title: Age-associated changes in gene expression in human brain and isolated neurons.
abstract: Previous studies have suggested that there are genes whose expression levels are associated with chronological age. However, which genes show consistent age association across studies, and which are specific to a given organism or tissue remains unresolved. Here, we reassessed this question using 2 independently ascertained series of human brain samples from 2 anatomic regions, the frontal lobe of the cerebral cortex and cerebellum. Using microarrays to estimate gene expression, we found 60 associations between expression and chronological age that were statistically significant and were replicated in both series in at least 1 tissue. There were a greater number of significant associations in the frontal cortex compared with the cerebellum. We then repeated the analysis in a subset of samples using laser capture microdissection to isolate Purkinje neurons from the cerebellum. We were able to replicate 5 gene associations from either frontal cortex or cerebellum in the Purkinje cell dataset, suggesting that there is a subset of genes which have robust changes with aging. Of these, the most consistent and strongest association was with expression of RHBDL3, a rhomboid protease family member. We confirmed several hits using an independent technique (quantitative reverse transcriptase polymerase chain reaction) and in an independent published sample series that used a different array platform. We also interrogated larger patterns of age-related gene expression using weighted gene correlation network analysis. We found several modules that showed significant associations with chronological age and, of these, several that showed negative associations were enriched for genes encoding components of mitochondria. Overall, our results show that there is a distinct and reproducible gene signature for aging in the human brain.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892-3707, USA.
authors.forename: Azad
authors.initials: A
authors.lastname: Kumar
authors.forename: J Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.forename: Alexandra
authors.initials: A
authors.lastname: Beilina
authors.forename: Allissa
authors.initials: A
authors.lastname: Dillman
authors.forename: Ravindran
authors.initials: R
authors.lastname: Kumaran
authors.forename: Daniah
authors.initials: D
authors.lastname: Trabzuni
authors.forename: Mina
authors.initials: M
authors.lastname: Ryten
authors.forename: Robert
authors.initials: R
authors.lastname: Walker
authors.forename: Colin
authors.initials: C
authors.lastname: Smith
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism*; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D020543:Proteome