Cardiac Proteomics Reveals Novel Longevity Mechanisms in Ames Dwarf Mice

Cardiovascular decline is a hallmark of aging and a major contributor to age-related mortality. Ames dwarf mice represent a unique model for investigating longevity mechanisms, as they live approximately 50% longer than wild-type littermates despite carrying an autosomal recessive mutation on chromosome 11 that causes severe dwarfism. To elucidate the molecular basis of their extended healthspan, we employed mass spectrometry-based proteomics to analyze cardiac tissue from one-year-old female Ames dwarf and age-matched wild-type mice. Our analysis revealed substantial proteomic remodeling in Ames hearts, encompassing multiple interconnected biological systems. Key alterations included dysregulation of cytoskeletal proteins, enhanced energy metabolism, modified branched-chain amino acid catabolism, altered purine synthesis pathways, and enhanced cellular stress responses. Notably, while some of these pathways that were altered have established associations with longevity, several represent novel discoveries in the context of lifespan extension. A particularly striking finding was the elevated expression of proteasome subunits and significantly enhanced β5i immunoproteasome activity in Ames hearts compared to controls. Since the immunoproteasome specializes in degrading oxidized and damaged proteins that are a major source of age-related pathology, this enhancement suggests a critical mechanism for maintaining cardiac proteostasis with age. Collectively, these findings indicate that Ames dwarf mice achieve extended lifespan through coordinated cardiac adaptations that optimize energy utilization, protein quality control, and metabolic efficiency, thereby reducing age-associated cardiovascular dysfunction and promoting longevity. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.