PROJECT SUMMARY The purpose of this R21 proposal is to establish the effects of aging and dietary creatine treatment on the brain's bioenergetic response to injury. Traumatic brain injury (TBI) is a significant problem among older adults. Older individuals have a higher risk of sustaining a TBI, and worse outcomes than younger adults. However, very few studies have focused on how aging affects pathological mechanisms in order to develop targets for treating TBI in older patients. This study will focus on one important mechanism – bioenergetic dysfunction – since our understanding of how aging affects the brain's bioenergetic response to injury is almost entirely lacking. The specific aims of this study are 1) to establish the effects of older age on the bioenergetic response to TBI, and 2) to manipulate the bioenergetic response to TBI with oral creatine supplementation in adult and aged rats. Creatine is a promising candidate treatment due to its pleioptrophic benefits including cellular energy buffering and preservation of mitochondrial function. Our studies will use a combination of in vivo neuroimaging and ex vivo mitochondrial measures to explore the metabolic response to TBI, and to post-TBI creatine treatment, over a time course from 1-14 days post-injury. We anticipate that successful completion of these studies will provide new insights into the effects of aging on bioenergetic mechanisms of TBI, and provide the first proof-of-concept evidence of creatine benefits for brain injury in aging. Given the lack of approved treatments for TBI, a safe, low-cost dietary intervention to improve outcomes in older individuals would have a significant positive impact on TBI survivors and their families.