A meta-analysis of caloric restriction gene expression profiles to infer common signatures and regulatory mechanisms

Abstract

Caloric restriction, a reduction in calorie intake without malnutrition, retards age-related degeneration and extends lifespan in several organisms. CR induces multiple changes, yet its underlying mechanisms remain poorly understood. In this work, we first performed a meta-analysis of microarray CR studies in mammals and identified genes and processes robustly altered due to CR. Our results reveal a complex array of CR-induced changes and we re-identified several genes and processes previously associated with CR, such as growth hormone signalling, lipid metabolism and immune response. Moreover, our results highlight novel associations with CR, such as retinol metabolism and copper ion detoxification, as well as hint of a strong effect of CR on circadian rhythms that in turn may contribute to metabolic changes. Analyses of our signatures by integrating co-expression data, information on genetic mutants, and transcription factor binding site analysis revealed candidate regulators of transcriptional modules in CR. Our results hint at a transcriptional module involved in sterol metabolism regulated by Srebf1. A putative regulatory role of Ppara was also identified. Overall, our conserved molecular signatures of CR provide a comprehensive picture of CR-induced changes and help understand its regulatory mechanisms.

Comparative transcriptomics across 14 Drosophila species reveals signatures of longevity

“…In addition, we searched GenAge and GenDR databases (de Magalhães, Curado & Church, 2009; Plank, Wuttke, van Dam, Clarke & de Magalhaes, 2012) to test if any of our longevity signature genes were experimentally confirmed for longevity effects in yeast, flies, worms, and mice. Specifically, we checked whether the genes showing positive correlation in our list had pro‐longevity and those showing negative correlation had antilongevity effects.…”

“…Our gene list was examined against GenAge/GenDR databases (de Magalhães et al., 2009; Plank et al., 2012) to determine how the longevity effects reported in model organisms relate to our gene dataset. To analyze microarray datasets, data were downloaded from Gene Expression Omnibus (GEO) database.…”

A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans

“…Interestingly, let‐363 , rps‐6 and sir‐2.1 are also in GenDR as associated with CR longevity effects (Wuttke et al ., 2012). Additionally, we found three genes so far not associated with longevity which have been suggested to play a role in CR: orthologs of fkb‐6 and gsy‐1 (both targets of rapamycin) are significantly overexpressed in mice under CR (Plank et al ., 2012). Additionally, cbp‐1 (a transcriptional factor that might be affected by TSA) is induced under CR and blocking it results in countering the protective effects of CR (Zhang et al ., 2009).…”

The effects of graded levels of calorie restriction: IX. Global metabolomic screen reveals modulation of carnitines, sphingolipids and bile acids in the liver of C57BL/6 mice

“…This would also be consistent with a shift towards lipolysis, which supports the idea that during CR, there is an increase in oxidation of fatty acids as opposed to glucose utilization. This compliments transcriptomic liver data from previous studies, which indicate CR increases fatty acid mobilization and metabolism in several strains of mice and rats (Selman et al ., 2006; Plank et al ., 2012; Collino et al ., 2013). Three key metabolic groups showed increased responses to the levels of restriction.…”