Optimising age-specific insulin signalling to slow down reproductive ageing increases fitness in different environments

Abstract

Intermittent fasting (IF) and reduced insulin/IGF-1 nutrient-sensing signalling (rIIS) increase lifespan via partially shared downstream genetic pathways. The relationship between IF and rIIS is unclear because IF reduces reproduction, while adulthood-only rIIS does not. Here, we show that early-adulthood (but not late-adulthood) IF and adulthood-only rIIS additively increase lifespan and slow reproductive ageing inC. elegans. Mechanistically, we show that in the combined IF + rIIS treatment, nuclear localisation of DAF-16 transcription factor is primarily driven by IF in early-life, and primarily driven by rIIS in late-life. Full factorial genome-wide RNA-seq across the life course demonstrates that early-adulthood IF and rIIS modulate the age-specific expression of pro-longevity genes. Early-adulthood IF, rIIS and combined IF + rIIS treatment downregulated genes involved in peptide metabolism in early life and differentially regulated immunity genes in later life. Importantly. combined IF + rIIS treatment uniquely regulated a large cluster of genes in mid-life that are associated with immune response. These results suggest that the combined impact of different treatments aimed at healthy ageing can achieve better outcomes by targeting different ages.