Abstract Human aging and the myriad of age-associated diseases are among the greatest challenges in our healthcare system and result in a significant economic burden. Thus, finding interventions that prevent, postpone, or even reverse age-related phenotypes are urgently needed. As aging is a complex, multifactorial process, targeting multiple pathways simultaneously are likely needed to optimally slow the aging process and prevent age- related disease. To this end, recent studies in animal models now indicate that combination of more than one gerotherapeutic can indeed enhance health and lifespan to a greater extent than monotherapies. Building on this concept, our proposed studies will utilize combination therapies involving several promising life-extending compounds all of which will be evaluated in combination with the growth hormone receptor antagonist (GHRA). GHRA is the primary focus of this proposal for several reasons: i) a strong body of evidence shows that reduction in GH action is associated with slowed aging; ii) disruption of GH action was found to extend lifespan in laboratory mice longer than any other method; iii) pharmaceutical inhibition of the GH/IGF-1 axis has been identified as the first of six most promising interventions to slow aging in a recent consensus statement of aging experts; iv) recent data show increases in median and maximal lifespan in female mice expressing GHRA; v) GHRA (Somavert, pegylated GHRA) is the only FDA approved drug that specifically targets GH action and has been shown to be safe and effective in humans; and vi) GHR antagonism has not been properly evaluated for aging research alone or in combination with other gerotherapeutic agents despite its clear promise as a gerotherapeutic drug. Thus, we hypothesize that combining GHR antagonism with other life-extending compounds will improve health and longevity to a greater extent than these individual therapies alone. In Aim 1, we seek to test novel combination therapies involving GHR antagonism for the first time. In Aim 2, we seek to understand the mechanistic changes that occur with these novel combinations. An intriguing role for GH in altering age-associated B cells – which has not previously been linked to GH action and is more recently appreciated to be important in aging-related pathologies – will also be assessed. Our long-term goal is to develop novel, mechanism-based, therapeutic approaches for attenuating the aging process in humans. In this proposal, feasible clinical combinations that employ existing nutraceuticals and FDA approved drugs will be given top consideration. As each of these compounds have their own unique limitations (i.e., show mild improvements individually, influence different aging pathways, can be sex-specific), their combination should target multiple aging-associated pathways simultaneously to maximize health and longevity.

Project Narrative As human aging and the resulting age-associated diseases are among the greatest challenges in our healthcare system, there is an urgent need to find interventions that prevent, delay, or even reverse these pathologies. While reducing GH action is highly effective in improving healthspan and lifespan in mice, aging is a complex, multifactorial process that will likely require targeting multiple pathways simultaneously for optimal benefits. Thus, the goal of this proposal is to evaluate gerotherapeutic strategies that combine GHR antagonism with other promising life extending compounds to reduce age-related disease and maximally enhance healthspan.