A new proteomic clock links accelerated ageing to ischaemic stroke: no country for old vessels

This editorial refers to ‘Accelerated ageing predicts earlier onset of ischaemic stroke: a proteomic and transcriptomic investigation’, by A. Qeck et al., https://doi.org/10.1093/eurjpc/zwaf691. For more than a decade, the field of vascular neurology has been tracking a worrying epidemiological trend: the incidence of ischaemic stroke among younger adults is rising in many regions, a pattern that cannot be fully explained by traditional risk factors alone. Multiple population-based studies and reviews have documented increasing stroke rates in adults under 50, suggesting that new or previously underappreciated mechanisms are contributing to earlier cerebrovascular vulnerability.1,2 Research on molecular measures of ageing, especially epigenetic clocks based on DNA methylation, has demonstrated relationships with cardiovascular outcomes, mortality, and subclinical atherosclerosis, implying that deviations between biological and chronological age could reflect cumulative physiological burden relevant to vascular disease.3 Proteomic approaches to measuring biological age were emerging rapidly; large-scale projects had begun to show that high-dimensional plasma protein signatures can predict mortality and multimorbidity and can be distilled into ageing clocks with substantial predictive power across diverse populations.4 Despite these advances, the explicit application of proteomic or transcriptomic ageing metrics to explain early-onset ischaemic stroke remained limited, and mechanistic links, particularly the possibility that unusual receptor systems or senescence-related pathways might drive vascular ageing, were only beginning to be explored within cardiovascular research.5 In the current issue of the European Journal of Preventive Cardiology, Quek et al.6 therefore entered fertile intellectual ground with a study that sought to translate the conceptual promise of biological ageing into a specific clinical problem: early-onset ischaemic stroke. By using a high-coverage proteomic platform and rigorous machine learning to build a proteomic ageing clock, they aligned with recent work4 showing that large-scale proteomic clocks can achieve high accuracy and predictive validity for age-related outcomes. The logic behind focusing on proteins is sound: proteins are proximal effectors of cellular function, inflammation, and vascular remodelling, processes central to stroke pathophysiology, and proteomic signatures may therefore capture dynamic aspects of biological ageing that other modalities (such as DNA methylation) reflect more indirectly. The field had already recognized epigenetic age acceleration as a biomarker linked to cardiovascular risk and subclinical atherosclerosis, so extending this paradigm to proteomics was a timely and rational next step.3 The principal empirical contributions are striking and merit careful reflection. First, the authors show that a substantial fraction of patients with acute ischaemic stroke (nearly 40% in their cohort) exhibit evidence of accelerated proteomic ageing compared with an age- and sex-stratified healthy reference sample. This high prevalence positions accelerated biological ageing as a common feature in the stroke population rather than a niche observation. Second, the magnitude of the association between accelerated age and stroke timing is clinically meaningful: accelerated agers experienced strokes on average nearly 9 years earlier than their non-accelerated peers. The effect persisted after adjustment for conventional vascular risk factors, suggesting that proteomic age captures risk dimensions not measured by standard clinical covariates. The paper further demonstrates that in younger patients (those under 50), the relation is particularly pronounced, with each additional year of proteomic-age excess increasing the odds of stroke by around 13%. These findings provide a plausible molecular explanation for part of the documented rise in early-onset stroke and suggest that ageing biology may partly account for cases that are cryptogenic by conventional assessment.6 Beyond cross-sectional associations, the longitudinal data in the study raise provocative questions about the bidirectional interplay between stroke and ageing. In a subset of patients rescanned 3 months after the index event, mean proteomic age increased by ∼2 years. Although this observation could reflect transient post-stroke inflammatory perturbations, it also raises an unsettling possibility: acute cerebrovascular injury might accelerate systemic molecular ageing, amplifying long-term vulnerability to recurrent events, cognitive decline, or frailty. This idea aligns with broader research on how acute insults can produce persistent physiologic shifts and with literature indicating that cellular senescence and the senescence-associated secretory phenotype contribute to cardiovascular pathology.7 Interrogating whether the post-stroke increase in biological age is durable, reversible, or predictive of long-term outcomes is an urgent priority for future longitudinal studies. The transcriptomic signals reported by Quek et al.6 add another novel layer. Their RNA-sequencing results identify enrichment of olfactory-signalling and sensory perception pathways in accelerated agers, an initially unexpected finding that gains plausibility when placed in the context of molecular biology work showing ectopic expression of olfactory receptors in vascular tissues and the heart. Experimental studies have demonstrated that certain olfactory receptors are expressed in the aorta and coronary endothelial cells and can modulate intracellular signalling pathways relevant to vasodilation, AKT signalling, and endothelial function. This ectopic receptor biology provides a mechanistic foothold for interpreting the transcriptomic enrichment observed in stroke patients with accelerated