Evolution of the Aging Brain Transcriptome and Synaptic Regulation
Open accessAbstract
Alzheimer's disease and other neurodegenerative disorders of aging are characterized by clinical and pathological features that are relatively specific to humans. To obtain greater insight into how brain aging has evolved, we compared age-related gene expression changes in the cortex of humans, rhesus macaques, and mice on a genome-wide scale. A small subset of gene expression changes are conserved in all three species, including robust age-dependent upregulation of the neuroprotective gene apolipoprotein D (APOD) and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV (CAMK4). However, analysis of gene ontology and cell type localization shows that humans and rhesus macaques have diverged from mice due to a dramatic increase in age-dependent repression of neuronal genes. Many of these age-regulated neuronal genes are associated with synaptic function. Notably, genes associated with GABA-ergic inhibitory function are robustly age-downregulated in humans but not in mice at the level of both mRNA and protein. Gene downregulation was not associated with overall neuronal or synaptic loss. Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes.
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Gene expression profiling studies of ageing mouse, rat, monkey and human brains have shown significant changes in the expression of synaptic genes.
“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 [13]
In a transcriptional profiling study of the ageing cortex in mice, rhesus macaques and humans, the greatest conserved change was age-dependent upregulation of the apolipoprotein D gene.
“In a transcriptional profiling study of the ageing cortex in mice, rhesus macaques and humans, the greatest conserved change was age-dependent upregulation of the apolipoprotein D gene (13).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [13]
More than 150 genes were found to undergo age-dependent expression changes in all three organisms.
“More than 150 genes were found to undergo age-dependent expression changes in all three organisms.”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [13]
A recent study directly comparing gene expression during ageing in mouse, rhesus macaque and human brain has revealed a major evolutionary divergence.
“Despite clear evidence of conservation of some ageing pathways and gene expression signatures, a recent study directly comparing gene expression during ageing in mouse, rhesus macaque and human brain has revealed a major evolutionary divergence (13).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [13]
A significant fraction of age-regulated genes, mostly predicted to participate in neuronal functions, are upregulated with age in mice but downregulated with age in humans.
“A significant fraction of age-regulated genes, mostly predicted to participate in neuronal functions, are upregulated with age in mice but downregulated with age in humans.”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [13]
Organ-specific analysis of brain ageing has revealed a progressive decline in mitochondrial gene expression in rats, rhesus macaques and humans.
“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 [13]
In the human and rhesus macaque prefrontal cortex, many genes involved in inhibitory neurotransmission mediated by GABA are strongly downregulated with age, potentially altering the balance between inhibitory and excitatory neurotransmission.
“In the human and rhesus macaque prefrontal cortex, many genes involved in inhibitory neurotransmission mediated by GABA (γ-aminobutyric acid) are strongly downregulated with age, potentially altering the balance between inhibitory and excitatory neurotransmission (13).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [13]
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References 37 · Cited by 334
- Authors
- Loerch, P. M., Lu, T., Dakin, K. A., Vann, J. M., Isaacs, A., Geula, C., Wang, J., Pan, Y., Gabuzda, D. H., Li, C., Prolla, T. A., & Yankner, B. A.
- Affiliations
- Harvard University (US)
- University of Wisconsin–Madison (US)
- Northwestern University (US)
- Corresponding author
- Yankner, Bruce A.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2008-10-02
- Volume
- 3
- Issue
- 10
- Pages
- e3329
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2553198
- OpenAlex
- W2103813752
- Cited by
- 334
- References
- 37
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 14 · 2023: 19 · 2022: 17 · 2021: 21 · 2020: 23 · 2019: 14 · 2018: 24 · 2017: 22 · 2016: 19 · 2015: 13 · 2014: 24 · 2013: 16 · 2012: 25
- FWCI
- 5.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Ellison Medical Foundation
- National Institutes of Health
- National Institute on Aging (R01AG027040, AG27916, P01AG027916, AG26651, R01AG026651, AG27040)
- National Institute of General Medical Sciences (T32GM074897)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- brain aging, transcriptome evolution, age-related gene expression, cortical gene expression, apolipoprotein D, CaMKIV, synaptic function, GABAergic inhibition, cross-species comparison, rhesus monkeys, mice, Alzheimer's disease, neurodegeneration, cognitive aging
- MeSH terms
- Adult, Aged, Aging, Animals, Brain, Humans, Synaptic Transmission, Phylogeny, RNA, Messenger, Species Specificity, Synapses, Blotting, Western, Evolution, Molecular, Mice
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