title: Effects of aging on circadian patterns of gene expression in the human prefrontal cortex.
abstract: With aging, significant changes in circadian rhythms occur, including a shift in phase toward a "morning" chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann's area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ∼ 10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life.
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Cho-Yi
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Logan
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Tianzhou
authors.initials: T
authors.lastname: Ma
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: George C
authors.initials: GC
authors.lastname: Tseng
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Campbell Family Mental Health Research Institute of Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada M6J 1H4; Department of Psychiatry, University of Toronto, Toronto, ON, Canada M5T 1R8; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Etienne
authors.initials: E
authors.lastname: Sibille
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; mcclungca@upmc.edu.
authors.forename: Colleen A
authors.initials: CA
authors.lastname: McClung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics*; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D017397:Prefrontal Cortex / Q000503:physiopathology*; D012890:Sleep / Q000235:genetics; D014158:Transcription, Genetic; D055815:Young Adult
keywords: aging; circadian rhythms; gene expression; postmortem; prefrontal cortex