Our goal is to establish a mechanism for failure of aging brain mitochondria to produce enough energy during stress, mitoenergetic failure. Without stress, we have recent evidence that mitochondria from old rat neurons in culture promote normal neuron survival, normal regeneration, normal glucose uptake and normal respiration, but do so with decrepit mitochondria which fail to upregulate energy production under stress. Compared to middle-age neurons, old neuron mitochondria are considerably depolarized, produce higher levels of ROS with lower glutathione antioxidant and maintain a more oxidized redox potential [ NAD(P)H / FAD ], all of which contribute to increased susceptibility to toxic stressors such as glutamate and beta-amyloid. Now we will use a well-established model of Alzheimer disease, LaFerla's 3xTg-AD mouse to test our hypothesis that redox potential and mitoenergetic function are impaired early in 3xTg-AD mice, compared to wild-type mice of the same age, but similar to old wild-type mice. More specifically, we hypothesize that an oxidized redox potential develops early during aging and causes a mitochondrial metabolic shift to begin a vicious cycle of insulin resistance, inhibited mitochondrial turnover and slothful energetics all of which are enforced by epigenetic mechanisms. To focus on the intrinsic neuronal differences with age, isolated from hormonal, vascular and immunologic aging, we will continue to culture neurons from these adult mice in a common culture condition. Neuron cultures also provide greater power for larger samples during exposure to varying concentrations of glutamate stress. In this mouse model of AD, Aim 1 will establish upstream causes of mitochondrial dysfunction as more oxidized redox potential and depolarized mitochondria, an age-related increase in ROS and lower glutathione.
Aim 2 will evaluate a mechanistic basis for mitoenergetic failure as an age-related increase in insulin signaling and decrease in transcriptional activators in the peroxisome proliferator family, especially PGC1a, PPAR? and NRF, also known to stimulate mitochondrial biogenesis. Since changes in mitochondrial function with age persist in culture, in Aim 3, we will test the hypothesis that premature aging of mitochondria is controlled by either a) the efficiency of autophagy for turnover of decrepit mitochondria or b) epigenetic controls of histone acetylation and CpG methylation. This work is a collaboration between an aging mitochondria and neuron culture expert, Greg Brewer, a mouse aging expert, Andrzej Bartke and an insulin signaling transcription aging expert, Michal Masternak, all at Southern Illinois University School of Medicine. Overall, completion of these experiments should provide definitive mechanistic evidence for age-related control of mitochondrial energetics and insulin sensitivity critical for resistance to stressors with age.
The overall goal of the proposed work is to determine the mechanism of action of aging within mitochondria of neurons in the aging brain. Once specific targets are identified, then appropriate behavioral, nutraceutical or pharmacological proscriptions can be developed. These issues are critical to the aging population in the U.S. who will constitute 23% of the population in 2040, 70 million people. 13 million of these people are expected to have Alzheimer disease with expected health care costs of $250 billion.
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