A groundbreaking study published in the latest issue of Aging sheds light on the intricate relationship between molecular markers of biological aging and cognitive function, offering fresh insights into how our brains age at the cellular level. This extensive analysis, led by researchers at Boston University, delves into the role of DNA methylation (DNAm) age acceleration—a cutting-edge epigenetic biomarker that reflects biological aging independent of chronological years—and its connection to performance on a digital cognitive test known as the Clock Drawing Test (dCDT).
The Clock Drawing Test has long been recognized as a simple yet effective tool to assess cognitive domains including memory, executive function, spatial abilities, and motor coordination. The digital adaptation (dCDT) offers enhanced precision and automation, delivering scores that quantify specific cognitive skills rather than a generalized outcome. By applying these measures within the framework of the Framingham Heart Study, the current research investigates whether molecular signatures of aging, particularly epigenetic modifications, can predict subtle cognitive changes before clinical symptoms manifest.
Epigenetic age acceleration is computed by examining DNAm patterns—chemical tags that regulate gene expression without altering the underlying DNA sequence. With age, DNAm profiles shift, reflecting accumulated molecular damage, exposure to environmental factors, and lifestyle influences. The acceleration metric captures the discrepancy between biological and chronological age, thus serving as a proxy for an individual’s “true” physiological aging rate. This study specifically assessed multiple established epigenetic clocks, including Horvath, PhenoAge, DunedinPACE, and GrimAge, each representing distinct facets of molecular aging.
A remarkable sample of 1,789 individuals drawn from the Framingham cohort provided the data pool, enabling the scientists to correlate biological age acceleration with subsequent dCDT performance recorded approximately seven years later. Statistically controlling for confounding variables such as baseline chronological age, sex, educational background, and blood cell composition, the researchers observed a compelling inverse association between DNAm age acceleration and dCDT scores. Notably, this relationship was most pronounced in participants aged 65 and older, underscoring potential age-dependent vulnerabilities in brain aging.
Among the epigenetic clocks analyzed, the DunedinPACE measure stood out as the most robust predictor of diminished cognitive performance in both younger and older adults. This finding suggests that this speedometer of aging not only marks age-related biological deterioration but also aligns closely with declines in neurological functions. Conversely, other clocks like Horvath and PhenoAge demonstrated significant cognitive associations primarily within the older population, implying their sensitivity to accumulated epigenetic changes manifesting in late life cognitive deficits.
The research further explored the influence of aging-related plasma proteins encapsulated within the GrimAge clock, specifically focusing on two markers: Plasminogen Activator Inhibitor-1 (PAI1) and Adrenomedullin (ADM). Elevated levels of these proteins, correlated with systemic aging and inflammation, were linked to poorer cognitive outcomes, particularly among senior participants. These protein biomarkers reinforce the concept that cognitive decline is not an isolated cerebral phenomenon but a reflection of systemic biological aging affecting multiple organ systems.
With the epigenetic clocks and protein markers collectively illustrating a molecular portrait of cognitive aging, the study presents a compelling case for the integrative monitoring of brain health. Digital cognitive testing tools like the dCDT, when paired with molecular assays of DNAm and plasma proteins, could usher in a new era of personalized aging diagnostics. Clinicians might one day utilize these combined biomarkers to detect early cognitive impairment, enabling timely intervention strategies long before overt dementia surfaces.
The mechanistic underpinnings remain a focus of ongoing research, but these epigenetic patterns likely reflect cumulative oxidative stress, chronic inflammation, and diminished cellular repair mechanisms—all processes intricately linked to neurodegenerative disease pathogenesis. Moreover, the heterogeneous associations across different epigenetic clocks reinforce the multifaceted nature of aging biology and the necessity for a composite biomarker approach rather than reliance on a single molecular indicator.
Figurative heatmaps presented in the original publication illuminate the nuanced relationships between standardized DNAm age acceleration increments and specific cognitive domains measured by the dCDT, such as spatial reasoning and motor skill execution. The P-values embedded within reveal the statistical weight of these associations, reaffirming their robustness despite adjustments for confounders. This graphical representation accentuates the precise cognitive functions most susceptible to biological aging effects, further refining potential targets for neuroprotective therapies.
The implications of this study extend beyond the realm of cognitive neuroscience and gerontology into public health and aging-related policy. Aging populations worldwide face burgeoning burdens of dementia and cognitive impairment, demanding innovative screening modalities capable of rapid, scalable deployment. The dCDT’s automated digital format combined with non-invasive blood-based epigenetic profiling presents a viable path forward, marrying technological accessibility with molecular sophistication.
Moreover, these findings challenge the long-standing primacy of chronological age in assessing brain health. By revealing how a person’s biological aging rate may diverge significantly from their chronological years, the study advocates for a paradigm shift toward more nuanced and individualized aging assessments. This molecular approach holds promise not only for early diagnosis but also for monitoring therapeutic responses and lifestyle interventions aimed at decelerating biological aging trajectories.
Ethical and practical considerations accompany the integration of these biomarkers into clinical and research settings. Issues concerning data privacy, equitable access, and interpretation of epigenetic data in diverse populations necessitate careful deliberation. Nonetheless, the clear associations established between DNAm age acceleration and cognitive decline underscore the urgency of advancing this field toward translational applications.
In summary, the Boston University-led team’s pioneering work within the longstanding framework of the Framingham Heart Study provides critical empirical evidence linking DNA methylation-based biological age acceleration with subsequent cognitive decline measured via the digital Clock Drawing Test. This convergence of epigenetic science and digital cognitive assessment heralds transformative possibilities in aging research and clinical practice, illuminating pathways to detect, track, and perhaps ultimately mitigate the ravages of cognitive aging.
Subject of Research: Not explicitly specified beyond research on molecular and cognitive aging.
Article Title: Association of DNA methylation age acceleration with digital clock drawing test performance: the Framingham Heart Study
News Publication Date: 21-Jul-2025
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Image Credits: © 2025 Li et al., licensed under Creative Commons Attribution License (CC BY 4.0)
Keywords: aging, epigenetic aging, DNA methylation, cognitive function, digital Clock Drawing Test
