Depletion of loss-of-function germline mutations in centenarians reveals longevity genes

Kejun Ying, José P. Castro, Anastasia V. Shindyapina, Alexander Tyshkovskiy, Mahdi Moqri, Ludger J. E. Goeminne, Sofiya Milman, Zhengdong D. Zhang, Nir Barzilai and Vadim N. Gladyshev ()
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Kejun Ying: Brigham and Women’s Hospital and Harvard Medical School
José P. Castro: Brigham and Women’s Hospital and Harvard Medical School
Anastasia V. Shindyapina: Brigham and Women’s Hospital and Harvard Medical School
Alexander Tyshkovskiy: Brigham and Women’s Hospital and Harvard Medical School
Mahdi Moqri: Brigham and Women’s Hospital and Harvard Medical School
Ludger J. E. Goeminne: Brigham and Women’s Hospital and Harvard Medical School
Sofiya Milman: Albert Einstein College of Medicine
Zhengdong D. Zhang: Albert Einstein College of Medicine
Nir Barzilai: Albert Einstein College of Medicine
Vadim N. Gladyshev: Brigham and Women’s Hospital and Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract While previous studies identified common genetic variants associated with longevity in centenarians, the role of the rare loss-of-function (LOF) mutation burden remains largely unexplored. Here, we investigated the burden of rare LOF mutations in Ashkenazi Jewish individuals from the Longevity Genes Project and LonGenity study cohorts using whole-exome sequencing data. We found that centenarians had a significantly lower burden (11-22%) of LOF mutations compared to controls. Similar effects were also observed in their offspring. Gene-level burden analysis identified 35 genes with depleted LOF mutations in centenarians, with 14 of these validated in the UK Biobank. Mendelian randomization and multi-omic analyses on these genes identified RGP1, PCNX2, and ANO9 as longevity genes with consistent causal effects on multiple aging-related traits and altered expression during aging. Our findings suggest that a protective genetic background, characterized by a reduced burden of damaging variants, contributes to exceptional longevity, likely acting in concert with specific protective variants to promote healthy aging.

Date: 2024
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DOI: 10.1038/s41467-024-52967-2

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