Cardiometabolic resilience in aging: Intersections of FOXO3, telomere dynamics, and inflammatory cytokines in the CHAMP cohort

Abstract

Cardiometabolic diseases (CMDs), including angina, diabetes, and hypertension, are major contributors to morbidity and mortality in aging populations, yet substantial heterogeneity in disease progression and survival suggests the presence of molecular mechanisms that promote cardiometabolic resilience in later life. This dissertation examines intersections among the longevity-associated gene FOXO3, leukocyte telomere dynamics, and inflammatory cytokine profiles in aging men from the Concord Health and Ageing in Men Project (CHAMP), a longitudinal cohort of more than 1,700 men aged 70 years and older. Associations between the FOXO3 rs2802292 genotype, survival outcomes, CMD status, telomere length, and circulating cytokines were evaluated using survival analyses and regression-based models. The FOXO3 longevity-associated G allele was associated with improved survival in individuals with cardiometabolic disease, with the strongest protective effects observed in angina and in advanced age, while no consistent survival advantage was observed in individuals with diabetes, hypertension, or without CMD. On the whole, leukocyte telomere length declined with age across the cohort. However, age-related telomere attrition was attenuated in G-allele carriers, most notably among individuals with angina, while telomere trajectories were similar across other CMD categories. Inflammatory cytokine profiles differed markedly by FOXO3 genotype across all CMDs, with G-allele carriers exhibiting broader and more coordinated immune and inflammatory regulation compared with TT homozygotes. Together, these findings suggest that cardiometabolic resilience in aging is driven primarily by FOXO3-mediated inflammatory regulation, with context-dependent effects on telomere dynamics.