Molecular aging in human prefrontal cortex is selective and continuous throughout adult life

Erraji-Benchekroun, Loubna; Underwood, Mark D.; Arango, Victoria; Galfalvy, Hanga; Pavlidis, Paul; Smyrniotopoulos, Peggy; Mann, J. John; Sibille, Etienne

doi:10.1016/j.biopsych.2004.10.034

Cited by 211 publications

(272 citation statements)

References 52 publications

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“…This restricted scope of transcript changes suggests that specific cellular populations and biological processes are selectively vulnerable during aging. Interestingly, the set of age-dependent genes in our group's study was very similar to those observed in other studies, 57,60-62,64,66-68 and in fact displayed high degree of conservation across cohorts and cortical brain regions. 58 Expression of genes playing a role in glial-mediated inflammation, oxidative stress responses, mitochondrial function, synaptic function and plasticity, and calcium regulation have now consistently been shown across multiple studies to be affected by aging, despite differences in sample size, selection of tissue type or brain region, expression analysis platforms, and analytical methods.…”

Section: Molecular Brain Aging: An Etiological Role In Lld?supporting

confidence: 88%

“…Overall, age-upregulated genes are mostly of glial origin and related to inflammation and cellular defenses, while downregulated genes display mostly neuron-enriched transcripts relating to cellular communication and signaling. 66 This consistency and specificity of age-related changes in fact fulfills criteria for biomarkers. Indeed, we have shown that the predicted age for a particular individual, based on regression analysis of expected age-related trajectories for those age-biomarkers (denoted as “molecular age”), is highly correlated with the chronological age of that individual.…”

Section: Molecular Brain Aging: An Etiological Role In Lld?mentioning

confidence: 76%

“…58 Expression of genes playing a role in glial-mediated inflammation, oxidative stress responses, mitochondrial function, synaptic function and plasticity, and calcium regulation have now consistently been shown across multiple studies to be affected by aging, despite differences in sample size, selection of tissue type or brain region, expression analysis platforms, and analytical methods. 57,60-62,64,66-68 Of note, not only is the identity of the genes and gene classes that are affected with aging consistent among studies but so are the directions of change. Overall, age-upregulated genes are mostly of glial origin and related to inflammation and cellular defenses, while downregulated genes display mostly neuron-enriched transcripts relating to cellular communication and signaling.…”

Section: Molecular Brain Aging: An Etiological Role In Lld?mentioning

confidence: 99%

“…Studies in rodent, monkey and human brains estimate the number of genes exhibiting age-related changes to represent less than 10%, and commonly less than 5%, of the entire genome. 60-66 In a study from our group, the age-related changes of a large number of genes using microarray technology were profiled in prefrontal cortex samples from human subjects aged 13-79 years. 66 The data from this study identified life-long progressive changes in expression with age of up to 7.5% of the genes tested.…”

Section: Molecular Brain Aging: An Etiological Role In Lld?mentioning

confidence: 99%

“…60-66 In a study from our group, the age-related changes of a large number of genes using microarray technology were profiled in prefrontal cortex samples from human subjects aged 13-79 years. 66 The data from this study identified life-long progressive changes in expression with age of up to 7.5% of the genes tested. This restricted scope of transcript changes suggests that specific cellular populations and biological processes are selectively vulnerable during aging.…”

Section: Molecular Brain Aging: An Etiological Role In Lld?mentioning

confidence: 99%

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The Age-by-Disease Interaction Hypothesis of Late-Life Depression

McKinney

Sibille

2013

The American Journal of Geriatric Psychiatry

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The phenomenological diagnosis of depression is successful in increasing diagnostic reliability, but it is a classification scheme without biological bases. One subtype of depression for which evidence suggests a unique biological basis is late-life depression (LLD), with first onset of symptoms after the age of 65. LLD is common and poses a significant burden on affected individuals, caretakers, and society. The pathophysiology of LLD includes disruptions of the neural network underlying mood, which can be conceptualized as the result of dysfunction in multiple underlying biological processes. Here, we briefly review current LLD hypotheses and then describe the characteristics of molecular brain aging and their overlap with disease processes. Further, we propose a new hypothesis for LLD, the Age-by-Disease Interaction hypothesis, which posits that the clinical presentation of LLD is the integrated output of specific biological processes that are pushed in LLD-promoting directions by changes in gene expression naturally occurring during brain aging, hence leading the brain to a physiological state that is more susceptible to LLD, since additional pushes by genetic, environmental and biochemical factors may now be sufficient to generate dysfunctional states that produce depressive symptoms. We put our propositions together into a decanalization model to aid in illustrating how age-related biological changes of the brain can shift the repertoire of available functional states in a pro-depression direction, and how additional factors can readily lead the system into distinct and stable maladaptive phenotypes, including LLD. This model brings together basic research on neuropsychiatric and neurodegenerative diseases more closely with the investigation of normal aging. Specifically, identifying biological processes affected during normal aging may inform the development of new interventions for the prevention and treatment of LLD.

