Functional characterisation of rare variants in genes encoding the MAPK/ERK signalling pathway identified in long-lived Leiden Longevity Study participants.

Abstract

Human longevity, which is coupled to compression of age-related disease, is a heritable trait. However, only few common genetic variants have been linked to longevity, suggesting that rare, family-specific variants may also play a role. We therefore investigated whole-genome sequencing data of long-lived individuals from the Leiden Longevity Study and identified family-specific variants residing in genes involved in the mitogen-activated protein kinase (MAPK) cascade, a lifespan-associated and evolutionarily conserved pathway emerging from studies in model organisms. We subsequently generated and functionally characterised mouse embryonic stem cells (mESCs) harbouring these variants. Two variants, located in NF1 (Phe1112Leu) and RAF1 (Asp633Tyr), reduce MAPK/extracellular signal-regulated kinase (ERK) signalling pathway activity in mESCs. At the proteomic and transcriptomic level, we observed prominent changes that were shared (e.g. upregulation of ribosomal proteins and Foxo3 expression) and opposing between the variants (e.g. downregulation of mTORC1 signalling-related proteins and Ets2 expression in the RAF1