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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG012694-17
Application #
8326043
Study Section
Special Emphasis Panel (NSS)
Program Officer
Wagster, Molly V
Project Start
1995-09-30
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
17
Fiscal Year
2012
Total Cost
$795,147
Indirect Cost
$234,995
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Organized Research Units
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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
Pop, Viorela; Head, Elizabeth; Berchtold, Nicole C et al. (2012) A? aggregation profiles and shifts in APP processing favor amyloidogenesis in canines. Neurobiol Aging 33:108-20
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
Fahnestock, Margaret; Marchese, Monica; Head, Elizabeth et al. (2010) BDNF increases with behavioral enrichment and an antioxidant diet in the aged dog. Neurobiol Aging :
Pop, Viorela; Head, Elizabeth; Hill, Mary-Ann et al. (2010) Synergistic effects of long-term antioxidant diet and behavioral enrichment on beta-amyloid load and non-amyloidogenic processing in aged canines. J Neurosci 30:9831-9
Head, Elizabeth (2009) Oxidative damage and cognitive dysfunction: antioxidant treatments to promote healthy brain aging. Neurochem Res 34:670-8
Christie, Lori-Ann; Opii, Wycliffe O; Head, Elizabeth et al. (2009) Short-term supplementation with acetyl-l-carnitine and lipoic acid alters plasma protein carbonyl levels but does not improve cognition in aged beagles. Exp Gerontol :
Long, Jiangang; Gao, Feng; Tong, Liqi et al. (2009) Mitochondrial decay in the brains of old rats: ameliorating effect of alpha-lipoic acid and acetyl-L-carnitine. Neurochem Res 34:755-63

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