Background:
Cardiac aging is a leading risk factor for heart failure and functional decline worldwide. It arises from coordinated changes in cell state, tissue architecture and intercellular communication. Although some molecular drivers have been identified, an incomplete understanding of myocardial tissue effects at spatial resolution has limited progress towards effective intervention.
Methods:
Here, we generated an integrated, spatial multi-omic map of age-dependent myocardial remodeling. To resolve transcriptional changes across anatomical scales, we combined Visium HD, Visium and Xenium spatial transcriptomics with single-nucleus RNA sequencing, proteomic profiling and functional phenotyping. Comparative analyses of young and aged hearts were performed to identify age-associated transcriptional programs, spatially localized cell states and anatomically restricted multicellular niches linked to cardiac aging.
Results:
We identify a previously undescribed infiltration niche that arises selectively in aged hearts and is reproducible across complementary spatial transcriptomic platforms. This niche is characterized by altered multicellular composition, inflammatory recruitment, tissue stress responses and pro-fibrotic remodeling programs. High-resolution spatial profiling further demonstrates that age-associated transcriptional alterations and cell-cell communication emerge within specific myocardial microenvironments, rather than being diffusely distributed throughout the tissue.
Conclusion:
Together, this study provides new insight into the spatial architecture of cardiac aging by providing an integrated spatial and molecular framework at tissue resolution. Our findings identify multicellular niche remodeling as a defining feature of cardiac aging and demonstrate high-resolution spatial multi-omics to uncover anatomically organized programs of age-associated decline. Moreover, our data reveal niche-restricted cell-cell communication as structural basis for age-associated pathology and nominate specific interactions as tractable targets for therapeutic intervention.