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Section: Molecular Brain Aging: An Etiological Role In Lld?supporting

confidence: 88%

Section: Molecular Brain Aging: An Etiological Role In Lld?mentioning

confidence: 76%

Section: Molecular Brain Aging: An Etiological Role In Lld?mentioning

confidence: 99%

Section: Molecular Brain Aging: An Etiological Role In Lld?mentioning

confidence: 99%

Section: Molecular Brain Aging: An Etiological Role In Lld?mentioning

confidence: 99%

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The Age-by-Disease Interaction Hypothesis of Late-Life Depression

McKinney

Sibille

2013

The American Journal of Geriatric Psychiatry

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Key Roles of CACNA1C/Cav1.2 and CALB1/Calbindin in Prefrontal Neurons Altered in Cognitive Disorders

Datta,

Yang,

Joyce

et al. 2024

JAMA Psychiatry

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ImportanceThe risk of mental disorders is consistently associated with variants in CACNA1C (L-type calcium channel Cav1.2) but it is not known why these channels are critical to cognition, and whether they affect the layer III pyramidal cells in the dorsolateral prefrontal cortex that are especially vulnerable in cognitive disorders.ObjectiveTo examine the molecular mechanisms expressed in layer III pyramidal cells in primate dorsolateral prefrontal cortices.Design, Setting, and ParticipantsThe design included transcriptomic analyses from human and macaque dorsolateral prefrontal cortex, and connectivity, protein expression, physiology, and cognitive behavior in macaques. The research was performed in academic laboratories at Yale, Harvard, Princeton, and the University of Pittsburgh. As dorsolateral prefrontal cortex only exists in primates, the work evaluated humans and macaques.Main Outcomes and MeasuresOutcome measures included transcriptomic signatures of human and macaque pyramidal cells, protein expression and interactions in layer III macaque pyramidal cells using light and electron microscopy, changes in neuronal firing during spatial working memory, and working memory performance following pharmacological treatments.ResultsLayer III pyramidal cells in dorsolateral prefrontal cortex coexpress a constellation of calcium-related proteins, delineated by CALB1 (calbindin), and high levels of CACNA1C (Cav1.2), GRIN2B (NMDA receptor GluN2B), and KCNN3 (SK3 potassium channel), concentrated in dendritic spines near the calcium-storing smooth endoplasmic reticulum. L-type calcium channels influenced neuronal firing needed for working memory, where either blockade or increased drive by β1-adrenoceptors, reduced neuronal firing by a mean (SD) 37.3% (5.5%) or 40% (6.3%), respectively, the latter via SK potassium channel opening. An L-type calcium channel blocker or β1-adrenoceptor antagonist protected working memory from stress.Conclusions and RelevanceThe layer III pyramidal cells in the dorsolateral prefrontal cortex especially vulnerable in cognitive disorders differentially express calbindin and a constellation of calcium-related proteins including L-type calcium channels Cav1.2 (CACNA1C), GluN2B-NMDA receptors (GRIN2B), and SK3 potassium channels (KCNN3), which influence memory-related neuronal firing. The finding that either inadequate or excessive L-type calcium channel activation reduced neuronal firing explains why either loss- or gain-of-function variants in CACNA1C were associated with increased risk of cognitive disorders. The selective expression of calbindin in these pyramidal cells highlights the importance of regulatory mechanisms in neurons with high calcium signaling, consistent with Alzheimer tau pathology emerging when calbindin is lost with age and/or inflammation.

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Analysis of whole genome biomarker expression in blood and brain

Rollins

Martin

Morgan

et al. 2010

American J of Med Genetics Pt B

186

151

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The consistency of peripheral gene expression data and the overlap with brain expression has not been evaluated in biomarker discovery, nor has it been reported in multiple tissues from the same subjects on a genome wide transcript level. The effects of processing whole blood, transformation, and passaged cell lines on gene expression profiling was studied in healthy subjects using Affymetrix arrays. Ficoll extracted peripheral blood mononuclear cells (PBMCs), Epstein-Barr virus (EBV) transformed lymphocytes, passaged lymphoblastic cell lines (LCLs), and whole blood from Tempus tubes were compared. There were 6,813 transcripts differentially expressed between different methods of blood preparation. Principal component analysis resolved two partitions involving pre- and post-transformation EBV effects. Combining results from Affymetrix arrays, postmortem subjects' brain and PBMC profiles showed co-expression levels of summarized transcripts for 4,103 of 17,859 (22.9%) RefSeq transcripts. In a control experiment, rat hemi-brain and blood showed similar expression levels for 19% of RefSeq transcripts. After filtering transcripts that were not significantly different in abundance between human cerebellum and PBMCs from the Affymetrix exon array the correlation in mean transcript abundance was high as expected (r = 0.98). Differences in the alternative splicing index in brain and blood were found for about 90% of all transcripts examined. This study demonstrates over 4,100 brain transcripts co-expressed in blood samples can be further examined by in vitro and in vivo experimental studies of blood and cell lines from patients with psychiatric disorders.

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Molecular aging in human prefrontal cortex is selective and continuous throughout adult life

Cited by 211 publications

References 52 publications

The Age-by-Disease Interaction Hypothesis of Late-Life Depression

The Age-by-Disease Interaction Hypothesis of Late-Life Depression

Key Roles of CACNA1C/Cav1.2 and CALB1/Calbindin in Prefrontal Neurons Altered in Cognitive Disorders

Analysis of whole genome biomarker expression in blood and brain

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