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Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment
Open accessAbstract
Gene expression microarrays provide a powerful new tool for studying complex processes such as brain aging. However, inferences from microarray data are often hindered by multiple comparisons, small sample sizes, and uncertain relationships to functional endpoints. Here we sought gene expression correlates of aging-dependent cognitive decline, using statistical profiling of gene microarrays in well powered groups of young, mid-aged, and aged rats (n = 10 per group). Animals were trained on two memory tasks, and the hippocampal CA1 region of each was analyzed on an individual microarray (one chip per animal). Aging- and cognition-related genes were identified by testing each gene by ANOVA (for aging effects) and then by Pearson's test (correlating expression with memory). Genes identified by this algorithm were associated with several phenomena known to be aging-dependent, including inflammation, oxidative stress, altered protein processing, and decreased mitochondrial function, but also with multiple processes not previously linked to functional brain aging. These novel processes included downregulated early response signaling, biosynthesis and activity-regulated synaptogenesis, and upregulated myelin turnover, cholesterol synthesis, lipid and monoamine metabolism, iron utilization, structural reorganization, and intracellular Ca2+ release pathways. Multiple transcriptional regulators and cytokines also were identified. Although most gene expression changes began by mid-life, cognition was not clearly impaired until late life. Collectively, these results suggest a new integrative model of brain aging in which genomic alterations in early adulthood initiate interacting cascades of decreased signaling and synaptic plasticity in neurons, extracellular changes, and increased myelin turnover-fueled inflammation in glia that cumulatively induce aging-related cognitive impairment.
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In the citing paper
“Gene expression profiling studies of ageing mouse, rat, monkey and human brains have shown significant changes in the expression of synaptic genes (7–13).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [10]
In the citing paper
“In particular, organ-specific analysis of brain ageing has revealed a progressive decline in mitochondrial gene expression in rats, rhesus macaques and humans (7,10,13).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [10]
In the citing paper
“Markers of inflammation in the blood and in specific tissues are associated with impaired motor and cognitive function (Blalock, Chen, Sharrow, Herman, Porter, Foster, and Landfield 2003;Speisman, Kumar, Rani, Foster, and Ormerod 2013;Zeier, Madorsky, Xu, Ogle, Notterpek, and Foster 2011) suggesting that the pro-inflammatory phenotype impairs the ability of older individuals to cope with age”
From Successful aging: Advancing the science of physical independence in older adults (2015) · cites this paper as Blalock et al. 2003
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Lu, T., Pan, Y., Kao, S.-Y., Li, C., Kohane, I., Chan, J., & Yankner, B. A. (2004) · Nature · doi:10.1038/nature02661 · Cited by 1,874
Neural plasticity in the ageing brain
Burke, S. N., & Barnes, C. A. (2005) · Nature reviews. Neuroscience · doi:10.1038/nrn1809 · Cited by 1,707
Neural mechanisms of ageing and cognitive decline
Bishop, N. A., Lu, T., & Yankner, B. A. (2010) · Nature · doi:10.1038/nature08983 · Cited by 1,323
Neurodegenerative diseases and oxidative stress
Emerit, J., Edeas, M. A., & Bricaire, F. (2003) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2003.11.004 · Cited by 1,057
Blalock, E. M., Geddes, J. W., Chen, K. C., Porter, N. M., Markesbery, W. R., & Landfield, P. W. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308512100 · Cited by 1,025
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Metadata
- Authors
- Blalock, E. M., Chen, K.-C., Sharrow, K., Herman, J. P., Porter, N. M., Foster, T. C., & Landfield, P. W.
- Affiliations
- University of Kentucky (US)
- University of Cincinnati (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-05-01
- Volume
- 23
- Issue
- 9
- Pages
- 3807-3819
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6742177
- OpenAlex
- W2132977458
- Cited by
- 570
- References
- 85
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 8 · 2023: 5 · 2022: 23 · 2021: 15 · 2020: 17 · 2019: 27 · 2018: 22 · 2017: 28 · 2016: 28 · 2015: 19 · 2014: 22 · 2013: 32 · 2012: 39
- FWCI
- 22.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag018228-02)
- National Institute on Aging (P01AG010836, R01AG014979, AG 14979, AG 10836, AG18228, R37AG004542, AG 04542)
- National Institute of Mental Health (MH 59891, R01MH059891)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- brain aging, hippocampal CA1, cognitive impairment, gene expression profiling, memory, inflammation, oxidative stress, mitochondrial function, myelin turnover, synaptogenesis, cholesterol biosynthesis, lipid metabolism, monoamine metabolism, iron utilization, intracellular calcium release, transcription factors, cytokines, synaptic plasticity, rats
- MeSH terms
- Aging, Algorithms, Animals, Behavior, Animal, Cognition, Cognition Disorders, Exploratory Behavior, Gene Expression Regulation, Hippocampus, Male, Memory, Psychomotor Performance, Rats, Inbred F344, Sensitivity and Specificity, Reproducibility of Results, DNA Probes, Biomarkers, Maze Learning, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Rats
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