Our overall objective is to use the aged canine to identify effective intervention strategies to reduce age-related cognitive decline and to prevent or reverse cellular and molecular events linked to cognitive dysfunction. We have shown that a diet enriched with antioxidants (AOX), both alone and in combination with behavioral enrichment (ENR), can improve and maintain cognitive function in aged dogs. The current proposal aims to refine our understanding ofthe mechanisms responsible for improved cognition and reduced brain pathology, building on our progress from the current grant period. We have demonstrated that the treatments reduce oxidative damage, improve mitochondrial function, reduce hippocampal neuron loss, and support neurogenesis. Interestingly, our recent data suggest that p-amyloid accumulation was not a primary target of the interventions, consistent with recent studies in humans. Rather, the interventions may be targeting cell health directly by curtailing pro-degenerative pathways driven by protease cascades.
In Aim 1, we will follow up on our recent discovery that the interventions attenuate mechanisms of neuronal degeneration, in particular activation of caspase cascades.
In Aim 2, we build on the success ofthe AOX and ENR inten/entions by teasing apart and optimizing the original ENR program. We test the hypothesis that long-term exercise intervention is the predominant ENR factor driving improved cognition and reduced age-related brain dysfunction. As in vivo indices of exercise-induced changes in brain function, we will use MRI to assess changes in cerebral blood volume and grey/white matter volume, and evaluate plasma and CSF biomarkers associated with aging and cognitive decline.
In Aim 3, we will characterize the cellular and molecular changes induced in the brain by exercise to delineate mechanisms underlying cognitive improvements. A strength of the proposed design will be validation of physiological and cognitive changes assessed in vivo with post mortem histological findings so that the protocol may be applied to humans to monitor the acquired benefit of exercise for each individual. These results will be compared to our previous findings, and will allow the parcelling out of key factors contributing to successful aging.

Public Health Relevance

We propose a series of innovative studies that will have a large impact on the field of lifestyle intervention strategies to combat brain aging. We will identify interventions that improve brain health and cognitive function in a complex animal that naturally models key aspects of brain aging in humans. We will assess in vivo biomarkers of exercise-induced changes in the brain, allowing direct translation to human studies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Wagster, Molly V
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University of California Irvine
Internal Medicine/Medicine
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Snigdha, Shikha; de Rivera, Christina; Milgram, Norton W et al. (2016) Effect of mitochondrial cofactors and antioxidants supplementation on cognition in the aged canine. Neurobiol Aging 37:171-8
Snigdha, Shikha; Prieto, G Aleph; Petrosyan, Arpine et al. (2016) H3K9me3 Inhibition Improves Memory, Promotes Spine Formation, and Increases BDNF Levels in the Aged Hippocampus. J Neurosci 36:3611-22
Snigdha, Shikha; de Rivera, Christina; Milgram, Norton W et al. (2014) Exercise enhances memory consolidation in the aging brain. Front Aging Neurosci 6:3
Snigdha, Shikha; Milgram, Norton W; Willis, Sherry L et al. (2013) A preclinical cognitive test battery to parallel the National Institute of Health Toolbox in humans: bridging the translational gap. Neurobiol Aging 34:1891-901
Snigdha, Shikha; Smith, Erica D; Prieto, G Aleph et al. (2012) Caspase-3 activation as a bifurcation point between plasticity and cell death. Neurosci Bull 28:14-24
Dowling, Amy L S; Head, Elizabeth (2012) Antioxidants in the canine model of human aging. Biochim Biophys Acta 1822:685-9
Pop, Viorela; Head, Elizabeth; Berchtold, Nicole C et al. (2012) Aβ aggregation profiles and shifts in APP processing favor amyloidogenesis in canines. Neurobiol Aging 33:108-20
Snigdha, Shikha; Christie, Lori-Ann; De Rivera, Christina et al. (2012) Age and distraction are determinants of performance on a novel visual search task in aged Beagle dogs. Age (Dordr) 34:67-73
Snigdha, S; Astarita, G; Piomelli, D et al. (2012) Effects of diet and behavioral enrichment on free fatty acids in the aged canine brain. Neuroscience 202:326-33
Snigdha, Shikha; Berchtold, Nicole; Astarita, Giuseppe et al. (2011) Dietary and behavioral interventions protect against age related activation of caspase cascades in the canine brain. PLoS One 6:e24652

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