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

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.