# Distinct, common and synergistic effects of insulin and IGF-1 receptors on healthy murine ageing

## TL;DR

Reducing both insulin and IGF-1 receptors in mice extends healthy lifespan and improves brain aging markers more than reducing either alone.

## Contribution

The study reveals synergistic and distinct effects of insulin and IGF-1 receptor reduction on healthy aging in mammals.

## Key findings

- Combined insulin and IGF-1 receptor reduction extended healthspan more than single reductions.
- Brain aging-related gene expression was reduced in mice with both receptor reductions.
- Weight gain was mainly affected by insulin receptor reduction, not IGF-1.

## Abstract

Reduced IGF-1 signalling is an evolutionarily conserved mediator of longevity, yet the magnitude of this effect is substantially larger in organisms retaining a common insulin and IGF-1 receptor. Whether this reflects the failure to simultaneously reduce IGF-1 and insulin signalling in mammalian model systems remains unexplored, as is the associated impact on markers of healthy ageing. We set out to address these uncertainties.

We compared the duration of healthy life (healthspan) in male mice with haploinsufficiency of the insulin receptor (IRKO), IGF-1 receptor (IGF-1RKO), or both (DKO), versus wildtype (WT) littermates. Cognitive performance was defined using nesting studies at 3- and 24-months of age. Brain transcriptome was characterised at 3- and 18-months of age using RNA-seq.

Healthspan was longer in DKO versus WT, with IRKO and IGF-1RKO being intermediate. At 2 years of age, DKO also exhibited preserved nesting behaviour in contrast with all other genotypes. Differential insulin sensitivity or weight gain during ageing did not explain the preserved healthspan of DKO, since these were comparable to IRKO littermates. Brain transcriptomics at 18 months of age revealed lower expression of canonical ageing-associated genes in DKO versus WT, although many of these findings were replicated in IRKO versus WT or IGF-1RKO vs WT.

Reduced insulin and IGF-1 receptor expression have both common and synergistic effects upon elements of healthy mammalian ageing, suggesting future ageing studies should consider targeting both insulin and IGF-1 signalling.

•The impact of reduced insulin and/or IGF-1 signalling on ageing were studied.•Weight gain was predominantly mitigated by reduced insulin signalling.•Healthspan was extended only with reduced insulin and IGF-1 signalling.•Insulin and IGF-1 signalling had shared and distinct impacts on brain transcriptome.•These mitigated canonical brain aging transcriptional changes.

The impact of reduced insulin and/or IGF-1 signalling on ageing were studied.

Weight gain was predominantly mitigated by reduced insulin signalling.

Healthspan was extended only with reduced insulin and IGF-1 signalling.

Insulin and IGF-1 signalling had shared and distinct impacts on brain transcriptome.

These mitigated canonical brain aging transcriptional changes.