HLA, aging, and longevity: a critical reappraisal

Area of Science:

• Immunogenetics
• Longevity Research
• Human Genetics

Background:

• The role of Human Leukocyte Antigen (HLA) genes in human longevity is debated.
• Previous studies suffer from significant methodological limitations, hindering definitive conclusions.
• Understanding genetic factors influencing lifespan is crucial for aging research.

Purpose of the Study:

• To critically evaluate existing data on HLA associations with longevity.
• To identify potential genetic markers and mechanisms contributing to exceptional lifespan.
• To explore the influence of specific HLA alleles, haplotypes, and homozygosity on longevity.

Main Methods:

• Review and critical analysis of existing literature on HLA and longevity.
• Identification of studies minimizing methodological biases.
• Examination of associations between HLA alleles, homozygosity, and the 8.1 ancestral haplotype with longevity.

Main Results:

• Despite methodological challenges, some HLA alleles are associated with longevity, though potentially increasing disease risk.
• Increased homozygosity at HLA loci appears linked to longevity.
• The 8.1 ancestral haplotype shows a sex-specific (males) association with longevity, potentially linked to immune response shifts.

Conclusions:

• The genetic architecture of longevity, including HLA, is complex and influenced by pleiotropic gene effects.
• The 8.1 ancestral haplotype's association with longevity may be explained by antagonistic pleiotropy, benefiting early life and aging.
• Further unbiased research is needed to clarify HLA's precise role in exceptional longevity.