GeroScience https://doi.org/10.1007/s11357-018-0042-y REVIEW ARTICLE A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME Biomarkers Workgroup Jamie N. Justice & Luigi Ferrucci & Anne B. Newman & Vanita R. Aroda & Judy L. Bahnson & Jasmin Divers & Mark A. Espeland & Santica Marcovina & Michael N. Pollak & Stephen B. Kritchevsky & Nir Barzilai & George A. Kuchel Received: 2 August 2018 /Accepted: 15 August 2018 # American Aging Association 2018 Abstract Recent advances indicate that biological ag- sufficient clinical events have accumulated to test the ing is a potentially modifiable driver of late-life function study hypothesis. Since there is no standard set of bio- and chronic disease and have led to the development of markers of aging for clinical trials, an expert panel was geroscience-guided therapeutic trials such as TAME convened and comprehensive literature reviews con- (Targeting Aging with MEtformin). TAME is a pro- ducted to identify 258 initial candidate biomarkers of posed randomized clinical trial using metformin to af- aging and age-related disease. Next selection criteria fect molecular aging pathways to slow the incidence of were derived and applied to refine this set emphasizing: age-related multi-morbidity and functional decline. In (1) measurement reliability and feasibility; (2) relevance trials focusing on clinical end-points (e.g., disease diag- to aging; (3) robust and consistent ability to predict all- nosis or death), biomarkers help show that the interven- cause mortality, clinical and functional outcomes; and tion is affecting the underlying aging biology before (4) responsiveness to intervention. Application of these Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11357-018-0042-y) contains supplementary material, which is available to authorized users. J. N. Justice (*) : S. B. Kritchevsky J. L. Bahnson : J. Divers : M. A. Espeland Internal Medicine Section on Gerontology and Geriatrics, and the Department of Biostatistical Sciences, Wake Forest School of Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Medicine, Winston-Salem, NC 27157, USA Forest School of Medicine, 1 Medical Center Blvd, Winston-Salem, NC 27157, USA S. Marcovina e-mail: [email protected] Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA 98109, USA L. Ferrucci National Institute on Aging, National Institutes of Health, M. N. Pollak Baltimore, MD 21224, USA Department of Oncology, Jewish General Hospital, McGill University, Montreal, Quebec H3T1E2, Canada A. B. Newman Department of Epidemiology, Graduate School of Public Health, N. Barzilai University of Pittsburgh, Pittsburgh, PA 15260, USA Department of Medicine, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA V. R. Aroda Department of Medicine, Division of Diabetes, Endocrinology, and G. A. Kuchel Hypertension Brigham and Women’s Hospital, Harvard Medical UConn Center on Aging, University of Connecticut School of School, Boston, MA 02115, USA Medicine, Farmington, CT 06030, USA GeroScience selection criteria to the current literature resulted in a Hypothetically, a biomarker of aging should re- short list of blood-based biomarkers proposed for flect the underlying biology, and a change in bio- TAME: IL-6, TNFα-receptor I or II, CRP, GDF15, marker levels should have parallel changes that occur insulin, IGF1, cystatin C, NT-proBNP, and hemoglobin in the susceptibility to disease and loss of function. A1c. The present report provides a conceptual frame- Thus, interventions targeting aging should result in work for the selection of blood-based biomarkers for use changes in biomarkers that will eventually delay the in geroscience-guided clinical trials. This work also incidence, accumulation, clinical evolution, and revealed the scarcity of well-vetted biomarkers for hu- functional consequences of chronic age-related dis- man studies that reflect underlying biologic aging hall- eases. One of the critical roles played by biomarkers marks, and the need to leverage proposed trials for could be that of surrogate endpoints reflective of risk future biomarker discovery and validation. and progression of several major diseases. In support of this role, the US Food and Drug Administration (FDA) and the Institute of Medicine highlighted the Keywords Biomarkers . Aging . Metformin . importance of biomarkers as surrogate measures in Randomized controlled trial . Epidemiology. Mortality. drug development and trials involving chronic dis- Inflammation eases such as cancer and heart disease; however, few existing biomarkers have sufficient clinical evidence of association with the rate of development of aging Introduction phenotypes and multi-morbidity ((IOM) 