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<p>Healthy aging is a complex process influenced by genetic, environmental, and lifestyle factors. Although prior genetic studies have identified loci associated with longevity, replication has often been limited by strong non-genetic influences. To investigate the genetic contributors to healthy aging, we performed a genome-wide association study (GWAS) and pathway analyses in 597 Super Seniors—individuals aged ≥ 85&#xa0;years with no history of cancer, cardiovascular disease, diabetes, dementia, or major pulmonary disease—compared to 420 mid-life population-based controls that represent the population before selection for survival from age-related disorders. Candidate variant analyses confirmed known associations at the <i>APOE</i> locus, where <i>APOE4</i> carriers had reduced odds of healthy aging (<i>P</i> = 0.0025), with stronger effects in females (<i>P</i> = 8.82 × 10⁻<sup>4</sup>). Several <i>FOXO3</i> variants (rs10457180, rs13217795, rs2802292) showed nominal associations with increased odds of being a Super Senior, again primarily among females. The GWAS, conducted on 8 million imputed variants, identified no genome-wide significant variants; however, suggestive associations were observed at the <i>EMG1/LPCAT3/C1S</i>, <i>AHI1</i>, <i>OR10P1</i>, <i>TRPC4</i>, <i>NR3C2</i>, and <i>IGFBP7</i> loci. The most significant locus, <i>EMG1/LPCAT3/C1S</i>, has been linked to red blood cell fatty acid levels, lipid homeostasis, atherosclerosis, and insulin resistance—processes relevant to healthy aging. Candidate pathway analyses identified significant enrichment after FDR correction in six key aging-related signaling pathways: PI3K–AKT (FDR = 0.0016), cellular senescence (FDR = 0.011), insulin (FDR = 0.012), autophagy (FDR = 0.017), p53 (FDR = 0.017), and mTOR (FDR = 0.027). Genome-wide pathway analysis further highlighted both known and novel genetic pathways influencing healthy aging.</p>

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Genome-wide association study and pathway analysis of healthy aging in Super Seniors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月11日

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  • Rawnak Hoque,
  • Stephen Leach,
  • Angela Brooks-Wilson

摘要

Healthy aging is a complex process influenced by genetic, environmental, and lifestyle factors. Although prior genetic studies have identified loci associated with longevity, replication has often been limited by strong non-genetic influences. To investigate the genetic contributors to healthy aging, we performed a genome-wide association study (GWAS) and pathway analyses in 597 Super Seniors—individuals aged ≥ 85 years with no history of cancer, cardiovascular disease, diabetes, dementia, or major pulmonary disease—compared to 420 mid-life population-based controls that represent the population before selection for survival from age-related disorders. Candidate variant analyses confirmed known associations at the APOE locus, where APOE4 carriers had reduced odds of healthy aging (P = 0.0025), with stronger effects in females (P = 8.82 × 10⁻4). Several FOXO3 variants (rs10457180, rs13217795, rs2802292) showed nominal associations with increased odds of being a Super Senior, again primarily among females. The GWAS, conducted on 8 million imputed variants, identified no genome-wide significant variants; however, suggestive associations were observed at the EMG1/LPCAT3/C1S, AHI1, OR10P1, TRPC4, NR3C2, and IGFBP7 loci. The most significant locus, EMG1/LPCAT3/C1S, has been linked to red blood cell fatty acid levels, lipid homeostasis, atherosclerosis, and insulin resistance—processes relevant to healthy aging. Candidate pathway analyses identified significant enrichment after FDR correction in six key aging-related signaling pathways: PI3K–AKT (FDR = 0.0016), cellular senescence (FDR = 0.011), insulin (FDR = 0.012), autophagy (FDR = 0.017), p53 (FDR = 0.017), and mTOR (FDR = 0.027). Genome-wide pathway analysis further highlighted both known and novel genetic pathways influencing healthy aging.