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

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.

Longevity in response to lowered insulin signaling requires glycine N‐methyltransferase‐dependent spermidine production

“…Studies examining the transcriptomic and proteomic changes that occur during aging, or in response to interventions that ameliorate its effects, have revealed several conserved prolongevity processes, including many metabolic changes (Afschar et al, ; Dobson et al, ; Hahn et al, ; Murphy et al, ; Narayan et al, ; Page et al, ; Stout et al, ; Tain et al, ; Teleman, Hietakangas, Sayadian, & Cohen, ). These include carbohydrate metabolism (Afschar et al, ), lipid and fatty acid metabolism (Dobson et al, ; Hahn et al, ; Murphy et al, ; Page et al, ), energy metabolism (Afschar et al, ), and protein and methionine (Met) metabolism (Narayan et al, ; Stout et al, ).…”

Combined analysis of whole‐exon sequencing and lncRNA sequencing in type 2 diabetes mellitus patients with obesity

“…As an important mediator of insulin binding to its receptors and exerting biological effects, IRS1 plays an important role in the control of blood glucose homeostasis . A recent study suggests that the cause of insulin deficiency in obese patients may be due to a weakened IRS1 signal .…”

“…As an important mediator of insulin binding to its receptors and exerting biological effects, IRS1 plays an important role in the control of blood glucose homeostasis. 19 A recent study suggests that the cause of insulin deficiency in obese patients may be due to a weakened IRS1 signal. 20 A study of African-Americans found that IRS1 mutations and endocrine disorders caused by obesity synergistically reduce insulin sensitivity, suggesting that IRS1 variability and obesity together become an important predictor of insulin resistance.…”

Signaling Network of Forkhead Family of Transcription Factors (FOXO) in Dietary Restriction

“…Interventions to disrupt the GH/IGF-1 (somatotropic) axis have been shown to have pro-longevity effects in mice. For example, mice with deletion of insulin receptor substrate 1 (IRS1) are long-lived with delay age-related processes [49]. Knockout of the mouse growth hormone receptor/binding protein (GHR/BP) gene also results in an extended lifespan [44,50,51].…”