Specific genetic mutations and loci are associated with exceptional human longevity
Multiple large-scale genomic and meta-analytic studies demonstrate that specific genetic variants, loci, and mutation burdens are reliably associated with exceptional human longevity.
The retrieved literature robustly supports the claim that specific genetic variants and loci are associated with exceptional human longevity. Multiple studies—including meta-analyses, whole-exome sequencing of centenarian cohorts, and functional validations—identify specific SNPs and genes (such as APOE, TOMM40, HLA-DQB1, and COL25A1) linked to extreme lifespan and protective pathways. While one study on the Sardinian Blue Zone found a lack of association for certain tested markers, the overwhelming weight of genomic and meta-analytic evidence across diverse global populations supports the claim.
P. Sebastiani, Harold T. Bae, Fangui X. Sun, S. Andersen, E. Daw, A. Malovini, T. Kojima, N. Hirose, N. Schupf, A. Puca, T. Perls. Meta-analysis of genetic variants associated with human exceptional longevity. 2013. https://doi.org/10.18632/aging.100594
A meta-analysis confirms that multiple specific genetic variants and combinations differentiate centenarians from non-centenarians.
Errigo A, Dore MP, Mocci G, Pes GM. Lack of association between common polymorphisms associated with successful aging and longevity in the population of Sardinian Blue Zone.. 2024. https://doi.org/10.1038/s41598-024-80497-w
A study of the Sardinian Blue Zone population found no significant deviation in most tested common longevity polymorphisms, suggesting certain markers do not universally apply across all isolated populations.
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Jhih-rong Lin, P. Sin‐Chan, V. Napolioni, G. G. Torres, J. Mitra, Quanwei Zhang, M. Jabalameli, Zhen Wang, Nha Nguyen, Tina Gao, M. Laudes, S. Görg, A. Franke, A. Nebel, M. Greicius, G. Atzmon, Kenny Q. Ye, V. Gorbunova, W. Ladiges, A. Shuldiner, L. Niedernhofer, P. Robbins, S. Milman, Y. Suh, J. Vijg, N. Barzilai, Zhengdong D. Zhang. Rare genetic coding variants associated with human longevity and protection against age-related diseases. 2021. https://doi.org/10.1038/s43587-021-00108-5
Whole-exome sequencing of centenarians identifies rare coding variants in conserved longevity pathways like insulin signaling and AMPK.
Ling Zhao, Fan Yang, Ke Xu, H. Cao, Gu-Yan Zheng, Yan Zhang, Jianxin Li, H. Cui, Xiaomin Chen, Zhiming Zhu, Hong-bo He, X. Mo, Brian K. Kennedy, Y. Suh, Yi Zeng, Xiao-Li Tian. Common genetic variants of the β2-adrenergic receptor affect its translational efficiency and are associated with human longevity. 2012. https://doi.org/10.1111/acel.12011
Specific single-nucleotide polymorphisms in the ADRB2 gene are shown to be significantly associated with enhanced human longevity.
Fang Lu, H. Guan, B. Gong, Xiaoqi Liu, R. Zhu, Yong Wang, J. Qian, T. Zhou, Xiao-yan Lan, Pu Wang, Ying Lin, Shi Ma, He Lin, Xiong Zhu, Rong-hui Chen, Xianjun Zhu, Yi Shi, Zhenglin Yang. Genetic Variants in PVRL2-TOMM40-APOE Region Are Associated with Human Longevity in a Han Chinese Population. 2014. https://doi.org/10.1371/journal.pone.0099580
Variants in the PVRL2-TOMM40-APOE locus demonstrate significant associations with human longevity in population studies.
Fan Yang, Liang Sun, Xiaoquan Zhu, Jing Han, Yi Zeng, C. Nie, Huiping Yuan, Xiaoling Li, Xiao-hong Shi, Yi-ge Yang, Caiyou Hu, Z. Lv, Zezhi Huang, C. Zheng, Si-ying Liang, Jin Huang, Gang Wan, Keyan Qi, B. Qin, S. Cao, Xin Zhao, Yongqiang Zhang, Ze Yang. Identification of new genetic variants of HLA-DQB1 associated with human longevity and lipid homeostasis—a cross-sectional study in a Chinese population. 2017. https://doi.org/10.18632/aging.101323
Specific new single nucleotide polymorphisms of HLA-DQB1 are identified as being associated with longevity and lipid homeostasis.
Ying K, Castro JP, Shindyapina AV, Tyshkovskiy A, Moqri M, Goeminne LJE, Milman S, Zhang ZD, Barzilai N, Gladyshev VN. Depletion of loss-of-function germline mutations in centenarians reveals longevity genes.. 2024. https://doi.org/10.1038/s41467-024-52967-2
Gene-level burden analysis reveals specific genes with depleted loss-of-function mutations that act as longevity genes.
Goyala A, Statzer C, Park JYC, Neundorf I, MacArthur MR, Gebauer JM, Ewald CY. A centenarian single nucleotide polymorphism in collagen gene COL25A1 promotes longevity in C. elegans.. 2025. https://doi.org/10.1038/s41514-025-00264-7
A centenarian-associated SNP in COL25A1 is shown to influence furin cleavage and promote longevity.
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