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

ABSTRACT: Human longevity, coupled to compression of age-related disease, is heritable. However, 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 families from the Leiden Longevity Study for family-specific variants. We identified 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. up-regulation of ribosomal proteins and Foxo3 expression) and opposing between the variants (e.g. down-regulation of mTORC1 signalling-related proteins and Ets2 expression in the RAF1Asp633Tyr variant cell line versus up-regulation in the NF1Phe1112Leu variant cell lines). These changes were accompanied by opposing effects on proliferation. Moreover, the RAF1Asp633Tyr variant improved resistance to replication stress, while this was not the case for the NF1Phe1112Leu variant. In conclusion, we identified two rare genetic variants in long-lived families that influence MAPK/ERK signalling in a manner that has previously been linked to increased lifespan in model organisms. Our findings suggest that mESCs offer a suitable starting point for studying rare genetic variants linked to human longevity, allowing for the identification of promising variants to pursue in in vivo model organism studies.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Embryonic Stem Cell

SUBMITTER: Ilian Atanassov  

LAB HEAD: Linda Partridge

PROVIDER: PXD063190 | Pride | 2026-03-16

REPOSITORIES: Pride