Wholesale Protein Changes with Age
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What exactly distinguishes an old cell from a new one? Telomeres may be shorter, but for the most part, the genome hasn't changed. The cell’s collective protein supply, or proteome, is another matter, however. Anyone interested in studying aging cells may want to check out today's Nature Genetics. Hao Li, Cornelia Bargmann, Cynthia Kenyon, and colleagues at the University of California, San Francisco, report a transcriptome profiling method that identifies age-related patterns in gene expression across different species.
First author Steven McCarroll and colleagues first identified highly conserved orthologs (i.e., versions of the same, or corresponding gene) from different organisms, including flies and roundworms. They then used microarray analysis to compare transcriptional profiles of these orthologs in young and middle-aged animals. While the authors found that most age-related transcriptional changes occurred only in a given species, pair-wise comparisons between organisms revealed gene categories that are regulated by age.
The scientists found 14 such categories that were shared between Drosophila and C. elegans. These included proteins that were components of mitochondrial membranes, ion transporters, peptidases, and DNA repair proteins, to name just a few. Most proteins were downregulated as animals aged, but DNA repair proteins, peptidases, and proteins involved in catabolism were upregulated. The complete list of genes, which numbers in the hundreds, is available as a supplementary figure online.
The authors also used the profiling method to explore the timing of gene regulation. They found, for example, that both C. elegans and Drosophila turned on proteins involved in heat and oxidative stress responses at the same developmental stage—early adulthood—suggesting that these regulatory switches are developmentally timed, rather than being a response to accumulated damage.
One result that is of particular interest to those working on neurodegenerative diseases is that the authors found genes encoding transporter ATPases are repressed as animals age. This may offer a "candidate mechanistic connection between two features of aging: reduction in ATP synthesis and decline in the physiological activity of neurons, muscle, and excretory processes," the authors write.—Tom Fagan
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Primary Papers
- McCarroll SA, Murphy CT, Zou S, Pletcher SD, Chin CS, Jan YN, Kenyon C, Bargmann CI, Li H. Comparing genomic expression patterns across species identifies shared transcriptional profile in aging. Nat Genet. 2004 Feb;36(2):197-204. PubMed.
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Harvard Medical School
This paper describes a new bioinformatics method for comparing gene expression patterns across species by comparing the results of diverse
DNA microarray experiments. The authors exemplify the power of this approach by analyzing gene expression changes associated with aging in two highly divergent animals, C. elegans and Drosophila. Groups of orthologous genes involved in mitochondrial metabolism, catabolism, repair processes, and cellular transport show similar age-related changes in the two organisms. The authors additionally show that transcriptional responses of worms and flies to oxidative stress and heat correlate with aging-related responses, solidifying the link between oxidative stress and aging. A new finding was the suppression of genes encoding transporter-ATPases, which may compromise neuronal and secretory processes in aged animals. These findings suggest that there may be phylogenetic conservation of some gene expression programs associated with aging.
Although orthologous genes corresponding to functional categories (known as gene ontology categories) were similarly regulated in aging Drosophila and C. elegans, the magnitudes of the expression changes were generally small. This highlights an important issue, which is the biological significance of modest expression changes affecting many related genes. An emerging theme in bioinformatics is that relatively modest expression changes in multiple members of an interacting gene group may be biologically important. An example of this phenomenon was recently reported for diabetes, in which multiple genes that mediate energy metabolism exhibit modestly reduced expression. The authors also demonstrated that their large-scale genomic comparison method could be used to identify conserved gene expression programs associated with other biological processes, including larval development, meiosis, and RNA degradation. Hence, it can be anticipated that comparative functional genomics will be an incisive tool for resolving conserved genetic programs corresponding to a variety of physiological and pathological processes. This approach should be facilitated by the expanding database of microarray results and improved statistical methods for evaluating such data.
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