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Updated: May 23, 2025

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Published on: September 17, 2020
Genetic predictors of longevity and survival in cellular homeostasis genes: A case-control study
Vera Erdman1, Anna Petintseva2, Yanina Timasheva1
1Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa 450054, Russia; Bashkir State Medical University, Ufa 450008, Russia.
Background:
Longevity is defined by the ability to maintain both physical and mental health throughout a long life and may results from adaptive mechanisms that mitigate aging's detrimental effects.
Methods:
The 20-year follow-up study of 3,312 unrelated individuals aged 18-114 years from the Volga-Ural region of Eurasia investigated variants in cellular homeostasis genes IGF1, PIK3R1, AKT1, MTOR, NFE2L2, KEAP1, HIF1A, TP53, and SIRT1, to identify associations with clinical aging phenotypes and healthy longevity.
Results:
In men, KEAP1 (rs1048290) CC genotype was a longevity and survival marker (OR = 2.39, P = 3E-05, HR = 0.54, P = 2.4E-03). NFE2L2 (rs6721961) TT genotype was linked to higher mortality (HR = 1.77, P = 0.031), particularly combined with KEAP1 (rs1048290) G and AKT1 (rs3803304) C alleles (HR = 2.8, P = 0.023). In women, AKT1 (rs3803304) C allele interacted with NFE2L2 (rs6721961) TT genotype (SF = 0.13, P = 3.6E-03), and was linked to longevity (OR = 2.22, P = 6.3E-03) and protection against cerebrovascular diseases (OR = 0.62, P = 5.1E-03). AKT1 (rs3803304) GG genotype, along with HIF1A (rs11549465) T and SIRT1 (rs3758391) T alleles (SF = 2.52, P = 1.5E-03), promoted survival (HR = 0.71, P = 0.014). In men, HIF1A (rs11549465) TT genotype predicted cardiovascular mortality (HR = 7.5, P = 5.5E-03). SIRT1 (rs3758391) TT genotype was associated with improved survival in individuals with diabetes (HR = 0.4, P = 5.8E-03) and multimorbidity (HR = 0.48, P = 0.025).
Conclusion:
Variants in NFE2L2, KEAP1, SIRT1, AKT1, and HIF1A, along with their interactions, were significantly associated with survival in age-related diseases and healthy longevity.
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