Human lifespan is influenced by genetic and environmental factors and their interactions.
Previous studies have found that genetic factors account for less than 10 percent or as much as 25 percent of the heritability of longevity.
Identifying genetic variants that lead to early death or longer life is critical.
On February 28, 2025, Junyoung Park's team from Stanford University published a paper in the journal Nature Communications entitled "Rare genetic associations with human lifespan in UK Biobank are enriched for oncogenic genes ".
This study found that APOE and ZSCAN23 were longeve-related loci for common variants, and loss-of-function mutations in TET2, ATM, BRCA2, CKMT1B, BRCA1, and ASXL1 genes were associated with shortened lifespan.
Missense mutations in DNMT3A, SF3B1, TET2, PTEN, SOX21, TP53, SRSF2, and RLIM were also associated with shortened lifespan.
The study evaluated 10,104,569 common variants in 393,833 individuals from UKB, including 35,551 dead subjects and 358,282 living subjects.
rs429358 was found to be the lead variant at the APOE locus on chromosome 19, and the presence of APOE-ε4 was an important cause of death.
At chromosome 6, which overlaps ZSCAN23, the top significant genome-wide variant is rs6902687, which is also closely associated with the occurrence of certain diseases.
Further study found that out of 26,230,624 variants with a minor allele frequency (MAF) of < 1%, a total of 1,830,070 variants (17,174 genes) were annotated as loss of function (LoF) or missense variants.
The analysis found that the burden of LoF variants in six genes was significantly associated with shorter life span: TET2, ATM, BRCA2, CKMT1B, BRCA1, and ASXL1.
In eight genes, the burden of missense variants predicted by AlphaMissense to be pathogenic was associated with shortened lifespan: DNMT3A, SF3B1, TET2, PTEN, SOX21, TP53, SRSF2, and RLIM.
Finally, three genes showed gene-wide significance for REVEL's predicted burden of missense variation: DNMT3A, PTEN, and TP53.
For important genes in the range of 14 genes in the burden analysis, the researchers assessed the association between variant carrier status and longevity using Cox proportional hazard regression.
Carriers of LoF variants in six genes were associated with reduced survival compared to non-carriers: CKMT1B, ASXL1, TET2, ATM, BRCA2, and BRCA1.
Similarly, carriers of the disease-causing variants predicted by AlphaMissense had significantly higher mortality rates than non-carriers of the following genes:
DNMT3A, SF3B1, PTEN, SOX21, TP53, SRSF2, RLIM and TET2.
This study, which combines large-scale GWAS with detailed analyses of rare variants, found that multiple gene mutations and lifespan are closely related, advancing the understanding of the genetic basis of human lifespan.
The new loci identified in this study warrant further exploration to understand their biological roles and their interactions with environmental factors, which will be critical to uncover the complex nature of aging and develop strategies to mitigate its adverse effects.
References:
https://www.nature.com/articles/s41467-025-57315-6
