The proBNPage Reduction (PBAR) Randomized Trial: a Pilot Study to Define the Characteristics of Future Randomized Trials Aimed at Evaluating the Effects of Anti-aging Treatments on a Surrogate of Biological Age in Healthy Older Adults

A) Background

Human life is relatively long so that, to assess the effect of any treatment on longevity, similarly long studies are needed. In addition, to demonstrate significant reductions in mortality, large samples are needed too. Thus, even though several promising treatments have been found in animal models, evidence of efficacy in humans has not come yet.

In an attempt to overcome these difficulties, several indicators of biological age have been proposed. Biological age may be defined as a measure, more reliable than chronological age, of how close to death an individual is. If such an indicator were available, assessing the efficacy of possible treatments would be relatively easy: one or two years of follow-up in relatively small groups might be sufficient to ascertain the arrest or even the inversion of the rise of the indicator.

In 2020 the authors proposed a new simple method to estimate a surrogate of biological age, the "proBNPage", starting from a single laboratory variable, NT-proBNP (the N-terminal fragment of type-B natriuretic peptide precursor). NT-proBNP is easily measurable in most laboratories. It is commonly used as a marker of heart failure, as it is released from the ventricular and atrial myocardium undergoing mechanical or ischemic stress. Several studies (both cross-sectional and longitudinal) have shown that this marker progressively increases with age. It is a good indicator of the risk of death even in subjects without cardiovascular diseases and, in particular, the authors have shown that NT-proBNP is associated with cardiovascular and all-cause mortality more strongly than chronological age. In addition, NT-proBNP is correlated with chronological age more strongly than all the main laboratory variables that had previously been proposed as biomarkers of biological age (as shown by the authors and subsequently also by others). Thus, starting from the equations of the regression lines of chronological age with NT-proBNP, the authors obtained two simple formulas, one for each sex, which allow the calculation of "proBNPage", in years, from the blood concentration of NT-proBNP.

Besides total and cardiovascular mortality, the authors have shown that other indicators of aging are independently associated with proBNPage, such as disease count, walking problems, the fitness assessed with a two-step test and the self-assessment of health status, in addition to previous myocardial infarction, previous stroke, peripheral artery disease and previous arterial revascularizations. Furthermore, in a recent study by other investigators, among more than 35000 clinical and laboratory biomarkers obtained from genomic, proteomic and metabolomic data in 4 cohorts of European populations, NT-proBNP was the marker most strongly associated with frailty in subjects without disability. Finally, in an older adult population, a further recent study has shown that NT-proBNP was the only independent risk factor of reduced intrinsic capacity among 20 laboratory variables, being associated with locomotion, hearing and vision disturbances and with some characteristic psychological aspects of aging.