From the molecular to the functional level: the aging continuum through blood pressure trajectories

The aging of the population is a worldwide process, which is causing significant changes in social needs and healthcare approach. In recent years, extending healthy rather than only total lifespan has become a major topic of clinical and translational research with the aim of transforming medicine from a disease-centered to a preventive, function-centered clinical practice. In order to promote healthy aging, the World Health Organization (WHO) developed the function-centered Integrated Care for Older Persons (ICOPE) model, focusing on the clinical domains of Intrinsic Capacity (IC): mobility, cognition, nutrition/vitality, mental health, vision and hearing. Although functional aging manifests late in life, disease signs and symptoms are preceded by aging-related changes at the physiological level, and even before at the molecular level. Accordingly, the aging process is characterized by physiologic multisystemic dysregulation, mirroring the complex interplay among age-related biological changes (inflammaging, mitochondrial dysfunction), epigenetics, and environmental exposures, which is in turn responsible of the multifaced manifestation and typical heterogeneity of late life [1]. While young, perturbations at the molecular level are ameliorated by homeostatic mechanisms, delaying their impact on function. Conversely, with aging there is an apparent depletion of physiological reserves and impaired ability to provide adequate response to both acute and chronic conditions, known as homeostenosis, which is critical in the progression towards unsuccessful aging [2]. As a result, when stressors and molecular perturbations reach a certain severity, they can modify physiological parameters, ultimately leading to diseases and loss of IC and frailty.

With this Editorial, we highlight two pieces of literature published in this month’s issue of the JNHA, that address the topic of arterial hypertension, a highly prevalent condition in the geriatric population. Focusing on the different points of view proposed by the authors, hypertension and blood pressure variability appear at the center of an intriguing continuum of the aging process, from the biological aging metrics to clinical manifestations, with prognostic implications in terms of frailty and mortality (Fig. 1).

Fig. 1.

The aging continuum through the lens of hypertension and blood pressure variability.

The observation that individuals do not age at the same pace has resulted in overcoming the previous concept of chronological age, in favor of biological aging, driven by multiple hallmarks at the molecular level including epigenetic alterations. DNA methylation patterns have been proposed as a measure of biological age, currently referred to as epigenetic clocks. The first generation of epigenetic clocks such as those developed by Horvath [3] and Hannum [4] were initially designed to predict chronological age. Recently, new models that derive their DNA methylation predictions of life expectancy and risk of mortality from markers of physiological dysregulation, have been computed such as the DNAm PhenoAge [5] and GrimAge [6]. The research by Feng et al. [7] supports the implication of biological aging, especially epigenetic aging, in the onset of hypertension and its associated mortality risk. Among individuals with hypertension from the National Health and Nutrition Examination Survey (NHANES), the authors reported an increased risk of all-cause and cardiovascular mortality associated with higher phenotypic age (PA) and phenotypic age acceleration (PAA), two biological aging metrics derived from the epigenetic clock DNAm PhenoAge [5]. Interestingly, the association between PA and all-cause mortality was predominantly mediated by arterial stiffness (42%) and PAA (30%) whereas heart/vascular age appeared to play a minor role in comparison (less than 7%). Although further validation is required, mendelian randomization also suggested a potential causal link between PAA, as a measure of accelerated epigenetic aging, and hypertension progression. Overall, epigenetic aging has been identified as playing a critical role in cardiovascular health. Notably, recent findings reported an association between accelerated epigenetic aging and hypertension incidence [8]. Other hallmarks of biological aging are considered to be important contributors to the pathogenesis of hypertension, including vascular inflammaging [9] and mitochondrial dysfunction [10]. Cellular senescence may additionally lead to hypertension, although this requires further investigation [11]. The recent technological and methodological developments in omics sciences, including transcriptomics, metabolomics and proteomics, are also expected to provide additional and valuable insights into hypertension pathophysiology at the molecular level [[12], [13], [14]]. The evidence from Feng and collaborators showing arterial stiffness to mediate the risk of death associated with biological aging is also very stimulating. Hypertension is the main risk factor for cardiovascular morbidity and mortality and age-related blood pressure increase represents a high-priority target for intervention. Indeed, advancing age plays a critical role in hypertension physiopathology, particularly through the ‘vascular phenotype’ which includes functional and structural changes such as endothelial dysfunction, vascular remodeling, increased arterial stiffness and inflammation, conditions largely found to be associated with aging [15]. Arterial stiffness, a key modification observed in vascular aging, is also associated with baroreflex impairment and endothelial dysfunction. The latter have recently been suggested to be linked with multiple hallmarks of aging, including inflammaging, and are also implicated in the increased fluctuations of blood pressure over time observed in late life [16].

In this issue from the JNHA, we also spotlight findings from Yu et al. [17] focusing on the trajectories of systolic blood pressure (SBP) and incidence of frailty, assessed through the frailty index, in middle-aged and older adults from the China Health and Retirement Longitudinal Study. Over 7 years, compared to ‘maintaining low-stable SBP’, both ‘remitting then increasing’ and ‘remaining stable at high SBP levels’ trajectories were associated with greater risk of developing frailty, which generally resulted to be superior in participants younger than 75 years. The latter finding also provides further material for the discussion on the most adequate management of hypertension across age groups. Nevertheless, the evidence on the effectiveness of the intensive therapeutic approach in frail older patients is limited, and this has led to differentiating the treatment targets according to age groups, with a specific focus on the global functional status of hypertensive patients [18]. Finally, the authors emphasized the importance of greater SBP variability in the risk of developing frailty. Beyond hypertension, BPV has gained growing attention over the past few years given its association with multiple age-related conditions and diseases, including cardio and cerebrovascular events, cognitive impairment and dementia [16]. In line with the evidence reported by Yu et al., findings from our group recently suggested an independent association between increased visit-to-visit BPV and both incident frailty [19] and decline in intrinsic capacity in a population of community-dwelling older adults from the Multidomain Alzheimer Preventive Trial (MAPT) [20]. Moreover, our report on higher levels of biomarkers of the antagonistic hallmark of aging “mitochondrial dysfunction” and greater SBP variability allows to speculate on the further connection between biological aging, BPV and loss of function [21].

In this unifying interpretation, accelerated biological aging observed in hypertensive adults, and the clinical manifestations of frailty in adults with poor BP control, configure an interesting continuum that proposes BP and its fluctuations, as a potential measure of aging. Furthermore, arterial hypertension is a condition with absolute impact on all organs and systems, closely implicated in the pathophysiology of numerous diseases typical of advanced age, from cognitive decline to cardiac pathologies, up to metabolic conditions and chronic organ damage, such as diabetes and chronic kidney failure. This is obviously of great interest and potential clinical impact, as it is an easily and routinely measurable clinical parameter, which can provide indirect information on the different levels of the aging process, from molecular pathophysiology to phenotypic prognostic and syndromic manifestations typical of the geriatric age.

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.