The long-term goal of my research career is to use state-of-the-art, non-invasive brain imaging methods (magnetic resonance imaging and spectroscopy (MRI/MRS) and positron emission tomography (PET)) to assess brain metabolic, hemodynamic and neuronal (structural and functional) integrity and its associations with cognitive function in animal models of healthy aging and of age-related neurodegenerative disorders. The goals of my training program are: 1) to "reversely translate" the neuroimaging methods for assessing hemodynamics and metabolism from humans to rodent models;2) to receive training in the biology of aging using rodent models, with an emphasis on metabolic physiology;3) to apply these newly found skills to the investigation of the mechanisms of action of aging and potential protective effects of caloric restriction (CR);and, 4) to have hands-on training in behavioral testing for rodents and identify the association between imaging and behavioral results. The research objective of this proposal is to use high-field MRI/MRS and PET to investigate the brain integrity of aging mice and identify possible protective effects of CR. In the brain, mitochondrial oxidative phosphorylation of glucose is the predominant source of energy (ATP production), supporting energy demands (maintaining neuronal integrity and basal firing rates). A widely accepted cause of the functional losses that accompany aging, both in the brain and in other organs, is decreased brain metabolism. In support of this viewpoint, a host of neuroimaging studies show that cerebral metabolic rates of oxygen (CMRO2), glucose (CMRGlc) and cerebral blood flow (CBF) decline with age and decline still more rapidly and profoundly in neurodegenerative disorders, such as Alzheimer's Disease (AD). It is generally believed, therefore, that preserving bioenergetics (i.e., glucose oxidative capacity) is critical fr optimizing lifespan and healthspan. Interventions have been introduced to preserve metabolism in aging process. CR perhaps is the most well-studied one for various model organisms of extended longevity, including Saccharomyces cerevisiae, Caenorhabditis elegans, rodents and monkeys. In the neuronal system, CR has shown to attenuate age-related metabolic dysfunction and neuromuscular synaptic loss and to enhance cognitive function. The rationale of the study, therefore, is to characterize the effect of CR on in vivo brain metabolic, hemodynamic, and neuronal (structural and functional) integrity in aging using non-invasive, multimodal neuroimaging methods, and the association of the neuroimaging indices with the cognitive testing. The central hypothesis of this proposal is that cerebral metabolic function will decline i normal aging and consequently reduce brain structural, functional and cognitive integrity;mice with CR intervention will demonstrate: preserved CMRO2, CBF, CMRGlc, total ATP concentration;and, thus preserved brain structure, functional connectivity, and cognition during aging. The hypothesis will be tested by pursuing three specific aims: 1) Determine effects of normal aging on brain metabolic and hemodynamic integrity and possible protective effects of CR;2) Determine effects of normal aging on neuronal (structural and functional) integrity and possible protective effects of CR;and, 3) Determine effects of normal aging on cognitive integrity and possible protective effects of CR. The approach is innovative, because it investigates the CR protective effect on in vivo brain metabolism in aging process with non-invasive neuroimaging methods;it uses complementary, multi- parametric, non-invasive imaging methods (MRI, MRS and PET) to explore the physiological effects of mitochondrial alterations, for the first time;it uses quantitative imaging techniques (developed by the PI for humans) at ultra-high field (11.7T) and in rodents, the first time this has been done;and, it will be the first study to investigate the correlation between cognitive effects (memory and spatial information processing) and brain imaging results in the CR mouse model. The proposed research is significant because 1) physiological effects of metabolic alterations in aging and age-related neuronal disorders, disease progression and treatment efficacy can be monitored non-invasively and nondestructively;2) the interplay between brain metabolic, structural and cognitive functions in aging can be identified;and, 3) these multi-metric imaging methods can be translated seamlessly from rodents to non-human primates and to humans. Collectively, the training provide by the Career Development Award will place me at the cutting edge of aging research, of animal neuroimaging, and of their combination: translational neuroimaging of aging. Translational neuroimaging is an emerging field with extraordinary promise. My ambition is to become pioneer in this emerging discipline.

Public Health Relevance

The purpose of the study is to use multimodal neuroimaging methods (PET, MRI and MRS) to investigate the brain integrity of aging mice and identify possible protective effects of caloric restriction (CR). The findings from the study will advance our understanding on the interplay between brain metabolic, structural and cognitive functions in aging. In addition, brain metabolism observed in long-lived animal models (e.g., with CR) might predict positive cognitive outcomes in humans. The findings are thus expected to be applicable to the health of human beings, especially for aging and age-related neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AG040164-02
Application #
8529429
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Wise, Bradley C
Project Start
2012-08-15
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$92,220
Indirect Cost
$6,700
Name
University of Texas Health Science Center San Antonio
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Lin, A-L; Powell, D; Caban-Holt, A et al. (2016) (1)H-MRS metabolites in adults with Down syndrome: Effects of dementia. Neuroimage Clin 11:728-35
Anderson, Katie L; Frazier, Hilaree N; Maimaiti, Shaniya et al. (2016) Impact of Single or Repeated Dose Intranasal Zinc-free Insulin in Young and Aged F344 Rats on Cognition, Signaling, and Brain Metabolism. J Gerontol A Biol Sci Med Sci :
Ramage, Amy E; Lin, Ai-Ling; Olvera, Rene L et al. (2015) Resting-state regional cerebral blood flow during adolescence: associations with initiation of substance use and prediction of future use disorders. Drug Alcohol Depend 149:40-8
Lin, Ai-Ling; Zhang, Wei; Gao, Xiaoli et al. (2015) Caloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain. Neurobiol Aging 36:2296-303
Guo, Janet; Bakshi, Vikas; Lin, Ai-Ling (2015) Early Shifts of Brain Metabolism by Caloric Restriction Preserve White Matter Integrity and Long-Term Memory in Aging Mice. Front Aging Neurosci 7:213
Lin, Ai-Ling; Rothman, Douglas L (2014) What have novel imaging techniques revealed about metabolism in the aging brain? Future Neurol 9:341-354
Lin, Ai-Ling; Coman, Daniel; Jiang, Lihong et al. (2014) Caloric restriction impedes age-related decline of mitochondrial function and neuronal activity. J Cereb Blood Flow Metab 34:1440-3
Pulliam, Daniel A; Deepa, Sathyaseelan S; Liu, Yuhong et al. (2014) Complex IV-deficient Surf1(-/-) mice initiate mitochondrial stress responses. Biochem J 462:359-71
Sancheti, Harsh; Patil, Ishan; Kanamori, Keiko et al. (2014) Hypermetabolic state in the 7-month-old triple transgenic mouse model of Alzheimer's disease and the effect of lipoic acid: a 13C-NMR study. J Cereb Blood Flow Metab 34:1749-60
Lin, Ai-Ling; Zheng, Wei; Halloran, Jonathan J et al. (2013) Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease. J Cereb Blood Flow Metab 33:1412-21

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