The search for genetic determinants of longevity in humans has, on the whole, not gone well. Only a very small number of widespread gene variants (such as those in the APOE gene) manage to show effects on life span in multiple study populations, and their effect sizes are largely much smaller than those attributed to exercise. The modern existence of large genetic databases has, if anything, pushed down the estimate of the degree to which genetic variation contributes to longevity. The study of the genetics of extremely long-lived individuals has been underway a while and has not produced data to support a credible set of longevity genes. We are left with a picture of thousands of relevant genes, with every single variant exerting a situational, small contribution, and collectively their influence on longevity far outweighed by the effects of lifestyle choices. Nonetheless, researchers continue to produce studies such as the one noted here, and as for any such study, based on past outcomes we should expect there to be low odds of the results replicating in a different study population.
Aging, age-related diseases, and longevity are interconnected processes influenced by shared molecular and genetic mechanisms. In this study, we investigated the role of genetic variation in the Chromogranin A (CHGA) gene, which encodes a multifunctional precursor of regulatory peptides, in human longevity and age-related traits. Using a case-control design with two age cohorts (older adults: 65-85 years; long-lived: 86-107 years), we analysed nine selected CHGA single nucleotide polymorphisms (SNPs) for associations with survival to advanced age and relevant clinical parameters.
Five SNPs (rs9658628, rs9658631, rs9658634, rs7159323, and rs7610) were significantly associated with longevity. In the older adult cohort, the 5′-UTR rs9658628-A allele was associated to reduced odds of reaching advanced age and correlated with increased insulin resistance, type 2 diabetes, and lower cognitive performance, traits typically linked to higher mortality risk. Paradoxically, this allele was also associated with a lower risk of cardiovascular disease, suggesting pleiotropic effects potentially mediated by its regulatory effects on CHGA expression across different tissues. Functional annotation supported rs9658628 as an expression quantitative trait locus (eQTL) for CHGA and neighboring genes (ITPK1, FBLN5 genes in particular) in relevant tissues. Additionally, the 3′-UTR rs7610-T allele was associated with both increased diastolic blood pressure and enhanced survival, highlighting the complexity of blood pressure regulation in aging.
These findings suggest that genetic variations in CHGA exert a complex and multifactorial influence on pathways related to metabolism, cognition, and vascular health, with possible consequences for longevity. This intricate pattern could be due to the multiple, sometimes opposing, functions of CHGA and its active fragments. The biological rationale and potential clinical implications of these associations call for further investigation and independent confirmation.
Link: https://doi.org/10.3389/fragi.2025.1625070
View the full article at FightAging
