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

Dietary restriction (DR) is the most studied non-genetic intervention capable of extending lifespan across multiple taxa. Modulation of specific genes, primarily within the insulin/insulin-like growth factor signalling (IIS) and the mechanistic target of rapamycin (mTOR) signalling pathways can also act to extend lifespan and health span in model organisms. For example, both male and female mice lacking insulin receptor substrate 1 (IRS1) are long-lived and are protected against several age-associated pathologies. However, it remains unclear as to how these particular interventions act mechanistically to produce their beneficial effects, and indeed whether different interventions act through shared or distinct processes. In the following study we investigated multi-tissue transcriptional responses in 15-month-old wild type and IRS1 null mice fed an ad libitum diet (WTAL and KOAL respectively) or fed a 30% DR diet (WTDR or KODR respectively). Using an RNAseq approach we noted little transcriptional overlap between liver, skeletal muscle, brain and white adipose tissue within either WTDR or KOAL mice, but that a high correlation coefficient of differentially expressed genes existed within the same tissue across WTDR and KOAL mice. Additionally, many metabolic features were similarly shared between WTDR and KOAL mice. Overall, we report that significant overlap exists in the tissue-specific transcriptional response between long-lived DR mice and IRS1 null mice, further supporting the notion of mechanistic overlap between these long-lived mouse models. However, there was evidence of disconnect between transcriptional signatures and in certain phenotypic measures between KOAL and KODR, in that additive effects on body mass and body composition were observed but that DR induced a unique set of genes and pathways in these already long-lived mice. Overall design: Gene expression analysis of four tissue types (brain, skeletal muscle, liver or white adipose tissue) from two genotypes of mice (wild type or insulin receptor substrate 1 gene knockout) in two dietary conditions (ad libitum or 30% dietary restriction). WTAL (n=2), WTDR (n=3), KOAL (n=3) and KODR (n=3).