Common and unique transcriptional responses to dietary restriction and loss of insulin receptor substrate 1 (IRS1) in mice.
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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 <i>ad libitum</i> diet (WT<sup>AL</sup> and KO<sup>AL</sup>) or fed a 30% DR diet (WT<sup>DR</sup> or KO<sup>DR</sup>). Using an RNAseq approach we noted a high correlation coefficient of differentially expressed genes existed within the same tissue across WT<sup>DR</sup> and KO<sup>AL</sup> 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 KO<sup>AL</sup> and KO<sup>DR</sup>, 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.
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Insulin Receptor Substrate Proteins
Endocrine Therapy Resistance
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Aging, 2018, 10 (5), pp. 1027 - 1052