Identification of transcriptional targets of healthspan in adipose tissue and modulation by resveratrol

Abstract

Although calorie restriction (CR) slows the aging process in diverse species, CR is not a pragmatic strategy to attenuate aging in free-living humans. Accordingly, there is growing interest in identifying CR mimetics—compounds that elicit the salutary effects of CR without a reduction in energy intake. Because increased white adipose tissue (WAT) is associated with accelerated onset of many age-associated diseases, and because a reduction of WAT is a consistent feature of CR, diet-induced changes in WAT bioactivity may be attractive targets for assessing the efficacy of CR mimetics. We analyzed gene expression datasets from WAT of obese mice and humans and found a significant modulation of 22 pathways indicating decreased mitochondrial function and an up-regulation of the immune response and lysosomal structure. The change with obesity was abrogated by long-term CR in WAT of both mice and rats for 13 of the 22 pathways. For those 13 pathways, consumption of the putative CR mimetic resveratrol both opposed the effect obesity and mimicked the effect of CR for 11 and 10 pathways in human and mouse adipose tissue, respectively. Numerous studies have shown that resveratrol delays diverse aspects of the aging process, suggesting that our observed transcriptional response in WAT is indicative of increased healthspan. We propose that these pathways may be used as a framework to screen for novel CR mimetics.