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Evolution of the aging brain transcriptome and synaptic regulation.

Loerch PM, Lu T, Dakin KA, Vann JM, Isaacs A, Geula C, Wang J, Pan Y, Gabuzda DH, Li C, Prolla TA, Yankner BA - PLoS ONE (2008)

Bottom Line: Many of these age-regulated neuronal genes are associated with synaptic function.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT
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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Genome-wide comparison of brain aging in humans, rhesus macaques, and mice.a. Venn diagram indicating the extent of overlap in age-related gene expression changes between the three species. The size of each circle corresponds to the number of age-related expression changes in each species. b. A group of 154 common aging genes provides an indicator of biological aging in all three species. Shown is a matrix of Pearson correlation coefficients that indicate the degree of overall similarity between any two samples (see Methods). Positively correlated sample pairs are indicated by red and negatively correlated pairs are indicated by blue. The degree of correlation correlates with color intensity. The species and age groups are indicated (Human: young ≤40 years; aged ≥70 years. Rhesus macaque: young 5–6 years; aged 28–31 years. Mouse: young 5 months; aged 30 months).
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pone-0003329-g001: Genome-wide comparison of brain aging in humans, rhesus macaques, and mice.a. Venn diagram indicating the extent of overlap in age-related gene expression changes between the three species. The size of each circle corresponds to the number of age-related expression changes in each species. b. A group of 154 common aging genes provides an indicator of biological aging in all three species. Shown is a matrix of Pearson correlation coefficients that indicate the degree of overall similarity between any two samples (see Methods). Positively correlated sample pairs are indicated by red and negatively correlated pairs are indicated by blue. The degree of correlation correlates with color intensity. The species and age groups are indicated (Human: young ≤40 years; aged ≥70 years. Rhesus macaque: young 5–6 years; aged 28–31 years. Mouse: young 5 months; aged 30 months).

Mentions: To identify age-related changes in gene expression, cortical samples from 13 young (≤40 years old) and 15 aged (≥70 years old) humans were hybridized to Affymetrix U133plus 2.0 arrays, 5-month-old (n = 5) and 30-month-old mice (n = 5) were hybridized to Affymetrix Mouse 430 2.0 arrays, and samples from 5–6-year-old (n = 5) and 28–31-year-old (n = 6) rhesus macaques were hybridized to Affymetrix whole genome rhesus arrays. Since the rhesus macaque genome has only recently been sequenced [9], the rhesus microarrays are based primarily on gene predictions. Therefore, we used an all-against-all protein BLAST to identify orthologous genes between the rhesus predictions and the other two species. For each homolog pair, we required a BLAST score of greater than 200, and at least 80% alignment of the human or mouse protein sequence with the rhesus sequence (Table S2). The final gene set was composed of genes that possess an ortholog in every species and are represented on all three array platforms. We then employed a two-sample t-test between young and aged age groups with a 1% false discovery rate (FDR) cut-off to identify 3542, 573, and 2347 age-related genes in mice, rhesus monkeys, and humans, respectively (Tables S3–5). Among these age-related changes, only 154 were significantly associated with aging in all three species (Fig. 1a and Table S6). To assess this gene group as an indicator of brain aging, the behavior of all 154 genes was compared across age groups and species to derive Pearson correlation coefficients. The resulting correlation matrix showed that this core gene set distinguishes between young and aged samples in all three species (Fig. 1b). Furthermore, this set of age-related gene expression changes distinguished between chronological and biological age. For example, a 30-year-old rhesus monkey more closely resembled a 70-year-old human than a 30-year-old human. This set of common age related expression changes is therefore linked to the biology of the aging process in the brain.


Evolution of the aging brain transcriptome and synaptic regulation.

Loerch PM, Lu T, Dakin KA, Vann JM, Isaacs A, Geula C, Wang J, Pan Y, Gabuzda DH, Li C, Prolla TA, Yankner BA - PLoS ONE (2008)

Genome-wide comparison of brain aging in humans, rhesus macaques, and mice.a. Venn diagram indicating the extent of overlap in age-related gene expression changes between the three species. The size of each circle corresponds to the number of age-related expression changes in each species. b. A group of 154 common aging genes provides an indicator of biological aging in all three species. Shown is a matrix of Pearson correlation coefficients that indicate the degree of overall similarity between any two samples (see Methods). Positively correlated sample pairs are indicated by red and negatively correlated pairs are indicated by blue. The degree of correlation correlates with color intensity. The species and age groups are indicated (Human: young ≤40 years; aged ≥70 years. Rhesus macaque: young 5–6 years; aged 28–31 years. Mouse: young 5 months; aged 30 months).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2553198&req=5

pone-0003329-g001: Genome-wide comparison of brain aging in humans, rhesus macaques, and mice.a. Venn diagram indicating the extent of overlap in age-related gene expression changes between the three species. The size of each circle corresponds to the number of age-related expression changes in each species. b. A group of 154 common aging genes provides an indicator of biological aging in all three species. Shown is a matrix of Pearson correlation coefficients that indicate the degree of overall similarity between any two samples (see Methods). Positively correlated sample pairs are indicated by red and negatively correlated pairs are indicated by blue. The degree of correlation correlates with color intensity. The species and age groups are indicated (Human: young ≤40 years; aged ≥70 years. Rhesus macaque: young 5–6 years; aged 28–31 years. Mouse: young 5 months; aged 30 months).
Mentions: To identify age-related changes in gene expression, cortical samples from 13 young (≤40 years old) and 15 aged (≥70 years old) humans were hybridized to Affymetrix U133plus 2.0 arrays, 5-month-old (n = 5) and 30-month-old mice (n = 5) were hybridized to Affymetrix Mouse 430 2.0 arrays, and samples from 5–6-year-old (n = 5) and 28–31-year-old (n = 6) rhesus macaques were hybridized to Affymetrix whole genome rhesus arrays. Since the rhesus macaque genome has only recently been sequenced [9], the rhesus microarrays are based primarily on gene predictions. Therefore, we used an all-against-all protein BLAST to identify orthologous genes between the rhesus predictions and the other two species. For each homolog pair, we required a BLAST score of greater than 200, and at least 80% alignment of the human or mouse protein sequence with the rhesus sequence (Table S2). The final gene set was composed of genes that possess an ortholog in every species and are represented on all three array platforms. We then employed a two-sample t-test between young and aged age groups with a 1% false discovery rate (FDR) cut-off to identify 3542, 573, and 2347 age-related genes in mice, rhesus monkeys, and humans, respectively (Tables S3–5). Among these age-related changes, only 154 were significantly associated with aging in all three species (Fig. 1a and Table S6). To assess this gene group as an indicator of brain aging, the behavior of all 154 genes was compared across age groups and species to derive Pearson correlation coefficients. The resulting correlation matrix showed that this core gene set distinguishes between young and aged samples in all three species (Fig. 1b). Furthermore, this set of age-related gene expression changes distinguished between chronological and biological age. For example, a 30-year-old rhesus monkey more closely resembled a 70-year-old human than a 30-year-old human. This set of common age related expression changes is therefore linked to the biology of the aging process in the brain.

Bottom Line: Many of these age-regulated neuronal genes are associated with synaptic function.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus