Abstract
BackgroundCaloric restriction (CR) counters deleterious effects of aging and, for most mouse genotypes, increases mean and maximum lifespan. Previous analyses of microarray data have identified gene expression responses to CR that are shared among multiple mouse tissues, including the activation of anti-oxidant, tumor suppressor and anti-inflammatory pathways. These analyses have provided useful research directions, but have been restricted to a limited number of tissues, and have focused on individual genes, rather than whole-genome transcriptional networks. Furthermore, CR is thought to oppose age-associated gene expression patterns, but detailed statistical investigations of this hypothesis have not been carried out.ResultsSystemic effects of CR and aging were identified by examining transcriptional responses to CR in 17 mouse tissue types, as well as responses to aging in 22 tissues. CR broadly induced the expression of genes known to inhibit oxidative stress (e.g., Mt1, Mt2), inflammation (e.g., Nfkbia, Timp3) and tumorigenesis (e.g., Txnip, Zbtb16). Additionally, a network-based investigation revealed that CR regulates a large co-expression module containing genes associated with the metabolism and splicing of mRNA (e.g., Cpsf6, Sfpq, Sfrs18). The effects of aging were, to a considerable degree, similar among groups of co-expressed genes. Age-related gene expression patterns characteristic of most mouse tissues were identified, including up regulation of granulin (Grn) and secreted phosphoprotein 1 (Spp1). The transcriptional association between CR and aging varied at different levels of analysis. With respect to gene subsets associated with certain biological processes (e.g., immunity and inflammation), CR opposed age-associated expression patterns. However, among all genes, global transcriptional effects of CR were only weakly related to those of aging.ConclusionThe study of aging, and of interventions thought to combat aging, has much to gain from data-driven and unbiased genomic investigations. Expression patterns identified in this analysis characterize a generalized response of mammalian cells to CR and/or aging. These patterns may be of importance in determining effects of CR on overall lifespan, or as factors that underlie age-related disease. The association between CR and aging warrants further study, but most evidence indicates that CR does not induce a genome-wide "reversal" of age-associated gene expression patterns.
Highlights
Caloric restriction (CR) counters deleterious effects of aging and, for most mouse genotypes, increases mean and maximum lifespan
The symbol p-value for up regulation (Pu) is used throughout to denote a p-value generated from a one-sided hypothesis test for up regulation by CR, while p-value for down regulation (Pd) denotes a p-value generated from a onesided hypothesis test for down regulation by CR
Microarray analyses provide a data-driven approach for judging which pathways serve as "hubs" that connect the diverse processes modulated by CR and aging, and this can lead to the construction of large gene interaction networks, with scope substantially greater than those generated by standard methods
Summary
Caloric restriction (CR) counters deleterious effects of aging and, for most mouse genotypes, increases mean and maximum lifespan. Previous analyses of microarray data have identified gene expression responses to CR that are shared among multiple mouse tissues, including the activation of anti-oxidant, tumor suppressor and anti-inflammatory pathways These analyses have provided useful research directions, but have been restricted to a limited number of tissues, and have focused on individual genes, rather than whole-genome transcriptional networks. Establishing the relative importance of these and other pathways in the mammalian CR effect provides avenues for development of CR mimetic compounds, and advances a mechanistic understanding that should shed light on unanswered questions It is unclear whether beneficial effects of CR arise from restriction of specific nutrients (e.g., fat, methionine) [1], and for unknown reasons, effects of CR on lifespan differ among genotypes [8,9]. These issues may be addressed, in part, by identifying pathways perturbed by CR and understanding their functional contribution to increased lifespan
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