Molecular predictors of incident frailty: a systematic review and critical appraisal of longitudinal evidence

Frailty is a multisystemic syndrome that significantly compromises quality of life. Current management strategies are largely reactive, often leading to suboptimal mitigation outcomes. Identifying predictors of incident frailty is therefore critical to shift this paradigm. This systematic review conducted in PubMed, Scopus and Web of Science (on 3 October 2023) included 45 longitudinal studies analysing biomarkers in human biological fluids and their associations with widely established frailty assessment tools. A total of 80 candidate biomarkers were identified, 20 of which were investigated in multiple studies. Notably, only one biomarker analysed in multiple studies was found to have broadly similar directionality in adjusted analyses, but overall certainty remains limited. While our findings suggest that some progress has been made towards the discovery of molecular predictors of incident frailty, a reliable biomarker set remains elusive, hindered by several methodological limitations. Nevertheless, frailty assessment has shown tremendous promise in the clinical setting, warranting further efforts to integrate existing tools with biomarkers. This systematic review highlights the untapped potential of biomarker discovery, as well as the current shortcomings in the field of frailty prediction, and offers direction for improving study design and reproducibility in future studies.