Dismantling Anti-Ageing Medicine: Why Age-Relatedness of Cardiovascular Disease is Proof of Robustness Rather Than of Ageing-Associated Vulnerability.

Ageing is perceived to be the common culprit behind the most prevalent noncommunicable chronic diseases (NCD) such as cardiovascular disease (CVD). Treating ageing as a means to prevent its downstream pathologies has become the logical extension of this idea, and the defining criterion of anti-ageing medicine (evidence-based early detection, prevention, and treatment of age-related diseases). Challenging the underlying rationale, we here argue that the disease's late-in-life occurrence is proof of a genetically conserved robustness that helps us resist disease long enough for it to masquerade as a consequence of living long rather than of living wrong. Robustness is an acknowledged hallmark phenomenon of all complex systems (while there exists no universally adopted definition, a hallmark of complex systems is that they consist of many networked components whose interactions may give rise to system behaviours which cannot be derived or predicted from a reductionist knowledge of the interacting parts, even if this knowledge is complete) and a key concept in the complexity sciences (a relatively new branch of science that attempts to find and understand the common mechanisms and patterns shared by all complex systems). To reconceptualise the age-relatedness of chronic diseases in this sense has important implications for medical research and practice. The goal of our essay is to open a discussion that may enhance the overall understanding of robustness and prevent a misguided redirection of funding away from established disease specific research and towards anti-ageing medicine. This essay is timely, as the forthcoming 11th version of the International Classification of Diseases (ICD) will be the first to recognise ageing as a condition, thereby legitimising anti-ageing medical research. On a more pragmatic note, and for the benefit of people alive today, we propose a practical strategy to remedy the mismatch between heritable robustness and the lifestyle challenges that gradually overwhelm it.

Vascular robustness: The missing parameter in cardiovascular risk prediction.

Undetected high risk for premature death of cardiovascular disease (CVD) among individuals with low-to-moderate risk factor scores is an acknowledged obstacle to CVD prevention. The vasculature's functional robustness against risk factor derailment may serve as a novel discriminator of mortality risk under similar risk factor loads. To test this assumption, we hypothesized that the expected inverse robustness-mortality association is verifiable as a significant trend along the age spectrum of risk factor-challenged cohorts. This is a retrospective cohort study of 372 adults (mean age 56.1 years, range 21-92; 45% female) with a variety of CV risk factors. An arterial model (VascAssist 2, iSYMED GmbH, Germany) was used to derive global parameters of arterial function from non-invasively acquired pulse pressure waves. Participants were stratified by health status: apparently healthy (AH; n = 221); with hypertension and/or hypercholesterolemia (CC; n = 61); with history of CV event(s) (CVE; n = 90). Multivariate linear regression was used to derive a robustness score which was calibrated against the CVD mortality hazard rate of a sub-cohort of the LURIC study (n = 1369; mean age 59.1 years, range 20-75; 37% female). Robustness correlated linearly with calendar age in CC (F(1, 59) = 10.42; p < 0.01) and CVE (F(1, 88) = 40.34; p < 0.0001) but not in the AH strata, supporting the hypothesis of preferential elimination of less robust individuals along the aging trajectory under risk factor challenges. Vascular robustness may serve as a biomarker of vulnerability to CVD risk factor challenges, prognosticating otherwise undetectable elevated risk for premature CVD mortality.

A novel principled method for the measurement of vascular robustness uncovers hidden risk for premature CVD death.

