INSPIRE-T Cohort Study Links Superior Cardiovascular Health to Decelerated Epigenetic Aging

A cross-sectional study of 1,099 participants in the INSPIRE-T cohort reports that ideal cardiovascular health is strongly associated with decelerated epigenetic aging—particularly in younger individuals and men—while accelerated GrimAge biological aging correlates with heightened cardiovascular risk.

Researchers analyzed baseline cross-sectional data from 1,099 participants (aged 20 to 100 years, 62.6% women) in the prospective observational INSPIRE-T cohort in France to assess the associations between biological aging, cardiovascular health (CVH), and cardiovascular risk (CVR).

Biological aging rates were calculated using five DNA methylation-based epigenetic clocks (including GrimAge, Horvath, Hannum, SkinHorvath, and Levine) and one inflammatory clock (iAge).

A one-standard deviation increase in the global Life's Essential 8 (LE8) cardiovascular health score was associated with a 2.7-year deceleration in GrimAge epigenetic aging after adjusting for chronological age, sex, and cohort interactions.

The association between superior CVH and slower epigenetic aging was most pronounced in men and in participants younger than 40 years of age, whereas no statistically significant association was observed in individuals aged 80 and older.

Conversely, accelerated epigenetic aging measured by GrimAge was associated with an increased likelihood of moderate-to-high 10-year cardiovascular risk, demonstrating a 9% odds increase under the Framingham Risk Score (OR = 1.09, 95% CI [1.03; 1.14]) and a 10% odds increase under the European SCORE2/SCORE2-OP score (OR = 1.10, 95% CI [1.04; 1.16]).

No robust, persistent associations were identified between global cardiovascular health and inflammatory aging via the iAge clock, and a paradoxical association was noted between accelerated inflammatory aging and lower risk on the Framingham score.

The findings suggest that epigenetic aging pathways are modifiable through targeted cardiovascular risk management and healthy lifestyle behaviors (such as smoking cessation, weight control, physical activity, and sleep management) rather than being fixed chronological trajectories.

It highlights the superior performance of second-generation surrogate-derived epigenetic clocks (specifically GrimAge) over first-generation clocks and inflammatory clocks in reflecting clinical somatic cardiovascular burden.

By demonstrating that the protective association between ideal cardiovascular habits and biological age deceleration vanishes in the oldest age bracket (80+), the study highlights a critical window of opportunity in early and mid-adulthood for preventative longevity interventions.

The study supports the adoption of second-generation epigenetic clocks, such as GrimAge, as reliable surrogate clinical endpoints and diagnostic biomarker tools for longevity therapeutic developers targeting metabolic and cardiovascular health.

The lack of consistent correlation with the inflammatory clock (iAge) suggests that single-pathway inflammatory clocks may have limited near-term clinical utility for multi-system disease risk assessments relative to genome-wide DNA methylation assays.

For biotechnology companies advancing rejuvenation therapies, this cohort data clinically validates that the epigenetic biological aging rate closely aligns with modifiable lifestyles and traditional medical risk metrics.

The publication of longitudinal and mediation analyses using follow-up data from the 10-year INSPIRE-T study to clarify if epigenetic aging acts as a direct causal mediator linking upstream lifestyle interventions to downstream clinical cardiovascular outcomes.