Advancing age is the major risk factor for many serious illnesses, including cancer, cardiovascular disease, and dementia. The rising number of older individuals is thus causing a major burden of ill health. However, individuals that reach an exceptional old age often seem to escape or delay age-related diseases, and part of this trait seems to be encoded in their genome. Hence, by studying the genome of long-lived individuals, we may be able to identify mechanisms that could be targeted for healthy ageing in the general population. My previous work suggests that large genome-wide association studies (GWAS) of long-lived individuals can be used to identify genetic variants involved in longevity. However, the common genetic variants thus far identified using GWAS only explain a minor part of the genetic component of longevity. This trait, therefore, may well be mainly determined by rare genetic variants, which can be detected using whole-genome or exome sequencing of long-lived families or exceptionally long-lived individuals. The aim of the proposed project is to establish the effect of genetic variants identified in genetic studies of long-lived individuals on general health and lifespan using cellular models and, subsequently, model organisms. To this end, I will use CRISPR/Cas9 gene editing to generate transgenic cell lines and mice that harbour genetic variants in candidate genes and pathways identified through GWAS and sequencing studies of long-lived families and individuals. I will subsequently use this information to create a high-throughput screening assay to identify compounds that can pharmacologically recapitulate the observed in vitro effects. As a proof-of-principle, I will start with functional characterisation of rare variants in genes involved in insulin/insulin-like growth factor 1 (IIS) and mammalian target of rapamycin (mTOR) signalling, given the well-known role of these networks in ageing in pre-clinical model organisms.
Fields of science
- HORIZON.1.1 - European Research Council (ERC) Main Programme