The detection of high risk for premature death of cardiovascular disease (CVD) among individuals with low-to-moderate risk factor scores is a major challenge. Systems biology suggests that the vasculature's functional robustness against risk factor challenges may serve as a novel discriminator of mortality risk under similar risk factor loads. However, principled methods to measure vascular robustness are not available. To develop a score for the vasculature's functional robustness we used a recently presented method that applies computational physiological modeling to the quantitation of vascular function. We hypothesized that the expected inverse robustness-mortality association is verifiable as a significant robustness-calendar age trend in a cross-sectional investigation of a population cohort of risk factor-challenged individuals. Using only functional parameters of the cardiovascular system we applied multivariate linear regression to derive from our study population of 372 adults gender-specific multivariate robustness scoring algorithms. For any individual, the deviation of his/her robustness score from the value of the regression function characterizes the deviation of the individual's fatal CVD event probability from its age-appropriate fatal CVD event probability. Robustness correlated linearly with calendar age in our risk factor-challenged but not in our unchallenged cohorts. This observation supports the hypothesis of preferential elimination of less robust individuals along the aging trajectory under risk factor challenges. We conclude that physiologically principled scoring for vascular robustness may serve as a biomarker of vulnerability to CVD risk factor challenges, prognosticating otherwise undetectable elevated risk for premature CVD mortality. NEW & NOTEWORTHY We developed a principled method for the derivation of a vascular robustness score that we translated into a correction factor for calendar age. We demonstrated the score's potential to uncover risk for premature cardiovascular death in apparently healthy young adults whose risk elevation remains hidden in conventional risk factor models.

The cardiovascular robustness hypothesis: Unmasking young adults' hidden risk for premature cardiovascular death.

An undetected high risk for premature death of cardiovascular disease (CVD) among individuals with low-to-moderate risk factor levels is an acknowledged obstacle to CVD prevention. In this paper, we present the hypothesis that the vasculature's robustness against risk factor load will complement conventional risk factor models as a novel stratifier of risk. Figuratively speaking, mortality risk prediction without robustness scoring is akin to predicting the breaking risk of a lake's ice sheet considering load only while disregarding the sheet's bearing strength. Taking the cue from systems biology, which defines robustness as the ability to maintain function against internal and external challenges, we develop a robustness score from the physical parameters that comprehensively quantitate cardiovascular function. We derive the functional parameters using a recently introduced novel system, VascAssist 2 (iSYMED GmbH, Butzbach, Germany). VascAssist 2 (VA) applies the electronic-hydraulic analogy to a digital model of the arterial tree, replicating non-invasively acquired pule pressure waves by modulating the electronic equivalents of the physical parameters that describe in vivo arterial hemodynamics. As the latter is also subject to aging-associated degeneration which (a) progresses at inter-individually different rates, and which (b) affects the biomarker-mortality association, we express the robustness score as a correction factor to calendar age (CA), the dominant risk factor in all CVD risk factor models. We then propose a method for the validation of the score against known time-to-event data in reference populations. Our conceptualization of robustness implies that risk factor-challenged individuals with low robustness scores will face preferential elimination from the population resulting in a significant robustness-CA correlation in this strata absent in the unchallenged stratum. Hence, we also present an outline of a cross-sectional study design suitable to test this hypothesis. We finally discuss the objections that may validly be raised against our robustness hypothesis, and how available evidence encourages us to refute these objections.

Are we losing the battle against cardiometabolic disease? The case for a paradigm shift in primary prevention.

BACKGROUND: Cardiovascular and diabetic disease are the leading and preventable causes of death worldwide. The currently prognosticated dramatic increase in disease burden over the next two decades, however, bespeaks a low confidence in our prevention ability. This conflicts with the almost enthusiastic reporting of study results, which demonstrate substantial risk reductions secondary to simple lifestyle changes. DISCUSSION: There is a case to be made for a disregard of the difference between statistical significance and clinical relevance of the reported data. Nevertheless, lifestyle change remains the main weapon in our battle against the epidemic of cardiometabolic disease. But along the way from risk screening to intervention to maintenance the compound inefficiencies of current primary preventive strategies marginalize their impact. SUMMARY: Unless we dramatically change the ways in which we deploy preventive interventions we will inevitably lose the battle. In this paper we will argue for three provocative strategy changes, namely (a) the disbanding of screening in favor of population-wide enrollment into preventive interventions, (b) the substitution of the current cost utility analysis for a return-on-investment centered appraisal of interventions, and (c) the replacement of standardized programs modeled around acute care by individualized and perpetual interventions.