MITOCHONDRIAL UNCOUPLING AND LIFESPAN Perspective and Conclusion Aging is correlated with changes in many different processes, including DNA replication and repair, apoptotic signaling, metabolic signaling and sensing, proteasomal and lysosomal activity, ATP production, and mitochondrial coupling efficiency. The inconsistent effects of uncoupling interventions on lifespan may reflect the limitations of current experimental approaches, or that we have not adequately considered the contexts in which mild uncoupling may be most effective at modulating lifespan. For example, under optimal maintenance conditions, as in Perez et al. (2009), oxidative damage may not be the determining factor in mortality; rather, it may be the failure of other mechanisms that triggers senescence. Ultimately, is mitochondrial uncoupling beneficial or detrimental to health and longevity? The answer to this question is hampered by an incomplete understanding of both the functions of uncoupling in maintaining energy homeostasis, and the biological mechanisms of aging. However, most evidence supports a role for mild uncoupling in ROS attenuation, and also in maintaining nutrient and energy homeostasis, both of which are likely important for optimizing lifespan. Conversely, when homeostasis is disrupted, as in insulin insensitivity, uncoupling may exacerbate dysfunction. An increased understanding of aging, the functions and physiological roles of the uncoupling proteins, as well as the development of targetable chemical uncouplers, could further the use of uncoupling as a therapeutic strategy to maintain healthy aging.
Posted on: Sat, 27 Jul 2013 18:02:19 +0000