Heart failure (HF) is a major cause of morbidity and mortality in older adults, and currently represents the leading cause of hospitalization in the elderly. Advanced age is one of the strongest risk factors for HF, although why this is the case and whether it is possible to intervene in this process, remain unclear. In this context, the role of Activin type II receptor (ActRII) ligands – and their potential catabolic effects in aging and disease – has been a subject of intense interest and controversy in HF. There is a fundamental gap in our understanding of how aging contributes to HF. Our over-arching hypothesis is that ActRII activation increases with age as well as biomechanical cardiac stress, and contributes to cardiac dysfunction in multiple forms of age-related HF. Our long-term goal is to understand the mechanisms linking ActRII signaling to cardiac dysfunction and learn whether these pathways can be targeted for therapeutic benefit. The objective of the current application is to examine the functional contribution of ActRII signaling in multiple age-related models of HF, and to elucidate the underlying mechanisms. Our preliminary data suggest that activity of the ActRII pathway increases with age, frailty, and HF in human cohorts, and with age and HF in mice. The increased activity appears driven predominantly by Activin-A rather than other ligands. In mice, elevating Activin-A levels was sufficient to cause cardiac dysfunction, while inhibition of the pathway in three distinct HF models prevented or reversed HF. The translational importance of these findings is underscored by the existence of pathway inhibitors currently in trials for other indications. The proposed work will be pursued in three integrated Specific Aims. In Aim 1, we will use specific and effective gain- and loss-of-function models to directly assess the role of ActRII signaling in HF, and to examine the role of ActRII in cardiomyocytes in vivo. In Aim 2, we will elucidate the mechanism(s) by which ActRII leads to cardiac dysfunction. In Aim 3, we will investigate the dynamic regulation of this pathway in biobanked samples from elderly patients with heart failure using targeted mass spectrometry assays in collaboration with Dr. Steven Carr, Director of Proteomics at the Broad Institute. The functional importance of correlative clinical data will be examined using in vivo models, which will be supported by in vitro investigation of primary cardiomyocytes to elucidate the underlying mechanisms. Our approach combines innovative hypotheses, technologies, unique animal models, and translational work in relevant clinical populations with the complementary expertise of an outstanding team of collaborating investigators. The proposed research is significant, because it is expected to advance our understanding of age-related HF and delineate pathways relevant to aging and disease with the potential to mitigate these clinically important conditions.