Abstract
BackgroundIdentifying biological pathways that vary across the age spectrum can provide insight into fundamental mechanisms that impact disease and frailty in the elderly. Few methodological approaches offer the means to explore this question on as broad a scale as gene expression profiling. Here, we have evaluated mRNA expression profiles as a function of age in two populations; one consisting of 191 individuals with ages-at-death ranging from 65–100 years and with post-mortem brain mRNA measurements of 13,216 genes and a second with 1240 individuals ages 15–94 and lymphocyte mRNA estimates for 18,519 genes.Principal FindingsAmong negatively correlated transcripts, an enrichment of mitochondrial genes was evident in both populations, providing a replication of previous studies indicating this as a common signature of aging. Sample differences were prominent, the most significant being a decrease in expression of genes involved in translation in lymphocytes and an increase in genes involved in transcription in brain, suggesting that apart from energy metabolism other basic cell processes are affected by age but in a tissue-specific manner. In assessing genomic architecture, intron/exon sequence length ratios were larger among negatively regulated genes in both samples, suggesting that a decrease in the expression of non-compact genes may also be a general effect of aging. Variance in gene expression itself has been theorized to change with age due to accumulation of somatic mutations and/or increasingly heterogeneous environmental exposures, but we found no evidence for such a trend here.SignificanceResults affirm that deteriorating mitochondrial gene expression is a common theme in senescence, but also highlight novel pathways and features of gene architecture that may be important for understanding the molecular consequences of aging.
Highlights
A decline in cell function with advancing age is a ubiquitous characteristic of all organisms
We began by performing several validation steps towards the initial goal of evaluating if age-related change in gene expression could be detected in the human brain
We explored an expanded list of genes that exceeded a relaxed significance threshold for enrichment or deficit based upon Gene Ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways
Summary
A decline in cell function with advancing age is a ubiquitous characteristic of all organisms. Two central evolutionary theories hypothesize that the detrimental effects of aging are due to an accumulation of mutations, or antagonistic pleiotropy, whereby genes with beneficial effects early in life become deleterious with age [3] These are not necessarily exclusive, and there is at present relatively strong evidence for both in studies of model organisms and in natural populations [3,4]. For example genes that make up the mitochondrial electron transport chain appear to decrease with age in different tissues, and this is supported in that decreases are evident in mice and flies [6] These studies remain relatively small in scale and few in number meriting larger studies in additional populations and tissues. We have evaluated mRNA expression profiles as a function of age in two populations; one consisting of 191 individuals with ages-at-death ranging from 65–100 years and with postmortem brain mRNA measurements of 13,216 genes and a second with 1240 individuals ages 15–94 and lymphocyte mRNA estimates for 18,519 genes
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