G.J. Brewer

Numerous reports document the decline in various aspects of mitochondrial function with physiological aging as well as the pathologic aging seen in Alzheimer’s disease, but remains unclear whether these deficits are the immediate response to an aging environment and the degree of their reversibility. By isolating neurons from the brains of rats and mice across the age-span and culturing them in a uniform environment, we eliminate the confounds of aging hormonal, vascular and immune systems. We find that a number of physiologic parameters related to mitochondrial function remain normal at rest in neurons from old animals, but these neurons reveal marked deficits when stressed. Functions that were similar in old and middle-age neurons at rest include glucose uptake, ATP levels, mitochondrial redox state and mitochondrial basal respiration. At rest, intracellular calcium and ROS levels were higher, while mitochondrial membrane potential and redox buffer glutathione were lower in old compared to middle-age neurons. Under metabolic stress from glutamate, rotenone, or the Alzheimer peptide A-beta, old neurons showed functional deficits in glucose uptake, ATP levels, respiratory capacity, NAD(P)H, cytochrome C levels, mitochondrial membrane potential, redox state and epigenetic histone acetylation and methylation. Remarkably, a brief treatment with 17-beta-estradiol reversed the dysfunctional old neuron baseline and glutamate-evoked increases in calcium with an EC50 200 fM as well as the deficits in complex IV, respiratory capacity and oxidized cardiolipin. Additionally, glutathione and ROS deficits in old neurons could be prevented by treatment with blueberry extract. Similarly, low glutathione and high ROS levels in Alzheimer transgenic mouse neurons could be reversed by a 15 hr. treatment with the NAD precursor nicotinamide (vitamin B3). The histone marks were rapidly reversed by histone deacetylase and methyltransferase inhibitors that rejuvenated levels of memory-essential BDNF. These observations suggest that critical deficits in aging mitochondrial function may be reversible by metabolic agents that target the NADH substrate of oxidative phosphorylation, rejuvenate complex IV and restore youthful histone epigenetics. Patel, J.R. (2003) Age-related changes in neuronal glucose uptake in response to glutamate and beta-amyloid J. Neurosci. Res.72:527-536.PM:12704814 Brewer,G.J.; Reichensperger,J.D.; Brinton,R.D. 2006. Prevention of age-related dysregulation of calcium dynamics by estrogen in neurons, Neurobiology of Aging 27:306-317. PM:15961189 Parihar, M.S., Brewer, G.J. 2007. Simultaneous age-related depolarization of mitochondrial membrane potential and increased mitochondrial ROS production correlate with age-related glutamate excitotoxicity in rat hippocampal neurons, J. Neuroscience Res. 85:1018-1032. PM:17335078. Parihar, M.S., Kunz, E., Brewer, G.J. 2008. Age-related decreases in NAD(P)H and glutathione cause redox declines before ATP loss during glutamate treatment of hippocampal neurons. J. Neurosci. Res. 86:2339-2352 PM:18438923. Jones, T.T. and Brewer, G.J. 2009. Critical age-related loss of cofactors of neuron cytochrome C oxidase reversed by estrogen. Exp. Neurology, 215:212-219. PM:18930048 PMCID:3018880 Brewer, G.J. Lindsey, A.L. Kunz, E.Z. Torricelli, J.R. Neuman, A. Fisher, D.R. Joseph, J.A. 2010. Age-related toxicity of β-amyloid associated with increased pERK and pCREB in primary hippocampal neurons: reversal by blueberry extract. J. Nutr. Biochem. 21:991-998. PM:19954954 PMCID: 2891857 Jones, T.T. and Brewer, G.J. 2010. Age-related deficiencies in complex I endogenous substrate availability and reserve capacity of complex IV in cortical neuron electron transport. Biochim. Biophys. Acta Bioenergetics, 1797:167-176. PMCID: PMC2812684. PMCID: 2812684 Ghosh, D. and Brewer, G.J., in preparation. Walker, M.D. and Brewer, G.J., submitted.

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