Carrying specific HLA alleles decreases the chance of reaching healthy old age

Abstract Human leukocyte antigen ( HLA ) genes regulate immune function and influence disease susceptibility, but their role in healthy aging is unclear. We investigated whether disease-associated HLA alleles affect the likelihood of becoming a cognitively healthy centenarian (CHC). Using imputed HLA genotypes from 3632 individuals—including 353 CHCs and 3279 middle-aged healthy Dutch individuals—we examined 59 HLA alleles previously linked to 12 diseases, including Alzheimer’s disease (AD), ten autoimmune disorders, and SARS-CoV-2. Six alleles were associated with reduced likelihood of becoming a CHC (ORs=0.59–0.74, FDR < 0.1), forming three haplotypes: a class II haplotype ( HLA-DRB1*01:01, HLA-DQA1*01:01 , HLA-DQB1*05:01), a class I haplotype (HLA-C*03:04 , HLA-B*40:01), and HLA-A*02:01 . These alleles showed pleiotropic effects, with AD-risk alleles strongly linked to lower CHC likelihood (5- to 10-fold). Our findings suggest HLA -driven immunity plays a complex role in longevity and may inform personalized strategies for age-related diseases with immunological components.