2010;Bio- markers Definitions Working 2001). The FDA cur- The geroscience hypothesis holds that a specific set rently does not consider aging an indication for drug of shared biological mechanisms of aging increases development or labeling, which may also impede the the susceptibility of aged individuals to several emergence of knowledge supporting discovery and chronic diseases and loss of function and that thera- validation of geroscience-relevant biomarkers. As a pies developed to target such shared Bdrivers^ have result, there are at this time no approved or common- the potential to delay the onset and progression of ly accepted biomarkers of aging for clinical trials, nor multiple chronic diseases and functional decline. The is there a consensus set of validated biomarkers of the inter-related cellular biologic processes that drive the biologic pillars or hallmarks of aging that would be biology of aging are known as Bpillars^ or applicable to clinical research. This poses a major Bhallmarks^ of aging, and accumulating evidence translational gap that must be bridged in order to from mammalian animal models supports the pre- facilitate scientific progress. mise that geroscience-guided interventions targeting The purpose of this report is to outline a conceptual these processes can extend healthspan and lifespan framework and evidence-based approach to the prioriti- (Barzilai et al. 2016; Burch et al. 2014; Espeland zation and selection of a panel of blood biomarkers for et al. 2017; Kennedy et al. 2014; Longo et al. 2015; use in randomized controlled clinical trials of a Sierra 2016a). A new generation of clinical trials is geroscience therapy. A multi-disciplinary Biomarkers being designed to test the geroscience hypothesis in Workgroup convened for a planning workshop and humans (Justice et al. 2016;Newmanetal.2016b; met weekly by phone over an 8-month period. The Sierra 2016b). One example is the proposed multi- Biomarkers Workgroup defined biomarker criteria, center clinical trial, Targeting Aging with MEtformin prioritized selection parameters, and provided guid- (TAME), which will evaluate whether metformin, a ance for resource development and inclusion of commonly used diabetes drug that also targets the biol- discovery-based platforms. The development of the ogy of aging, can (1) prevent or delay the incidence of TAME trial served as an opportunity to apply the multiple age-related chronic diseases, (2) help maintain selection criteria to putative blood-based biomarkers function, and (3) influence biological markers of aging identified through an exhaustive literature review. in older persons (Barzilai et al. 2016). To accomplish The result is an evidence-based short list of proposed this latter aim, a strategy to select the most appropriate biomarkers for the TAME trial, and a framework that biomarkers of aging to be included in geroscience- could be applied to next-generation clinical trials guided clinical trials is needed. targeting aging. GeroScience Conceptual framework The criteria above were developed for research stud- ies in humans. Foundational efforts to identify and cat- Biomarker definitions According to consensus defini- egorize the cellular and molecular Bhallmarks^ of aging tions by Baker and Sprott (Baker III and Sprott 1988; introduced a host of potential biomarkers for mammali- Sprott 1988, 2010), and the American Federation for an aging based on evidence in mouse models and some Aging Research (AFAR), biomarkers of aging are simpler organisms such as Caenorhabditis elegans and measures of a biological parameter that, either Drosophila melanogaster. Clinical translation of these alone or as a multivariate composite, monitor a biomarkers can be problematic, with barriers such as biological process underlying aging rather than ef- access to tissues, environmental or genetic control, and fects of a specific disease; predict the rate of aging use of resource and assays that are not feasible in clinical and mortality better than chronological age; can be research. However, reports often mix evidence from safely tested across repeat measures in the same animal models and humans indiscriminately, and aside organism; and work in humans and in laboratory from a few thoughtful reviews and studies, relative- animals such as mice. The Biomarkers Workgroup ly, little work has emerged on measures of the adapted these definitions to develop selection biologic Bhallmarks^ of aging specifically for hu- criteria tailored to the context of geroscience- man research (Burkle et al. 2015;Khanetal.2017; guided randomized clinical trials: Rochon et al. 2011). Accordingly, the present framework presented focuses solely