Artificial intelligence-assisted meta-analysis of the frequency of ACE I/D polymorphisms in centenarians and other long-lived individuals

Current research on the angiotensin-converting-enzyme (ACE) gene has yielded controversial results on whether different ACE polymorphisms are linked with human longevity. ACE polymorphisms are a risk factor for Alzheimer’s disease and age-onset diseases that may contribute to the mortality of older people. Our goal is to consolidate existing studies with assistance from artificial intelligence and machine-learning-assisted software to come to a more precise understanding of the role of the ACE gene in human longevity. The I (insertion) and D (deletion) polymorphisms in the intron are correlated with the levels of circulating ACE; homozygous D (DD) is high and homozygous I (II) is low. Here, we performed a detailed meta-analysis of the I and D polymorphisms using centenarians (100+ years old), long-lived subjects (85+ years old), and control groups. ACE genotype distribution was analyzed across a total of 2,054 centenarians and 12,074 controls, as well as 1,367 long-lived subjects between the ages of 85-99, using the inverse variance and random effects methods. The ACE DD genotype was found to be favored in centenarians (OR: 1.41 [95% CI: 1.19-1.67], P < 0.0001) with a heterogeneity of 32%, and the II genotype slightly favored the control groups (OR: 0.81 [95% CI: 0.66-0.98], P = 0.03) with a heterogeneity of 28%, corroborating results from previous meta-analyses. Novel to our meta-analysis, the ID genotype was found to be favored in control groups (OR: 0.86 [95% CI: 0.76-0.97], P = 0.01) with a heterogeneity of 0%. The long-lived group showed a similar positive association between the DD genotype and longevity (OR: 1.34 [95% CI: 1.21-1.48, P < 0.0001) and a negative association between the II genotype and longevity (OR: 0.79 [95% CI: 0.70-0.88], P < 0.0001). The long-lived ID genotype did not show significant findings (OR: 0.93 [95% CI: 0.84-1.02], P = 0.79). In conclusion, the results suggest a significant positive association of the DD genotype with human longevity. However, despite the previous study, the results do not confirm a positive association of the ID genotype with human longevity. We suggest a few paradoxical observations: (1) inhibition of ACE can increase longevity in model systems from nematodes to mammals, seemingly opposite to the finding in humans; (2) exceptional longevity associated with homozygous DD is also associated age-related diseases with higher mortality risks in homozygous DD. We discuss ACE, longevity, and age-related diseases.