A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME Biomarkers Workgroup

Abstract

Recent advances indicate that biological aging is a potentially modifiable driver of late-life function and chronic disease and have led to the development of geroscience-guided therapeutic trials such as TAME (Targeting Aging with MEtformin). TAME is a proposed randomized clinical trial using metformin to affect molecular aging pathways to slow the incidence of age-related multi-morbidity and functional decline. In trials focusing on clinical end-points (e.g., disease diagnosis or death), biomarkers help show that the intervention is affecting the underlying aging biology before sufficient clinical events have accumulated to test the study hypothesis. Since there is no standard set of biomarkers of aging for clinical trials, an expert panel was convened and comprehensive literature reviews conducted to identify 258 initial candidate biomarkers of aging and age-related disease. Next selection criteria were derived and applied to refine this set emphasizing: (1) measurement reliability and feasibility; (2) relevance to aging; (3) robust and consistent ability to predict all-cause mortality, clinical and functional outcomes; and (4) responsiveness to intervention. Application of these selection criteria to the current literature resulted in a short list of blood-based biomarkers proposed for TAME: IL-6, TNFα-receptor I or II, CRP, GDF15, insulin, IGF1, cystatin C, NT-proBNP, and hemoglobin A1c. The present report provides a conceptual framework for the selection of blood-based biomarkers for use in geroscience-guided clinical trials. This work also revealed the scarcity of well-vetted biomarkers for human studies that reflect underlying biologic aging hallmarks, and the need to leverage proposed trials for future biomarker discovery and validation.

Keywords: Aging; Biomarkers; Epidemiology; Inflammation; Metformin; Mortality; Randomized controlled trial.

Conflict of interest statement

JNJ, NB, JB, JD, MAE, LF, SBK, SM, ABN, MP, and GAK report no conflicts of interest to this work. VRA was the MedStar Health Research Institute’s principal clinical trial investigator for studies involving Elcelyx (delayed release metformin).

Figures

Fig. 1

Overview of process to derive a pre-specified list of candidate biomarkers for geroscience-guided clinical trials. Steps taken to identify, prioritize, and select blood-based candidate biomarkers for the proposed multicenter clinical trial on aging, Targeting Aging with MEtformin (TAME)

Fig. 2

Graphical table. IL-6, CRP, TNFRII: Giovannini et al. ; Kennedy et al. ; Lopez-Otin et al. ; Michaud et al. ; Cameron et al. ; Fontana et al. ; Harvie et al. ; Lettieri-Barbato et al. . GDF15: Bauskin et al. ; Brown et al. , ; Jiang et al. ; Kempf et al. ; Lankeit et al. ; Welsh et al. ; Wiklund et al. . IGF-1, Insulin: Bartke et al. ; Barzilai et al. ; Breese et al. ; Brown-Borg and Bartke ; Fontana et al. ; Kenyon ; Lee et al. ; Longo and Finch ; Masternak and Bartke ; Rincon et al. ; Fontana et al. ; Harvie et al. ; Pijl et al. ; Guevara-Aguirre et al. ; Steuerman et al. . Cystatin C: Odden et al. ; Sebastiani et al. ; Barron et al. ; Foster et al. ; Shlipak et al. ; Svensson-Farbom et al. ; Wu et al. ; Hart et al. , ; Newman et al. ; Sarnak et al. . NT-proBNP: Braunwald ; Masson et al. ; Omland et al. ; Sanders et al. . Hemoglobin A1c: Dubowitz et al. ; Palta et al. ; Pani et al.