Gene-expression profile of the ageing brain in mice
Abstract
Ageing of the brain leads to impairments in cognitive and motor skills, and is the major risk factor for several common neurological disorders such as Alzheimer disease (AD) and Parkinson disease (PD). Recent studies suggest that normal brain ageing is associated with subtle morphological and functional alterations in specific neuronal circuits, as opposed to large-scale neuronal loss. In fact, ageing of the central nervous system in diverse mammalian species shares many features, such as atrophy of pyramidal neurons, synaptic atrophy, decrease of striatal dopamine receptors, accumulation of fluorescent pigments, cytoskeletal abnormalities, and reactive astrocytes and microglia. To provide the first global analysis of brain ageing at the molecular level, we used oligonucleotide arrays representing 6,347 genes to determine the gene-expression profile of the ageing neocortex and cerebellum in mice. Ageing resulted in a gene-expression profile indicative of an inflammatory response, oxidative stress and reduced neurotrophic support in both brain regions. At the transcriptional level, brain ageing in mice displays parallels with human neurodegenerative disorders. Caloric restriction, which retards the ageing process in mammals, selectively attenuated the age-associated induction of genes encoding inflammatory and stress responses.
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Dietary restriction increases IκBα, a NF-κB inhibitor, and decreases the p65 subunit of NF-κB in mouse neocortex.
“A previous gene profiling study provided evidence that DR increased IκBα, a NF-κB inhibitor, and decreased the p65 subunit of NF-κB in mouse neocortex [147].”
From Dietary Restriction and Neuroinflammation: A Potential Mechanistic Link (2019) · cites this paper as [147]
In 18-month-old mouse retinas, supplementation with 24:5n-3 significantly down-regulated genes from the 'aging cerebellum' gene set compared with control (NES = −1.82, FDR = 5.83 × 10−4).
“Further analysis demonstrated significant down-regulation of genes from the “aging cerebellum” gene set (35) (NES = −1.82 and FDR = 5.83 × 10−4) in retinas from 18-month-old mice after supplementation with 24:5n-3 compared with control, including significant down-regulation of apolipoprotein E (Apoe) transcript (log2FC = −0.79 and padj = 0.001) (Fig. 5F).”
From Retinal polyunsaturated fatty acid supplementation reverses aging-related vision decline in mice (2025) · cites this paper as [35]
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 [8]
Caloric restriction has beneficial effects on the function of the brain and its vulnerability to age-dependent pathology.
“Caloric restriction has also been widely documented to have beneficial effects on the function of the brain and its vulnerability to age-dependent pathology.”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [8]
Caloric restriction prevents many age-dependent gene expression changes in the mouse brain, reduces age-related brain atrophy in rhesus macaques, and has significant beneficial effects on the age-dependent impairment of learning and memory in rodents and humans.
“It prevents many age-dependent gene expression changes in the mouse brain (8,43), reduces age-related brain atrophy in rhesus macaques (75) and has significant beneficial effects on the age-dependent impairment of learning and memory in rodents (76,77) and humans (78).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [8]
Early transcriptional profiling studies found surprisingly few genes altered by aging.
“The first studies of aging using this approach revealed that surprisingly few genes were altered by aging at the transcriptional level [2-4].”
From PGC-1α in aging and anti-aging interventions (2009) · cites this paper as [3]
Accumulated pro-inflammation and oxidative stress in the brain, often observed in aged brains and aged microglia, could cause sustained suppression of Trem2 expression and thus an impairment of TREM2-dependent microglial functions.
“accumulated pro-inflammation and oxidative stress in the brain, which is often observed in aged brains and aged microglia (90–94), could cause sustained suppression of Trem2 expression and thus an impairment of TREM2-dependent microglial functions.”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [92]
While there may be hallmarks of aging that occur in most cell types, such as mitochondrial dysfunction and loss of proteostasis, the data argue against the hypothesis that aging induces a single universal molecular program in all cells and tissues.
“Thus, while there may be hallmarks of aging that occur in most cell types, such as mitochondrial dysfunction and loss of proteostasis 1,4,54 , our data argue against the hypothesis that aging induces a single universal molecular program in all cells and tissues 16 .”
From Single-cell transcriptomic profiling of the aging mouse brain (2019) · cites this paper as [4]
The first study examining the effects of caloric restriction on the transcriptome profile of aged mice revealed key reversal of aging-associated markers, such as complement subunits, lysozyme, antigen presentation proteins, heat shock proteins, and other inflammation and stress-related genes.
“Indeed, the first study examining the effects of caloric restriction on the transcriptome profile of aged mice revealed key reversal of aging-associated markers, such as complement subunits, lysozyme, antigen presentation proteins, heat shock proteins, and other inflammation and stress-related genes (Lee et al, 2000).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Lee et al, 2000
Comprehensive studies of mouse brain aging covering more than a few regions and at high temporal resolution do not exist to the authors' knowledge.
“Alternatively, expression profiling in model organisms like M. musculus enables quantitative data with minimal confounding factors, but comprehensive studies covering more than a few regions and at high temporal resolution (Hargis and Blalock, 2017; Lee et al., 2000; Tabula Muris Consortium, 2020; Zahn et al., 2007) do - to our knowledge - not exist.”
From Atlas of the aging mouse brain reveals white matter as vulnerable foci (2023) · cites this paper as Lee et al., 2000
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- Authors
- Lee, C.-K., Weindruch, R., & Prolla, T. A.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Weindruch, Richard
- Prolla, Tomas A.
- ORCID
- Lee, Cheol-Koo
- Venue
- Nature Genetics
- Published
- 2000-07
- Volume
- 25
- Issue
- 3
- Pages
- 294-297
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1488124756
- Cited by
- 1,055
- References
- 25
- Citations by year
- 2026: 2 · 2025: 18 · 2024: 14 · 2023: 18 · 2022: 12 · 2021: 34 · 2020: 22 · 2019: 23 · 2018: 29 · 2017: 24 · 2016: 33 · 2015: 38 · 2014: 31 · 2013: 37 · 2012: 44
- FWCI
- 25.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ca078723-04)
- National Institute on Aging (P01-AG-11915, P01AG011915)
- National Cancer Institute (R01 CA 78723)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Antioxidants, Aging, Portulaca oleracea
- Keywords
- brain aging, gene expression profiling, neocortex, cerebellum, neuroinflammation, oxidative stress, neurotrophic support, caloric restriction, Alzheimer's disease, Parkinson's disease, neurodegeneration
- MeSH terms
- Aging, Animals, Brain, Cerebellum, Male, Mice, Inbred C57BL, RNA, Messenger, Gene Expression, Neocortex, RNA Stability, Mice
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