span as a function of that predicted allometrically using the equation ( Long-lived P. leucopus has caught the attention of biogerontolo...