Mid- and late-life cardiovascular health indicators and changes in biological ageing Markers; a multi-cohort study

Cardiovascular (CV) health-related risk factors may influence the epigenetic-based pace of biological ageing (BA). However, given that early-life lifestyle factors can have lasting effects on DNA methylation (DNAm), observed associations may reflect cumulative exposures rather than short-term changes in older adults. We investigated whether CV risk factors are associated with changes in the pace of ageing in midlife and older adults.

We analysed baseline DNA methylation data from 4848 participants across three cohorts, AGES-RS (n = 2602), CARDIA (n = 1568), and InCHIANTI (n = 678), using Illumina arrays, with two to four time points per cohort. Pace of ageing was measured using DunedinPACE (DDPACE). Cardiovascular risk factors included smoking status, DNAm-derived pack-years, physical activity (PA), body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP), total cholesterol, blood fasting glucose, and their composite score (adapted Life's Simple 7 [adapted-LS7]). We conducted three analyses: (1) prospective analysis of CV risk factors (exposures) and DDPACE (outcome); (2) delta analysis of changes in DDPACE; and (3) shift analysis focusing on participants whose pace of ageing accelerated (accelerators: ≥1 SD above the mean) or decelerated (decelerators: ≤1 SD) over time. After excluding individuals with consistently average, fast, or slow ageing patterns, we conducted each analysis at the 5-year and 9⁺-year follow-ups.

Across cohorts, >55% were female. Mean (SD) age ranged from 40.3 (3.6) in CARDIA to 76.3 (5.2) in AGES-RS. DDPACE also varied: 0.92 (0.13) in CARDIA vs. 1.10 (0.11) in AGES-RS. Within 5-year follow-up, smoking (current and former), pack-years of smoking, BMI, and blood glucose level were longitudinally associated with faster ageing (higher DDPACE; P < 0.05 (two-sided, linear mixed modeling)) in each cohort and in the meta-analyses. PA, diet, and higher adapted-LS7 scores were linked to slower ageing. Delta analyses confirmed consistent associations in AGES-RS, CARDIA, and the meta-analysis. In the meta-analysis of the 5-year shift model, higher pack-years, BMI, SBP, and DBP increased odds of being in the "accelerator" group compared to a "decelerator" (P < 0.05 (two-sided, logistic regression)), while higher adapted-LS7 scores increased odds of being a "decelerator" (P < 0.05 (two-sided, logistic regression)). Midlife prospective analysis in AGES-RS (∼age 50) showed similar patterns. Longer-term follow-ups (9+ years) in CARDIA and InCHIANTI showed similar but less consistent findings with the 5-year follow-up.

Targeting modifiable CV risk factors, particularly smoking, physical inactivity, and poor cardiometabolic health, may help slow ageing and reduce age-related disease burden in midlife and older adults.

National Institute on Aging, National Heart, Lung, and Blood Institute, Icelandic Heart Association, and Italian Ministry of Health.