Tissue slides in a research laboratory. Editorial illustration.
The aging heart can become stiffer as inflammatory signals persist and the tissue builds up scar-like material. A study in Aging Cell found that some of the molecular changes linked to those processes clustered around the valves and the aorta where it leaves the heart. The map, made in mice, shows how a whole-heart measurement can hide important differences between regions.
Evidence level Early Research. The team mapped gene activity in mouse hearts and compared selected findings with human data.
How researchers mapped the changes
The researchers compared hearts from 6- and 24-month-old mice of both sexes. They measured RNA in whole hearts, then examined gene activity in individual cells and cell nuclei to identify which cell types contributed to the changes. Spatial transcriptomics, which measures RNA while preserving its position in a tissue section, showed where those signals were concentrated.
The team focused on macrophages, immune cells involved in clearing debris and coordinating repair, and fibroblasts, which maintain the network of proteins that supports the tissue. Persistent inflammation can shift repair toward fibrosis, the buildup of structural material such as collagen. That can make tissue less flexible. The experiments mapped gene activity associated with those processes.
What stood out at the valves and aortic root
The valves and proximal aorta had especially prominent macrophage and fibroblast signatures. With age, some macrophages expressed more genes associated with recruiting immune cells, including the signalling gene Ccl8. Fibroblast changes included altered expression of genes involved in tissue structure and more expression of Cdkn1a in some cells. That gene encodes p21, a protein involved in stopping cell division and often studied in cellular senescence.
Several general markers for macrophages and fibroblasts stayed relatively stable in the spatial maps. The changing signals therefore pointed to differences in what cells were doing. Some changes also became more apparent in the heart muscle itself as mice aged.
Valves and nearby vessels were already identifiable as regions rich in signals related to tissue maintenance and immune activity. That offers a possible reason these changes converged there. The study did not determine whether remodeling began in those regions or whether they were especially sensitive to changes elsewhere.
What the map can help researchers test
The researchers found some overlapping stress-related gene activity in human cardiac fibroblast data, but fewer than half of the enriched processes were shared between species. The mouse map also measured RNA, so further work needs to confirm where the corresponding proteins accumulate and whether the changes affect heart function.
The results give researchers specific regions and cells to examine when testing treatments for age-related scarring or inflammation. A useful next experiment would ask whether changing those local signals improves valve or heart function. This study did not test a treatment.
Related reading on a separate study of mitochondria in aging heart muscle.
Original research
Aljakna Khan A, Sintou A, Zhao Y, et al. Alterations in the Immune-Fibrotic Axis Are Spatially Localized in the Aging Heart. Aging Cell, November 5, 2026.