NIA Translational Geroscience Network: An infrastructure to facilitate geroscience‐guided clinical trials

Abstract

Aging processes are the leading risk factor for most serious diseases and disabilities across the lifespan including dementias, cancers, atherosclerosis, and frailty as well as impaired physical resilience to such stresses as infections, or surgery.1-3 Conditions related to fundamental aging mechanisms are the major drivers of morbidity, mortality, and health costs but have proven difficult to control. The number of age-related chronic diseases per individual increases with aging, leading to multi-morbidity and dampening the public health impact of preventing any single age-related disease.4 A strategy to address all of these conditions is a “root cause” approach: targeting the aging mechanisms that represent shared upstream contributors or drivers. This strategy motivates the Geroscience Hypothesis that targeting aging will delay, prevent, or alleviate these conditions as a group in contrast to the traditional one-disease-at-a-time approach. Targeting various aging mechanisms using different gerotherapeutic and lifestyle interventions has shown beneficial effects in pre-clinical models.5, 6 However, testing the Geroscience Hypothesis in clinical trials will require novel, standardized, integrated approaches, appropriate frameworks, and a workforce trained to support this innovative root cause approach. To facilitate translation of potential gerotherapeutic interventions into clinical trials, the National Institute of Aging supported development of the Translational Geroscience Network (TGN; R33AG061456; https://www.gerosciencenetwork.org/), comprised of scientists and clinicians from Mayo Clinic, University of Connecticut, Johns Hopkins University, University of Minnesota, Wake Forest University, Harvard University, University of Michigan, and University of Texas. The TGN arose from the recommendations developed as part of earlier grant to address translational gaps. Findings were summarized in a series of publications.6, 7 The TGN has developed a framework that facilitates and speeds translation by optimizing resource utilization and promotes development of shared protocols and outcome measures, while avoiding duplication and counter-productive competition (Figure 1). The TGN continues to grow and is becoming a national resource. Additional centers have joined the network as affiliated or full members. Importantly, the TGN has attracted not only established investigators from different fields of medicine, but junior scientists initiating careers in Geroscience, which will enable growth of a future workforce for the field. The TGN has started with small-scale proof-of-principle “use case” studies.8, 9 A key goal of these initial studies is to standardize protocols and develop novel analytical methods to combine study results that will permit assessment of safety and tolerability of gerotherapeutics, involving both repurposed and newly discovered drugs across disorders/diseases. Additionally, trends for target engagement and effectiveness are being tested across studies using combinatorial approaches to facilitate determination of sample sizes for definitive, randomized, placebo-controlled Phase 2b and three clinical trials using optimized gerodiagnostics, interventions, and trial strategies. By testing aging mechanism-based interventions against a range of chronic conditions, the chances of success may be enhanced. This endeavor can be “de-risked” and sped up by conducting multiple studies in parallel, each using similar approaches, but for different age-related conditions, in a manner that allows pooling of data for analyses. For example, parallel studies of senolytics are being conducted that include frailty measures. The panel of ancillary measures of aging processes is assayed using blood and other body fluids, as well as tissues, and cells across all TGN-associated trials.9, 10 This approach allows delineating molecular pathways that are perturbed by different interventions in various scenarios in order to identify those that are shared, particularly those associated with aging conditions in preclinical studies. This will test the Geroscience Hypothesis, advance understanding of basic aging biology, and identify which pathways to prioritize in developing new drugs and by distributing biobanked samples to the basic biology of aging community for detailed ancillary mechanistic “reverse translational” analyses. Based on the more than 80 studies ongoing and planned trials (Figure 2), the intent is to sharpen focus and move toward well-powered Phase 2b and three trials. It is especially important to use more than one set of agents that target various aging processes, test their effects on more than one chronic disease or aging-associated condition, and do so at more than one institution, using shared metrics and Standard Operating Procedures to enhance analytical sensitivity overall. This approach will allow parallel rather than sequential verification of reliability and reproducibility and increase the chances of successfully testing this novel transformative paradigm and of developing treatments with enormous potential to impact public health through delaying, preventing, alleviating multiple diseases, and increasing the period of life free of disabilities. Tamar Tchkonia wrote the letter which all authors reviewed and approved. We would like to thank the site leaders of TGN, Drs. Lew Lipsitz, Douglas Kiel (Harvard), Laura Niederhofer (University of Minnesota), Raimond Young (University of Michigan), and Jeremy Walston (Johns Hopkins University), and all coinvestigators for their contributions to network. We are grateful to Tammy Evanas and Kathleen McDonald for supporting TGN operations and, also Dr. Larissa Langhi Prata and Dr. Tamar Ratishvili for their help in designing figures. The authors declare no conflicts of interest. Not applicable. This work has been supported by National Institute on Aging grant R24 AG44396 (James L. Kirkland) and R33 AG0614569 (James L. Kirkland, George A. Kuchel, Tamara Tchkonia, and Stephen B. Kritchevsky).

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