An immune-related genetic factor reduces the odds of exceptional longevity in northern European men

The Genetics of Human Longevity group, led by Professor Almut Nebel, has identified a specific version of an immune gene (HLA-DRB1), crucial for fighting infections, that influences the ability to live past 95 years.This finding is particularly important given the limited number of known genetic factors associated with longevity so far.Thestudy, supported by the Research Training Group for Translational Evolutionary Research (TransEvo), was recently published in Genome Medicine.

The investigation focused on the human leukocyte antigen (HLA) region, which contains large group of genes with thousands of different versions (alleles) across the human population. This diversity is thought to allow our immune systems to combat a wide range of pathogens. However, as the new study shows, some of these variants can have a “dark side” later in life. The researchers have discovered that men with a specific version of the HLA-DRB1 gene, known as HLA-DRB1*15:01, are less likely to live past 95 years.

“This is a fascinating example of an evolutionary concept called antagonistic pleiotropy”, explains lead author Nicolás Mendoza-Mejía. “This means that an allele that is beneficial in early life, likely by providing a strong immune response against pathogens, can become detrimental at advanced ages”. The reduced longevity associated with the HLA-DRB1 variant may be driven by its reported increase in Alzheimer’s disease risk, particularly in men.

The researchers confirmed this genetic link in three large European cohorts from Germany, Denmark and the United Kingdom. Interestingly, this HLA-DRB1 variant originated from one of the three main ancestors of Europeans, the steppe herders, about 5000 years ago. As they domesticated livestock, they were exposed to animal-borne pathogens. Therefore, HLA-DRB1*15:01 might have provided a protective advantage. However, in modern populations, where infectious pressure is lower but neurodegenerative risk is higher, this trait can become unfavourable due to evolutionary mismatch, particularly among older men.

Original Publication:
Mendoza-Mejía, N., Kolbe, D., Özer, O., Dose, J., Torres, G. G., Franke, A., Nygaard, M., & Nebel, A. (2025). HLA-DRB1*15:01 is associated with a reduced likelihood of longevity in northern European men. Genome Medicine, 17(1), 125. https://doi.org/10.1186/s13073-025-01554-1