Common and unique transcriptional responses to dietary restriction and loss of insulin receptor substrate 1 (IRS1) in mice.

Melissa M Page,Colin Selman,Eugene F Schuster,Manikhandan Mudaliar,Dominic J Withers,Pawel Herzyk

doi:10.18632/aging.101446

Abstract

Dietary restriction (DR) is the most widely studied non-genetic intervention capable of extending lifespan across multiple taxa. Modulation of genes, primarily within the insulin/insulin-like growth factor signalling (IIS) and the mechanistic target of rapamycin (mTOR) signalling pathways also act to extend lifespan in model organisms. For example, mice lacking insulin receptor substrate-1 (IRS1) are long-lived and protected against several age-associated pathologies. However, it remains unclear how these particular interventions act mechanistically to produce their beneficial effects. Here, we investigated transcriptional responses in wild-type and IRS1 null mice fed an ad libitum diet (WTAL and KOAL) or fed a 30% DR diet (WTDR or KODR). Using an RNAseq approach we noted a high correlation coefficient of differentially expressed genes existed within the same tissue across WTDR and KOAL mice and many metabolic features were shared between these mice. Overall, we report that significant overlap exists in the tissue-specific transcriptional response between long-lived DR mice and IRS1 null mice. However, there was evidence of disconnect between transcriptional signatures and certain phenotypic measures between KOAL and KODR, in that additive effects on body mass were observed but at the transcriptional level DR induced a unique set of genes in these already long-lived mice.

Highlights

Multiple studies have demonstrated that aging in a variety of animal species can be modulated through dietary, genetic and pharmacological means [1,2,3]
The greatest transcriptional overlap was observed between skeletal muscle and white adipose tissue (WAT); eight common genes were up-regulated including genes involved in fatty acid metabolism and thyroid hormone regulation such as Elovl6 and Thrsp, and Lmod1, and 15 common genes were down-regulated including those involved in inflammation and angiogenesis such as Serpina3n, Serpina3c, Thbs2, and Mest/Peg1
Structural constituents of ribosome and haptoglobin binding were again over-represented in the up-regulated gene category along with several Gene Ontology (GO) terms linked to mitochondrial processes, including oxidoreductase activity, electron carrier activity and cytochrome-c oxidase activity

Summary

Introduction

Multiple studies have demonstrated that aging in a variety of animal species can be modulated through dietary, genetic and pharmacological means [1,2,3] It has been established since the early 20th century that dietary restriction (DR), defined here as reductions in energy intake, reductions in specific macro or micronutrients or intermittent fasting in the absence of malnutrition, extends lifespan across many taxa [1,4,5,6,7,8]. In an attempt to better understand whether commonality (or lack thereof) exists in putative mechanisms between long-lived models, studies examining the impact of interventions such as DR on a range of parameters such as lifespan, metabolism and transcription have been undertaken in long-lived genetic mutants. [24]) suggesting that within C. elegans at least those mechanisms underlying DR-induced longevity appear distinct to those extending lifespan in IIS mutants. It should be noted that IIS may underlie a particular response to DR [25], and that the DR protocols employed may impact on the interactions observed [26]

Methods

Results

Conclusion