The concept of intrinsic capacity (IC), proposed by the World Health Organization (WHO), represents the sum of an individual’s physical and mental reserves. Unlike disease-centered approaches, IC allows a holistic and functional view of aging, becoming a fundamental metric for healthy aging strategies. However, its clinical application faces practical obstacles, such as the need for multidimensional assessments and specific equipment. Given this, the development of molecular biomarkers for IC is an emerging priority.
In this context, Fuentealba et al. (2025) proposed an epigenetic clock based on DNA methylation (DNAm) as a predictive tool for IC, integrating data from the INSPIRE-T cohort with validation in the Framingham Heart Study (FHS). The model, called IC clock, was trained based on five IC domains: cognition, locomotion, sensory, psychological and vitality. Vitality, here, was measured objectively through handgrip strength, recognized as a robust marker of physiological reserve and healthy aging.
The final model included 91 CpG sites and showed significant correlation with clinical CI (rₛ = 0.61; P < 10⁻⁹⁴). Notably, the DNAm prediction of CI was highly negatively correlated with chronological age (rₛ = -0.92), although the CpG sites with the highest weight in the model were not strongly associated with age, suggesting that the CI clock captures biological aspects of aging distinct from traditional epigenetic clocks.
Compared with first- and second-generation epigenetic models such as Horvath, Hannum, PhenoAge, and GrimAge, clock CI demonstrated superior performance in predicting all-cause mortality (HR = 1.38; P = 1.67 × 10⁻²⁴), as well as cardiovascular mortality and heart failure. Furthermore, individuals with high levels of epigenetic CI lived, on average, 5.5 years longer than those with low levels, even after adjusting for age and sex.
From a functional perspective, IC DNAm correlated positively with markers of physical health, bone mineral density, lung performance and subjective health assessments. On the other hand, reduced levels of IC DNAm were associated with systemic inflammatory markers (such as IL-6 and C-reactive protein) and neurodegenerative markers (such as tau protein), evidencing a relationship between IC and immunosenescence and chronic inflammation processes.
Transcriptomic analysis revealed a gene signature of 578 differentially expressed genes associated with IC DNAm. Among them, CD28 stands out, whose high expression correlated with higher IC and suggests preservation of T cell function. On the other hand, genes such as CDK14/PFTK1, associated with inflammation and neurodegenerative diseases, were expressed in greater quantities in individuals with low epigenetic IC. This profile reinforces the association between IC and immune system integrity, especially in the context of aging.
Interestingly, the study also identified correlations between DNAm IC and lifestyle factors. Adherence to reduced sugar intake guidelines and consumption of marine-derived omega-3 fatty acids (such as DHA and EPA) were associated with higher levels of epigenetic IC, signaling the potential for dietary interventions in maintaining physiological function across the lifespan.
As a neuroscientist, I was struck by the association between specific domains of IC and distinct molecular processes: for example, vitality with mitochondrial pathways, the psychological domain with DNA repair, and the sensory domain with proteostasis. These findings reinforce the idea that functional decline with age is multifactorial and can be accurately tracked by epigenetic biomarkers, offering a new lens for personalized medicine of aging.
In summary, the IC clock represents a promising, noninvasive and scalable tool to quantify functional capacity in a molecular manner. Although further validation in diverse clinical settings is needed, this work opens a new era in health assessment during aging, integrating genomics, epigenetics, immunology and epidemiology into a single marker of global function.
Reference:
FUENTEALBA, Matías et al. A blood-based epigenetic clock for intrinsic capacity predicts mortality and is associated with clinical, immunological and lifestyle factors. Nature Aging, [sl], 2025. DOI: https://doi.org/10.1038/s43587-025-00883-5. Available at: https://www.nature.com/articles/s43587-025-00883-5. Accessed on: 18 June. 2025.
