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

Date Published: May 20, 2018

Publisher: Impact Journals

Author(s): Melissa M. Page, Eugene F. Schuster, Manikhandan Mudaliar, Pawel Herzyk, Dominic J. Withers, Colin Selman.


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.

Partial Text

Multiple studies have now demonstrated that aging in a variety of animal species can be modulated through dietary, genetic and pharmacological means [1–3]. For example, 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 [1,4–8]. In addition, DR also improves late-life health (healthspan) in a range of organisms [1,5,9,10]. Similarly, genetic modulation of a number of signalling pathways, most notably the nutrient sensing insulin/insulin-like growth factor (IIS) and mechanistic target of rapamycin (mTOR) pathways, extends both lifespan and healthspan in model organisms [11–17], and genetic polymorphisms within these same pathways correlate with longevity in humans [18,19].

In the present study we identified transcriptional signatures within liver, skeletal muscle, brain and inguinal white adipose tissue and measured metabolic parameters in two established mouse models of longevity; genetic global knockout of IRS1 (Irs1-/-, KOAL) and dietary restriction (WTDR) and in Irs1-/- mice subject to 12 months of 30% DR (KODR). We observed very little transcriptional overlap between tissues within either KOAL or WTDR. Such tissue-specific differences within our long-lived models is supported by a recent transcriptomic and proteomic studies in rodents [39,40] and in long-lived IIS mutant flies [41], and indicates that the underlying processes that act overall to modulate longevity and affect healthspan may act independently on specific organs and tissues.




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