Unveiling the genetic biomarkers for ageing: evidence from a large sample genome-wide association study and in vivo validation.

Background: Ageing, marked by cumulative molecular damage, now leaves most adults spending nearly a decade in poor health. To date, no therapies directly target the ageing process. We performed a large-scale genome-wide association study to identify potential drug targets for extending health span.

Methods: By combining genetic and experimental evidence, we prioritise therapeutic targets with the potential to extend healthy lifespan. Using two-sample Mendelian randomisation (MR) across 26 152 expression quantitative trait loci instruments, we screened for causal links between 5430 potential drug target genes and four ageing phenotypes - frailty index (n = 175 226), HannumAge (n = 34 710), intrinsic epigenetic age acceleration (n = 34 710), and telomere length (n = 742 174). We re-evaluated high-confidence loci with summary-databased MR (SMR) and validated them by quantitative polymerase chain reaction (qPCR), Nissl staining, and Western blotting in three- and 20-month-old C57BL/6 mice. Finally, replication in a meta genome-wide association study (GWAS) of long-lived individuals vs. controls across 20 diverse cohorts upheld the association. This integrated genetic-experimental strategy prioritises candidate therapeutic targets for interventions aimed at extending healthy lifespan.

Results: Two-sample MR mapped 47 gene-ageing links spanning frailty, telomere length, and two epigenetic clocks. The SMR confirmed 11 with consistent directions and heterogeneity in the dependent instrument support. Both qPCR and Western blot in three- and 20-month C57BL/6 mice confirmed age-dependent down-regulation of UBA7, PLA2G4B, and ATP8B4, validating their functional relevance. Finally, replication in a longevity meta-GWAS specifically confirmed the association for UBA7.

Conclusions: These findings highlight UBA7, PLA2G4B, and ATP8B4 as promising targets for interventions aimed at extending health span, shedding light on the biological mechanisms of longevity.