Moderation: M. Gogol, Coppenbrügge; G. Fuellen, Rostock
The complex process of aging as identified by basic research provide potential targets and rationale for drug-based interventions. Beside others metformin, an anti-diabetic drug, comes into the focus because of its effects on AMP-activated protein kinase (AMPK) activation and mTORC1 inhibition in model organism as well as the reduction of cardiovascular endpoints and cancer incidence in clinical studies. The U.S. initiative for the TAME (Targeting Aging with Metformin) study has the goal to proove this concept in a randomized clinical trial. As arguments for such a trial have a scientific background it might be not so easy to realize the study. A crucial point will be the assessment throughout the study to be sure that potential intervention effects are not biased. Further difficulties may arise from the question which methods are the best to analyze complex and dynamic data. In this symposium, the above mentioned points will be presented and discussed.
Biologists of aging have begun to identify drugs that target cellular pathways controlling life-span in animal models. The National Institute on Aging sponsors the rigorous Interventions Testing Program (ITP) which systematically evaluates compounds for their ability to increase the life span and health span of mice. The ITP’s animal testing paradigm doesn’t translate well to humans. Typically, mice are given the drug starting at 4-month or 12 months of age and then they are followed until death. In humans this is roughly equivalent to enrolling 18 and 40 year olds and following them for another 50 – 80 years. This is infeasible and possibly unethical. It is more feasible to track short-term cellular and physiologic changes associated with human lifespan and health-span. However, this approach does not fit well with the United States Food and Drug Administration’s (FDA) regulatory framework. Therefore, short-term studies currently cannot support the approval of a new drug or a new indication for an existing drug. The solution is to test compounds for their ability to delay the onset of a collection of age-related health conditions including cancer, heart disease, stroke and dementia. This symposium describes the Targeting Aging with Metformin Study (TAME). TAME is a prototype trial designed in consultation with the FDA to achieve two goals: 1. To establish the efficacy of metformin for preventing multiple age-related diseases, and 2. to provide an approval path to stimulate new research and investment in drugs that might delay the consequences of aging.
Including elderly people in clinical trials is a challenge while we have no single or core set of biomarkers, which allows us to define precisely the biological age of participants. As our understanding about diseases and functional decline grow, we can state that the occurrence of manifest diseases (syndromes) is only one step in a long going (patho-)physiological process. There are prodromal states without any clinical signs followed by a subclinical state before diseases occur clinically. Furthermore, the time course of aging may be different in various organs as well as the interactions of different systems are not so well understood yet, especially in the context of multimorbidity. Also psychological and social factors may influence the process in part or in total in a positive or negative manor. Other potential biasing factors, e.g. gender, race, environment, must be recognized and adjusted for. The talk will address potential pitfalls for interventional studies in an elderly population.
Individualizing healthspan-promoting interventions is the precision medicine approach to healthy aging. Interventions in rhesus demonstrate that healthy aging can be promoted. In the form of caloric restriction mimetics, feasible diet and small-molecule interventions are now on the horizon. These interventions must ultimately be combined in individualized ways. In turn, good (omics) biomarkers are needed. I will therefore discuss the specific problems posed by trials for individualized healthspan-promoting interventions, regarding the overall design, choice of trial participants, interventions, endpoints and of the variables to be measured, ranging from blood counts to omics data. A key question is how to single out the variables that may qualify as the most useful biomarkers.
The rational based therapeutic objectives might not necessarily align with older (but also younger) patients objectives and especially their expectations. Moreover, complex therapeutic schedules are very demanding and can have a significant impact on patients flexibility and spontaneity. Successful interventions will have to navigate through medical needs and personal expectations with a realistically manageable therapeutic schedule. Some basic considerations might already resolve major medication issues that could have been predicted.
Diskutant: A. Simm, Halle (Saale)