ageing. While the causal relevance of these pathways to stroke risk remains to be established, their identification broadens the mechanistic hypotheses (Figure 1) beyond canonical inflammatory or metabolic axes and invites targeted mechanistic follow-up.8,9 Potential mechanisms linking accelerated biological ageing to early cerebrovascular vulnerability. The study does not come without limitations. Foremost among the concerns is generalizability: the work is single centre with a majority Asian cohort, and proteomic baseline levels and ageing trajectories can differ across populations due to genetics, diet, environmental exposures, and socioeconomic factors. Independent validation in multi-ethnic cohorts is therefore essential before inferring that the specific proteomic signature or the precise effect sizes reported will hold broadly. Another fundamental limitation is the observational design, which cannot prove causality. Accelerated biological age may reflect cumulative unmeasured exposures (such as chronic psychosocial stress, environmental toxins, or early-life adversity) that both accelerate ageing and increase vascular risk, rather than serving as a direct causal agent.10 Prospective studies with serial preclinical sampling will be necessary to determine whether proteomic acceleration precedes stroke by years and whether it meaningfully improves prediction beyond established risk models. The acute-phase confounder is another interpretative challenge: stroke induces systemic inflammation and metabolic change that can transiently alter circulating proteins; despite adjustments for sample timing and inflammatory markers, disentangling chronic ageing signals from acute illness effects is nontrivial. Designing proteomic ageing clocks that are robust to acute perturbations, either by selecting proteins less sensitive to inflammation or by applying correction algorithms, will be vital for clinical application. In addition, discovery platforms such as Olink report NPX values, which are relative measures; translating these results into clinical tests requires identification of a reduced protein panel with absolute quantitation and validation across laboratories, a substantial but surmountable translational step that others working on proteomic ageing clocks have already begun to address.4 The policy and therapeutic implications of linking biological age to stroke risk are far reaching. If proteomic age proves to be a robust, independent predictor of stroke onset and progression, it could be incorporated into risk stratification frameworks to identify younger adults who might benefit from earlier preventive interventions. Such a shift would move the paradigm from a sole focus on single traditional risk factors to a more integrated assessment of systemic vulnerability. Moreover, biological age could serve as a proximal outcome for trials testing interventions that target core ageing processes, lifestyle interventions known to affect molecular ageing measures, pharmacologic approaches that modulate inflammation or metabolism, and emerging senolytic therapies aimed at removing senescent cells. The rationale for senolytic approaches in cardiovascular disease is already under active experimental and early clinical investigation,11,12 and the intersection of ageing biology and cerebrovascular prevention supports pursuing such strategies, albeit cautiously and within rigorous randomized frameworks. Mechanistically oriented research should pursue several parallel lines. First, replication of the olfactory-receptor and sensory-signalling transcriptomic findings in independent stroke cohorts and in purified vascular cell types would determine whether these pathways are artefacts of circulating RNA heterogeneity or reflect genuine vascular biology. Second, animal and cell-based models could test whether modulating identified receptors or downstream signalling nodes alters endothelial resilience, atherogenesis, or responses to ischaemia. Third, longitudinal human studies should measure proteomic and epigenetic age repeatedly before and after interventions, both behavioural and pharmacologic, to probe modifiability and to test whether reductions in biological age translate into fewer vascular events. Finally, implementation science is needed to evaluate how such complex biomarkers would be communicated to patients, how they would affect clinical decision-making, and what ethical considerations arise when informing individuals that their biological age exceeds their chronological years. The study by Quek et al.6 thus represents an important step in bringing multi-omic ageing metrics into direct conversation with a pressing clinical problem: early-onset ischaemic stroke. It advances the field by demonstrating that proteomic age can be measured with high precision, that accelerated ageing is common among stroke patients and strongly associated with earlier onset, and that novel transcriptomic pathways may underlie these associations. The next decade of research will determine whether biological age becomes a practical component of stroke risk assessment and prevention or remains a powerful but primarily research-focused lens on disease biology. In either case, the work underscores a broader conceptual shift: understanding vascular disease not only as a consequence of individual risk factors but as an emergent property of lifelong molecular trajectories. Pursuing that perspective may open new avenues for prevention, intervention, and mechanistic discovery. Fahimeh Varzideh (Writing—original draft [lead]), Pasquale Mone (Writing—original draft [supporting]), and Gaetano Santulli (Writing—review & editing [lead]) The Santulli Lab is supported in part by the National Institutes of Health (NIH): National Heart, Lung, and Blood Institute (NHLBI: R01-HL164772, R01-HL159062, R01-HL146691, T32-HL144456) and by the American Heart Association (AHA, 24IPA1268813). Not applicable.